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Neuroscience and Biobehavioral Reviews 28 (2004) 143–180


The selfish brain: competition for energy resources
A. Petersa,*, U. Schweigerb, L. Pellerine, C. Hubolda, K.M. Oltmannsb,
M. Conradc, B. Schultesa, J. Bornd, H.L. Fehma
Department of Internal Medicine, University of Luebeck, Ratzeburger Allee 160, D-23538 Germany
Psychiatry and Psychotherapy, University of Luebeck, Ratzeburger Allee 160, D-23538 Germany
Institute of Mathematics, University of Luebeck, Ratzeburger Allee 160, D-23538 Germany
Institute of Neuroendocrinology, University of Luebeck, Ratzeburger Allee 160, D-23538 Germany
Institut de Physiologie, Universite de Lausanne, 7 Rue du Bugnon, 1005 Lausanne, Switzerland
Received 1 December 2003; revised 12 March 2004; accepted 17 March 2004

The brain occupies a special hierarchical position in the organism. It is separated from the general circulation by the blood-brain barrier,
has high energy consumption and a low energy storage capacity, uses only specific substrates, and it can record information from the
peripheral organs and control them. Here we present a new paradigm for the regulation of energy supply within the organism. The brain gives
priority to regulating its own adenosine triphosphate (ATP) concentration. In that postulate, the peripheral energy supply is only of secondary
importance. The brain has two possibilities to ensure its energy supply: allocation or intake of nutrients. The term ‘allocation’ refers to the
allocation of energy resources between the brain and the periphery. Neocortex and the limbic-hypothalamus-pituitary – adrenal (LHPA)
system control the allocation and intake. In order to keep the energy concentrations constant, the following mechanisms are available to the
brain: (1) high and low-affinity ATP-sensitive potassium channels measure the ATP concentration in neurons of the neocortex and generate a
‘glutamate command’ signal. This signal affects the brain ATP concentration by locally (via astrocytes) stimulating glucose uptake across the
blood-brain barrier and by systemically (via the LHPA system) inhibiting glucose uptake into the muscular and adipose tissue. (2) High-
affinity mineralocorticoid and low-affinity glucocorticoid receptors determine the state of balance, i.e. the setpoint, of the LHPA system. This
setpoint can permanently and pathologically be displaced by extreme stress situations (chronic metabolic and psychological stress,
traumatization, etc.), by starvation, exercise, infectious diseases, hormones, drugs, substances of abuse, or chemicals disrupting the endocrine
system. Disorders in the ‘energy on demand’ process or the LHPA-system can influence the allocation of energy and in so doing alter the
body mass of the organism. In summary, the presented model includes a newly discovered ‘principle of balance’ of how pairs of high and
low-affinity receptors can originate setpoints in biological systems. In this ‘Selfish Brain Theory’, the neocortex and limbic system play a
central role in the pathogenesis of diseases such as anorexia nervosa and obesity.
q 2004 Elsevier Ltd. All rights reserved.
Keywords: ATP, adenosine triphosphate; KATP, ATP-sensitive potassium channels; Naþ/Kþ-ATPase, sodium potassium dependent adenosine triphosphatase;
BBB, blood–brain barrier; LHPA, limbic-hypothalamus-pituitary –adrenal; SNS, sympathetic nervous system; MR, mineralocorticoid receptors; GR,
glucocorticoid receptors; VMH, ventromedial hypothalamus; PVN, paraventricular nucleus; LH, lateral hypothalamus; ARC, arcuate nucleus; CRH,
corticotropin-releasing hormone; ACTH, adrenocorticotropin; POMC, pro-opiomelanocortin; a-MSH, a-melanocyte-stimulating hormone; MC,
melanocortin; NPY, neuropeptide Y; GABA, g-amino-butyric acid; BDNF, brain-derived neurotrophic factor; NMDA, N-methyl-D -aspartate; AMPA,
amino-3-hydroxy-5-methyl-4-isoxazol propionate; LTP, long-term potentiation; LTD, long-term depression; CREB, cAMP responsive element binding

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
2. Physiological glucose regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
2.1. Setpoints in the brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
2.1.1. Setpoint of brain ATP regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
2.1.2. Setpoint of limbic-hypothalamic-pituitary – adrenal system regulation . . . . . . . . . . . . . . . . . . . . . . . . . 152
2.1.3. Homeostasis: brain ATP and the LHPA system in balance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153

* Corresponding author. Tel.: þ 49-451-500-3546; fax: þ49-451-500-4807.
E-mail address: (A. Peters).

0149-7634/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.

144 A. Peters et al. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180

2.2. Load of the brain-supplying regulatory system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
2.2.1. Malnutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
2.2.2. Psychological stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
2.3. Sleep and the consolidation of setpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 166
2.3.1. Stressors and the limbic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
2.3.2. Stress reactions and the limbic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
2.3.3. Memory formation during sleep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
3. Pathological glucose regulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
3.1. Hypoglycemia unawareness (type 1 diabetes mellitus). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
3.2. Anorexia nervosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
3.3. Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
3.4. Type 2 diabetes mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173

1. Introduction transportation mechanisms across the blood – brain barrier
[2,3]. Thus, the transfer of substrates and hormones into the
How does the human organism control its energy supply? brain is very strictly controlled. The capacity of the brain to
The answer to this question is the key to treating many store energy is extremely limited, but maintenance of the
diseases: obesity and the so-called metabolic syndrome with energy supply to the brain is of prime importance to the
diabetes mellitus, hyperlipoproteinemia, hypertension and survival of the whole organism. It is not therefore
cardiovascular diseases belonging to these disorders. surprising that the energy content immediately available
Gynecological diseases including polycystic ovaries or to the brain, i.e. in the form of adenosine triphosphate
psychiatric disorders such as depression or eating disorders (ATP), is strictly regulated within extremely narrow
are also associated with disrupted regulation of energy boundaries. The brain is almost exclusively dependent on
supplies. Two different processes can be distinguished that the metabolization of glucose. As such, selection of
regulate energy metabolism: energy supply (appetite, intake substrates by the brain is highly specific, while peripheral
of foods) and allocation (assignment). The various organs of organs (muscle) can metabolize glucose, fat or proteins.
the body must compete for the allocation of a limited Fatty acids can not traverse the blood –brain barrier. Only
number of energy resources. in special situations, such as with hypo or hypernutrition,
The brain occupies a special position amongst all the does the organism produce significant amounts of alterna-
organs concerning energy metabolism. It is the central tive substrates such as ketones or lactate that can traverse
organ for regulating energy supply, and it is able to receive the blood – brain barrier and assume a role in supplying
information about the peripheral organs via peripheral energy to the brain. Finally, the brain is able to memorize
(e.g. hepatic) sensors and their afferent neuronal pathways. information about its control actions and their subsequent
Conversely, it can also control the functions of many effects, and to learn from the outcomes. It can use its
peripheral organs, e.g. the skeletal musculature, the heart, plasticity to optimize its control behavior.
the gastrointestinal tract or the sexual organs, via its Overall, therefore, the unique position of the brain is
efferent nerve pathways. It is probable that this control is characterized by
not just restricted to physical movements and the function
of many inner organs, but that it also includes the 1. its physical barrier properties,
regulation of energy metabolism. The neuronal discharge 2. its high energy consumption,
and release of neurotransmitters and neuropeptides requires 3. its low energy storage capacity,
exceptionally large amounts of energy [1]. The energy 4. its substrate specificity,
consumption of the brain, related to its small proportion of 5. its plasticity, and
the entire body mass, is much larger than the energy 6. its ability to record information from and to control
consumption of all other organs (e.g. muscle). The peripheral organs.
proportion of energy consumed by the human brain
exceeds the proportion found in all other known species. In order to account for the idiosyncrasies of the brain’s
This fact may be relevant for the origin of characteristics energy supply and to establish the meaning of these for the
and disorders of metabolism found primarily in humans, entire organism, we propose here a new paradigm for the
e.g. obesity. The brain is separated from the general regulation of energy supply in the organism:
circulation by the blood –brain barrier. Specific substrates
(such as glucose and lactate) or hormonal signals (such as † The brain prioritizes adjustment of its own ATP
insulin or leptin) are transported exclusively by specific concentration. For this reason it activates its stress

A. Peters et al. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 145

system and in so doing competes for energy resources ‘leptin resistance’. Such a leptin resistance is found both as
with the rest of the organism (allocation). an inherited phenomenon with monogenetic defects [9,10]
† The brain then alters the appetite (food intake) so that it can and as an acquired phenomenon after overfeeding [11].
alleviate the stress system and return it to a state of rest. A large number of neurotransmitters, neuropeptides and
their receptors that mediate the leptin effect in the brain, e.g.
With these two postulates, the brain simultaneously anorexigens such as ‘Melanocyte Stimulating Hormone’
represents the highest regulatory authority and the consumer (a-MSH), have been studied in detail over the last few years
with the highest priority. The brain looks after itself first. [12]. The phenomenon of leptin resistance has as such been
Such selfishness is reminiscent of an earlier concept in which well described, but its origin has so far escaped explanation.
the brain’s selfishness was addressed with respect to The glucostatic and the lipostatic theories have explicitly
addiction [4]. We chose our title by analogy but applied it or implicitly provided the basis for a large number of
in a different context, i.e. the competition for energy research strategies and therapeutic interventions for diabetes
resources. During stress and times of shortage it safeguards mellitus, obesity and other diseases. Against this, however,
its own supply even at the expense of all the other organs. The a range of observations have accumulated that can not be
brain’s obligation to alleviate its stress system in a second satisfactorily explained by these views and research
step and allow it to return to a state of rest is not trivial. From a approaches:
regulatory-theoretic standpoint we presume that the stress
system is adjusted around a so-called setpoint at which it is at † If healthy people are advised in a study to overeat
a state of rest. In the second step the brain therefore pursues considerably over a period of months, they do increase
the objective of satisfying its own energetic needs and those substantially in weight during this time, but within a few
of the entire organism on a long-term basis in the most months they can return again to their initial body weight
economic way possible. The regulation of the mass of the [13]. Clinical experience on the other hand shows that
various body compartments such as the adipose tissue is then although many people show good body mass regulation at
considered to be a secondary objective with this paradigm. the start of their life, in later life (e.g. in the third decade),
According to traditional paradigms the brain regulates their body mass increases. If these people then attempt to
body mass by changing the intake of foods. Maintenance of reduce their body weight by dieting, the ‘yo-yo’ effect
blood glucose within narrow limits is also of key importance then sets in, and one gets the impression that body weight
for maintaining health. The ‘lipostatic’ theory was orig- is regulated at a new, raised virtual setpoint [14].
inally formulated by Kennedy 1953 [5]. Jeffrey Friedman Phenomena such as the yo-yo effect show that the system
and coworkers of the New York Rockefeller University of body mass regulation is more complex than previously
supported this view in 1994 with their ground-breaking assumed. If only a simple defect within the regulatory
finding of the hormone leptin [6]. With leptin, a hormone system for weight regulation exists, such persons should
was discovered in fat and muscle tissue that sends a be able to return to and maintain their initial body weight
feedback signal to the brain so that the brain is informed with their normal nutrition after a diet. However, the body
about the status quo of peripherally stored energy. Most mass often exceeds the previous maximum. The fact that
researchers considered this to be a closed regulatory system only few people succeed in reaching and maintaining their
in which the absorption of nutrients is the regulator, body initial body weight means that the traditional view that
mass is the controlled parameter, and leptin is the feedback changes can be found within the assumed closed loop of
signal. Notably, before leptin was discovered, the research the body mass regulatory system (e.g. single or multiple
team of Stephen Woods and Daniel Porte at the University gene mutations) is too simple.
of Washington, Seattle, presented compelling evidence for † The study of metabolic, endocrine and behavioral
insulin being an adiposity signal [7,8]. With the ‘gluco- phenomena in repeated hypoglycemia has shown that
static’ theory, blood glucose is considered to be the the brain has mechanisms for protecting its functionality
regulated parameter in the center of the regulatory system actively within certain limits despite the existence of
and it is assumed that endocrine changes (for example very variable blood glucose concentrations. The energy
insulin, glucagon, growth hormone, and cortisol) and supply of the brain therefore represents more than just a
behavioral changes are mainly responsible for maintaining by-product of the energy supply of the whole organism.
the concentration of blood glucose within narrow limits. † If the energy supply of the brain is threatened, lipostatic
The implicit assumption that an adequate energy supply to signals do not play any significant role in behavioral
the brain automatically results from the constant behavior of regulation: ravenous hunger with hypoglycemia occurs
the fat reserves and the blood glucose is common to both the independently of the adipose tissue mass of the organism.
glucostatic and the lipostatic theory. Another common † Traditional treatment concepts of type 2 diabetes mellitus
feature is the assumption that with obesity a defect can be are derived from the glucostatic theory and aim at
traced to the closed feedback loop. It can indeed be shown normalization of blood glucose concentrations. The
that with most overweight people leptin is not able to restrict United Kingdom Prospective Diabetes Study showed
the intake of foods. This phenomenon has been termed that ‘tight’ blood glucose control results in a reduction in

in a higher-ranking regulatory system providing it with and also reductions in body fat. † Appetite. † Traumatization and psychiatric conditions such as supports a significant role of genetic factors. which includes the sympathetic nervous system. the LH is inhibited via a-MSH. i.146 A. The appetite regulatory subsystem controls the total amount of glucose available for allocation (red arrow). the appetite stimulating lateral hypothalamus (LH) is activated via NPY. If the stimulatory and inhibitory feedback-signals in the cerebral cortex. These observations side effects of such concepts using hypoglycemic agents or cast doubt on the priority of lipostatic signals in particular. the limbic system and the hypothalamic sites for allocation (ventromedial hypothalamus) and intake (lateral hypothalamus) of foods. the LHPA system strives to achieve a balance whereby the stimulating and suppressing feedback signals are of the same magnitude. in the LHPA system. if the energy content is too large in the periphery. The limbic-hypothalamic-pituitary-adrenal (LHPA) system. the LHPA system is stimulated via high-affinity brain mineralocorticoid receptors (MR). explain only a small proportion of obesity and diabetes mew’s and the Royal London School of Medicine cases up until now. so that glucose is allocated more to the musculature and adipose tissue. The NPY. Feedback signals on the energy status in the brain (glucose). despite strict glycemic control.g. the glutamate command signal is stimulated in the cerebral cortex via high-affinity ATP-sensitive potassium channels.g. Fig. even where defects in commands. Peter G. The fact that people of a similar genetic period. † Cortical balance. plays a decisive role in allocating glucose. Here.e. early on. † Despite intense research and the outstanding methodology penic comas) or oversupply of fat stores (body mass gain) that is now available. the peripheral organs (leptin). and on the activity of the LHPA system (cortisol) act on the various hierarchical levels of the system. The cerebral cortex sends a ‘glutamate cinnabd’ signal to the subordinate regulatory subsystems: 1. The observed obesity epidemic commented in the editorial that the ‘inevitable rise in throughout the entire industrialized world illustrates this glycosylated HBA1c witnessed throughout the study [17. 2. insulin. if the brain-ATP is too high. the brain ATP suppresses the VMH. The ‘Fishbone Model’ of glucose metabolism. systems. The energy content of the brain and peripheral tissues is measured with multiple sensors. it is suppressed via low-affinity brain glucocorticoid receptors (GR). The depressive or eating disorders lead to modifications in traditional view fails to consider that a disorder might the stress hormone system and various central transmitter also lie outside the feedback system for weight regulation. No effects on the overall mortality were observed. however (e. Peters et al. the allocation-subsystem strives for a balance whereby the feedback signals from the brain and the periphery are of the same magnitude. . it is suppressed via low-affinity ATP-sensitive potassium (KATP) channels. If the serum cortisol is too low. leptin activates the ventromedial hypothalamus (VMH) that allocates glucose to the brain. genetic defects have been able to occurred [15]. undersupply of the brain (recurrent neurogluco. the organism achieves a state of energetic homeostasis. Thus. † Limbic balance. As have not yet been observed until now. Kopelman from the Bartholo. emphasizes the background under defined environmental conditions need for a better understanding of the pathogenesis of type remain of normal weight or develop excessive overweight 2 diabetes in susceptible individuals’ [16]. They can also lead to considerable increases e. if the energy content of the brain is too large. the cerebral cortex. † Allocation. The key feedback-signal for regulating the intake of foods is brain glucose. Coordinates indicate positions in the model that are referred to in the text. the allocation sybsystem assigns glucose via the glucose transporter 1 (GLUT1) to the brain.18]. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 the risk of microvascular but not of macrovascular diseases the fundamental mechanisms of lipostasis or glucostasis [15]. If the energy content is too low in peripheral tissues. 1. if the serum cortisol is too high. Nauruans or Pima Indians) [19]. and via GLUT4 to the muscle and adipose tissue (yellow arrow). In this way the system strives for a balance whereby the opposing effects of high-affinity and low-affinity KATP channels are of the same magnitude.and a-MSH-signals are filtered in the arcuate nucleus (ARC) and conveyed only under certain circumstances to the LH. The activity of the LHPA-system is indicated by the serum cortisol concentration. If the brain-ATP is too low. If the energy content is too great in the muscle and adipose tissue. and in the hypothalamus are balanced.

testing of such hypotheses shall allow a redefinition of sympathetic nervous system is mediated by leptin and insulin the scope within which the theory is valid. We example. We are also aware that the assignments proposed [24]. so that the sympathetic nervous system is 2. We followed the advice that ‘everything should Is the model oversimplified or too abstract? be made as simple as possible. In the model. to the brain and muscle. we decided can then alleviate the stress system and return it to a state of to assign only a single functional mechanism and a single balance. a small group of scientists have signals.1. which includes the caudal fundamental structure. Flow charts of complicated control those relevant here may in part be fulfilled by other redundant systems can be simplified by mathematical transformations structures. at that time as a substrate for the brain. has a ‘fishbone’ like specificities of the model presented are less important than structure. but not simpler’ [27]. A list of various possible redundant signals was within the body. however.1. This example shows that leptin and insulin transmit To answer this we propose a principle whereby the brain related or similar signals to the brain. insulin 2. Peters et al. leptin conveys a signal to certain hypothalamic neurons [25] and in this way invokes an increase in sympathetic nervous system 2. ghrelin) escape mention here so that the true energy supply is only valid within a certain scope. Only the degree of redundancy.1. The stimulatory insulin feedback pathway can be shown that ingestive behavior is influenced by a widely integrated into the fishbone model without changing its distributed neural network. but we feel that the to 2 organs. In the changing the basic model structure.g. The activation of the future. e. How does the stimulated and the appropriation of glucose by the brain is brain maintain ATP constant at a specific concentration? ensured.1. that there might be a better selection for such a substitute. Setpoints in the brain in the same way informs the brain that glucose is stored and unavailable for supplying the brain. many experiments that are cited here in support of the reviewed the literature and indeed often found two or more model have only been carried out under special experimental biological mechanisms for each individual component in the conditions in in-vitro or in animal studies. many studies in humans cited here redundancy in glucose regulation. The brain We have in fact refrained from including a large number initially adjusts its own ATP-concentration by burdening its of biological mechanisms that might also fulfill functions in own stress system and competing for energy resources the model. Setpoint of brain ATP regulation can influence the same hypothalamic neurons in the same manner [26]. The regulatory principles of this paradigm have anatomical structure to a single signal pathway in the model. and not brainstem. since recent work has clearly messages. been formulated mathematically as a dynamic system and Leptin acts for example as a ‘substitute’ for a class of signals graphically illustrated in the form of a so-called ‘fishbone that contains insulin amongst other elements. but have not yet been mathematical model. The trivial structure: it represents a hierarchically organized limbic system and the hippocampus for example are system with a forward pathway (similar to the spine of a fish) extremely complex structures per se. Also. Such a special model structure is suitable for the general basic principle proposed here for energy dealing with different levels of complexity. and Readers and authors are faced with a dilemma regarding that in the future hormones might be discovered that fulfill the needs of simplicity and complexity. more details are fulfill all the functions described in the model. The fishbone model has a simple but not a the selection of brain structures referred to in this paper.e. resistin. the hormone leptin conveys a signal to broadened or narrowed. Correspondingly. There may be controls this concentration using high-affinity and low-affinity . limbic and cortical structures [20 –22]. metabolism. The brain changes eating behavior so that it presented in an earlier manuscript [23]. However. and is not therefore available phenomena which until now have escaped clarification. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 147 While most research continues to focus on crucial distinguished differences in the timing of their feedback hypothalamic circuits. One point of view might be that important hormones The newly presented theory regarding the regulation of (e. Insulin sends a similar signal analogous to this. The most simple model for allocating energy resources here might be the subject of some debate. We are aware explained in chapter 2). A. pathways (the fishbones). In this review article we would like to the brain that energy has been stored in peripheral organs. Several can be added to the fishbone model (new fishbones) without hypotheses can be derived from the presented model. and of course. For complexity of energy metabolism is not delved into. The paradigm proposed by us places the regulation of Is the model too complex or explicit? ATP-concentration in the brain at the focal point. 1.1. Physiological glucose regulation activity and thereby an increased allocation of glucose to the brain. Measurement with two receptors. apply the ‘selfish brain theory’ to offer new explanations for particularly in the adipose tissue. i. This may likewise account for mechanisms. Insulin 2.1.g. whether it be as well. between merely a this function better and so have a greater biological relevance suggestive and an explicit representation of specific than the ones mentioned here. supporting many and multiple paired stimulatory and inhibitory feedback other specific functions not relevant here. As such there appears to be much confirmed in humans. Correspondingly. in principle they transmit redundant already broken new ground. the relevancy of the model. Redundant signal pathways have only been performed in men but not in women. and which can model’ [23] (an overview is given in Fig. is changed through such additions.

the KATP channels are opened. but also on many other cell types. If the energy content the ‘neuroglucopenic’ coma. These KATP channels are nigra [50 – 53]. the low-energy adenosine found in human neocortex [54]. and are closed as a activity of the GABA ergic population predominates. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 ATP-sensitive potassium channels. The high-affinity ATP-sensitive while bound low-affinity ATP-sensitive potassium potassium channels in the neocortex play an essential role in channels permit GABA-ergic activity. This assumption is also KATP channel: at the ‘nucleotide binding domain’ of the so.e.43 – 47]. affinity ATP-sensitive potassium channels are also . these the low-affinity ATP-sensitive potassium channels are membranous KATP channels are closed. where they are localized both presynaptically couple bioenergetic metabolism to membrane-excitability and postsynaptically [48]. its clinical correlate is the ‘hypoglycemic’. Although it has not been diphosphate (ADP) can open the ATP-sensitive potassium confirmed in any single experiment. balance between excitatory and inhibitory neuronal popu- binding sites. i. With low brain ATP concentrations the glutamatergic population is low intracellular ATP content the high-affinity ATP-sensitive dominantly active. while at high ATP concentrations the potassium channels are mainly occupied.e. SUR1 and SUR2 [36–39]. This phenomenon has (such as the excitatory amino acid glutamate) or neuropep. a high intracellular ATP to ADP ratio. ATP and ADP bind to specific parts of the that reduce the GABAergic tone. while In contrast. low-affinity ATP-sensitive potassium channels potassium channel. protecting against seizures and neuronal damage [42]. while reserves. we do presume from channels. Contrastingly. With closed KATP localized on inhibitory neurons. However. Glutamatergic neurons raise brain ATP. those also have a cytoprotective function: with energy deficiency that exert an inhibitory effect on the excitatory population. slight energy deficit can be reversed via low-affinity ory-theoretic criteria of an ‘energy sensor’ (or more simply an ATP-sensitive potassium channels [53]. neuronal population that depends on intracellular ATP Interestingly enough. For this reason the intracellular ratio of ATP to ADP current data that in human neocortex there are also is a key regulator for the functional state of the ATP-sensitive presynaptic. GABA-ergic neurons lower it. but non-critical ATP- of the neuron is high enough. i. or better said factor’. this distribution pattern channels a potassium efflux from the cell is prevented via this leads to the following dynamic behavior: with critically ion channel. There are KATP channels in the entire cortex channels (KATP) belong to a special class of ion channels that [33. At assigned to two subtypes. result.30]. These ATP-binding properties allow them to be lations changes depending on brain ATP concentration. supported by the clinical observation that with progressive called sulfonylurea receptor (SUR). ATP binds to high. If on the other hand a fall in intracellular exclusively to the high-affinity ATP-sensitive potassium ATP content occurs. the KATP channels allow a content in both neuronal populations. It is worthy of note that both low-affinity and closed by intracellular ATP. All the function of the cell is turned off and the residual energy is in all. with high intracellular ATP content the low. ‘ATP sensor’). Peters et al.and low-affinity ATP-sensitive concentration for survival of the neuron. KATP is present not only at neurons and neuroendocrine KATP channels reduce the liberation of g-amino-butyric acid cells. Such neurons are able to be electrically active with a low ATP content. i. in the hippocampus [49] and in the substantia skeletal and smooth muscle [29. such as those of (GABA): e. that together with the energy deficiency in the brain there is initially an excitatory actual channel pores forms a single morphological unit [31]. 3. BDNF) from its nerve endings. with high cerebral ATP concen- and its function is deactivated. The neuron releases neurotransmitter populations are functionally inactive.e. Bound high affinity ATP-sensitive potassium The corresponding KATP channels are then opened and the channels permit glutamatergic neuronal activity. ATP-sensitive potassium channels no longer bind adequately. i. Calcium flows reduced ATP both the excitatory and inhibitory neuron into the cell interior. These high-affinity ATP-sensitive potassium channels An effective regulatory system for brain ATP can be are found in the cortex and in many other brain areas on described with the following overall principle: excitatory neurons [40. ATP-sensitive potassium occupied. Of decisive importance is the fact that the channels: those with high-affinity and low-affinity ATP. these high-affinity potassium channels. followed by a calming The SUR protein belongs to the ‘ATP binding cassette (ABC) of the cortex. 3a).41].148 A. which with a membranous. The KATP channels therefore trations the inhibitory neurons also become active. a biphasic activity pattern results for the excitatory saved for structural maintenance of the cell [33–35]. 2. While the energy-rich ATP high-affinity ATP-sensitive potassium channels have been closes these potassium channels. These findings are consistent with a family’ [32]. The KATP channel therefore represents a presynaptically mediated GABAergic tone. molecular structure that fulfills the regulat. In some brain areas presynaptic [28]. which enables depolarization. if the ATP-concentration declines to a very low and thereby critical 1. to those on the excitatory neurons that release neuron is hyperpolarized (and thereby electrically stabilized). cell function is deactivated.e. ATP binds almost neuronal excitation. If one assumes that the high-affinity ATP-sensitive If one provides an excitatory neuron with sufficient energy potassium channels are located on excitatory neurons. glutamate.g. stage with a raised seizure tendency. been described as a ‘global silencing’ of the cerebral cortex tides (such as the neurotrophin ‘brain-derived neurotrophic [55]. there are two different types of KATP content (Fig. With low. the channels.

the cascade of molecular events represents a direct mechanism brain must open the blood – brain barrier for glucose and cut for the coupling between synaptic glutamate release and off the supply to peripheral tissues.2.1. In order to allocate glucose to itself. This transmitters and only consume energy.3. Hierarchically. a secure regulatory system that balances the brain ATP The end-feet of the astrocytes are equipped with specific around a certain concentration. The LHPA system is a neuroendocrine inhibit the glutamatergic neurons with the help of their system closely associated with stress in mammals [65]. The sympathetic nervous system leads to a tight coupling between glutamate and sodium projects with its efferent nerve pathways to the adrenal uptake [58]. brain prevent glucose uptake into muscle and adipose it has only been verified for the glutamatergic population tissue? that they also serve for energy replenishment [56]. order to provide lactate to active neurons as an energy Here. The energy that arises during the glycolytic for energy resources within the organism. Astrocytes enclose most glutamatergic releasing hormones stimulate adrenocorticotropin (ACTH) synapses and collect released glutamate with a highly release into the general blood circulation within the efficient and specific transporter system. which is then released and there is not an adequate food supply (such as during times of made available as an energy source for neighboring neurons starvation). In this supply itself by requesting energy firstly from the body way the preconditions for a functional coupling between periphery and secondly from the environment. These limbic neurons project with axons directly the (local) response of astrocytes to glutamatergic activity in or via the VMH into the paraventricular nucleus (PVN). The the recovery of glutamate and the restoration of the sodium sympathetic system also innervates the pancreatic b cells gradient. Glutamate is converted into rule. This tissue on the other. while in the neuron The brain controls the allocation of glucose between the lactate utilization will be employed for closing the brain on the one hand and the musculature and adipose postsynaptic KATP channels and for excitation [64]. Systemic ‘energy resource request’. Although all neurons independently of the type of 2. If this process to lactate.1. described as a ‘balance setpoint’ for brain ATP. as well as sodium. For this synaptic activity and glucose uptake are fulfilled: glutamate purpose the brain must invest considerable expense.1. glucose allocation to the neuron via the blood –brain barrier As mentioned above. ACTH ultimately stimulates the release of cortisol driven by the electrochemical sodium gradient. and enclose practically all the capillary walls within the brain. a specific type of glial cell. Glucose is broken down in order to actually procure the requested amount of energy. activates its glutamate transporter and stimulates glucose activate its stress systems or acquire new food resources in uptake into astrocytes [60. the brain has no other possibility but to compete [62.61].and potassium-dependent adenosine triphosphatase the musculature and adipose tissue where it suppresses .63].g. system allows a rapid reaction to stressful stimuli and Which molecular mechanisms can glutamate utilize to ultimately guarantees a return to homeostasis via complex enhance energy substrate availability for parenchymal feedback mechanisms. breakdown of glucose to lactate is used in the astrocytes How does the brain compete with the body for energy to support the activity of the Naþ/Kþ-ATPase and to resources? convert glutamate into glutamine [59]. There is no ATP exchange between astrocytes affinity ATP-sensitive potassium channels and the glutama. Astrocytic ‘energy on demand’. Transporters are pituitary. it is the glutamatergic neuronal and the astrocytes. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 149 Up to now we have demonstrated the first and the second (Naþ/Kþ-ATPase) [59]. regions that carry out this control: the hippocampus and the The principle ‘energy on demand’ has been used to describe amygdala. These three simple rules again into glutamate so that the neuronal glutamate pool is regarding the interplay between ATP. Peters et al. Glutamate that is freed at the synapse upon neuropeptides are formed and released such as cortico- excitation is rapidly removed again to allow subsequent tropin-releasing-hormone (CRH) and vasopressin. How can the neurotransmitter released (glutamate or GABA) use energy. Peripheral glucose uptake can be restricted through GABAergic neurons on the other hand do not mediate any activation of the limbic-hypothalamic-pituitary – adrenal such allocation of glucose to the brain [57]. In the limbic system there are two core role in allocating glucose across the blood – brain barrier. The gradient is restored by the activation of the [66] where it suppresses insulin release [67 – 69]. The astrocyte is now confronted with two tasks: medulla where it stimulates the liberation of adrenaline.e. the sympathetic nervous system is activated and substrate [56]. the two different refilled again. a fact that from the adrenal cortex. The brain can exists between astrocytes and cerebral capillaries. A close morphological and cytological relationship 2. This concentration can be transporter molecules. population that activates the allocation of glucose to the brain. so that each cell type must secure its own tergic and GABAergic neuronal populations describe energy supply. but instead (LHPA) system. These transmission events. In the next chapter we shall explain the third rule and glutamine which is released by astrocytes and taken up by how the glutamate command signal promotes an increase in the neuronal terminal. i. A. e. glucose transporter 1 (GLUT1). There it is enzymatically converted the brain’s energy content. the limbic system cells? therefore represents the highest authority in the control of The astrocyte. and neurons. plays a key stress reactions.1.

is under the direct influence of the limbic (for the whole brain). purchasing behavior for foodstuffs) ATP-sensitive potassium channels increase the cortical related to feeding. Signals originating in the LH appear to reach brain influences the amount of ATP available to it. brain by favoring glucose utilization in brain while whereby these two components have reciprocal functions impeding it in muscle and adipose tissue. In If the output to the VMH is weak. The limbic system parts of the cortex will also signal their needs to the limbic functions as a transducer between this integrated glutamate system.75]. the signal to the LH is mediate the activation of the LHPA system with brain rather robust and less altered. On the other hand the glutamate command signals between glutamatergic and GABAergic neuronal activity at input into the limbic system. recurrent glucose deficiency [73]. i. however. On the one hand the glutamate suppress the glutamate command signal. The allocation controlling VMH is apparently able to adjust the allocation of glucose to the therefore ranked higher than the appetite controlling LH. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 the uptake of glucose [70 –72]. The VMH mobilizes glucose for the brain within of glutamate receptors also brings about a strong activation seconds. Energy supply for the brain projections to different parts of the brain [88]. systems: one setpoint signal is conveyed via neuronal What effects do cortical glutamatergic neurons have on pathways to the VMH (allocation). the appetite controlling summary. glutamatergic tone and in so doing the glutamate command Fig. whereas the LH is inhibited by this signal [84].e. while the LH strives to increase the controlled by a hypothalamic center. other integrated within the limbic system. The cerebral cortex sends the ‘glutamate command’ The activated neurons of the LH also provide ‘orexi- signal to both of its regulatory subsystems that control genic’ (i. The VMH The LH is a key region of the brain that controls appetite increases the proportion of circulating glucose to be and eating behavior [76]. ‘energy resource request’ signals. Here the VMH environment? (allocation) and the LH (appetite) are stimulated. Thus. to an attenuation of hunger (LH) [83]. subcortical nuclei. hypothalamus. 2a summarizes the command principle once again: signal. Feeding and fasting is not simply assigned to the brain. The above-mentioned team (and only with sufficient food intake) to an increase in also succeeded in establishing a link between cortical glucose supply to the brain. As an example.and high-affinity ATP-sensitive and ultimately also have an influence on complex potassium channels as a feedback signal. In this way the command signal triggers an astrocytic ‘energy on demand’ primary regulatory system strives for a cortical balance process. Allocation and food large network of neurons located at many different sites supply therefore determine the proportion of glucose that is (thalamus.81]. those channels . multiple locally effective both cases.g. High-affinity behavioral patterns (e. energy needs. Peters et al. The limbic system but also in memory formation (see the chapter ‘memory also coordinates the order in which the VMH or LH are formation during sleep’). In this way. With low other brain sites by first descending to the parabrachial ATP in the brain the high-affinity ATP-sensitive potassium nucleus [77]. [85 –87]. The NMDA receptor plays a key hypoglycemia leads to attenuation of VMH-mediated role for the pyramidal cells of the limbic system and has a counter-regulation (e.79]. primarily glutamate receptors of the NMDA subtype amplified or suppressed [80. These results from the activity of the two regulatory subsystems.e. brainstem. The amount of glucose available to the medulla). we assign the LH as one representative channels are closed for the most part (i. The limbic system transduces the Patricia Molina and coworkers of the Louisiana State signals to the VMH and the LH differently. the limbic system might act both as a detector command signal and setpoints of subordinate hypothalamic and transducer of global brain energy needs. allocation of glucose to muscle and adipose tissue. appetite increasing) neuropeptides via glucose allocation and appetite. In the limbic system. These setpoint signals are How does the brain request energy resources from the conveyed to the subordinated hypothalamus. orexigen-secreting neurons increase the drive for feeding Brain ATP binds to low. with glutamate being the mediator in system. The stimulation of other subtypes activated. conveys the ‘energy resource request’ signal first to It is well known that stress systems can restrict the the VMH. Upon cortical excitation. adrenaline. where they are transduced into which the ATP concentrations are optimal. but an activation of the LH only leads after a delay of the LHPA system [74. Here. the LHPA anatomical site to the functional component ‘appetite’ in system can increase the glucose concentration in the blood. also trigger the LH to increase appetite and initiate food intake [78.150 A. cortical glutamatergic neuronal populations are LH is disinhibited. In addition to that direct limbic mechanism ‘glutamate command’ signals from cortical neurons are requesting energy (internal sensing or detector area). but not function not only for setting the tone of the LHPA system.e. a systemically effective ‘energy resource request’ signal The LH. Low-affinity ATP-sensitive potassium channels cortical glutamatergic neuronal populations release gluta- increase the cortical GABAergic tone and in so doing mate upon excitation. The limbic system therefore glutamatergic activity and the activation of stress systems. and another is conveyed limbic neurons? to the LH (appetite). While the signal University in New Orleans were able to show recently that to the VMH is adapted under certain conditions.g. and assigned to the brain. in addition to Glutamate is a potent stimulus that stimulates neurons in activating the ‘energy on demand’ signal (local). the model. but rather by quite a total amount of circulating glucose. glucagon)[82].

/ Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 151 .A. Peters et al.

with high affinity. Here. Both receptors are balance setpoint. Cortisol binds in the limbic system to high-affinity mineralocorticoid (MR) and low-affinity glucocorticoid (GR) receptors. the primarily active What influences do MR and GR have on the activity of glucocorticoid in humans [65]. affinity to GR. Brain ATP binds to low. MR – GR heterodimers and GR – GR large number of researchers have since managed to homodimers. During the GR. In this study patients limbic system. including the concentrations were illustrated [97]. An amplification mechanism for leptin activity is localized in the arcuate nucleus (ARC). / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 enabling the stimulation of glutamatergic neuronal popu. The type I or MR in the brain other dimer-types compete with the MR –MR homodimer for resembles the MR in the kidney and has a high specificity these GRE binding sites in the genome and inhibit its effect. while with high cortisol concentrations high cortisol concentrations. With low cortisol concentrations and develops its effects mainly cortisol concentrations there was a marked increase in during the evening nadir of the cortisol circadian profile. for selectively binding cortisol. at low leptin concentrations. neuronal population decreases the brain’s energy demand. At ACTH secretion. The cally and functionally. Pyramidal cells in the hippocampus and the amygdala In this way a regulatory system results that resembles the express both MR as well as GR receptors [91]. In the brain. membrane and reach the cell nucleus where the cortisol- Starting in the year 1968 with the milestone paper of Bruce bound receptors form dimers with one another [94 – 96]: McEwen at the Rockefeller University in New York [89].2. Energy supply for the brain results from the activity of the two regulatory subsystems. formed in the cell nucleus and are then released into the cytosol of the neuron. Peters et al. The activity of the LHPA- system determines the allocation of glucose to the brain and the periphery. while NPY on the other hand suppresses the effect of leptin on the VMH. MR is bound with low trations continuously to very high concentrations. while at high leptin concentrations the appetite suppressing a-MSH is mainly produced. In lations).93]. In this investigation a bell-shaped R Fig. (B) The LHPA system as a regulatory subsystem of brain ATP regulation. (A) The primary regulatory system for brain ATP regulation. Two bound MR and GR complexes can traverse the nuclear types of corticosteroid receptors are known in the brain. and with high cortisol concentrations GR suppress its activity. but the MR-mediated stimulation and a GR-mediated suppression bound GR dominates in its effect and is decisively involved of the LHPA-system. MR with Cushing’s disease.1. three years later the group showed in vivo that on the other hand is high. High-affinity ATP-sensitive potassium channels increase the cortical glutamatergic tone and in so doing the glutamate command signal. and the GABAergic reduced hippocampal firing activity [90]. were infused with cortisol. 2. The presence of GR receptors cortisol effects over a very broad range of cortisol has been confirmed in many brain regions. If the brain ATP fact. Cortisol traverses the external cell 2. In this way the primary regulatory system strives for a cortical balance between glutamatergic and GABAergic neuronal activity at which the ATP concentrations are optimal. the appetite stimulating NPY is primarily produced. The LHPA-system restricts the GLUT4-mediated glucose uptake into muscle and adipose tissue and with this increases the GLUT1-mediated glucose uptake into the brain. the hypothalamus. many cortisol molecules bind to GR and MR. function of these limbic MR and GR receptors is to modify and which is able to regulate brain ATP around a specific memory storage and retrieval [92. a-MSH stimulates the allocation centre (VMH) and thereby amplifies the direct effect of leptin. (C) Leptin and its amplifier.e. MR also bind cortisol. . and these demand further energy. the type II or GR binds This assumption is supported by a unique study in which cortisol with a low affinity. i. Setpoint of limbic-hypothalamic-pituitary –adrenal membrane of the neuron without a specific transporter and system regulation binds in the cytosol with high affinity to MR and with low How does the brain regulate the activity of its LHPA. the MR is the LHPA system and with that the secretion of cortisol? localized most densely in the limbic system. With low cortisol concentrations MR stimulate the LHPA-system. a MR – MR homodimers. corticoid responsive element’ (GRE) in the genome. e. Contrastingly. The cerebral cortex sends the ‘glutamate command’ signal to both of its regulatory subsystems that control glucose allocation and appetite. These receptor properties allow MR and GR to infusion. In the hierarchically subordinate hypothalamus (PVN) only GR-receptors act inhibitorily at high cortisol concentrations.152 A. Leptin conveys the feedback-signal regarding energy status in the adipose and muscle tissues to the hypothalamic VMH where leptin stimulates the allocation of glucose to the brain. where it binds cortisol system while cortisol-bound GR prevents this stimulation. Cortisol is the feedback-signal for the LHPA-system. after morning awakening there was a marked decline. The cortisol concentration as well as the system? number of MR and GR present in the cytosol determine how We propose that it regulates this with the aid of high. This finding is consistent with an or during a stressful incident. The homodimer MR –MR binds to a ‘gluco- characterize the two brain receptor subtypes both biochemi. the low-affinity ATP-sensitive peripheral injection of a larger dose of a glucocorticoid potassium channels are also closed. and the pituitary. Only cortisol affinity and low-affinity brain corticosteroid receptors. who had had both adrenal glands binds cortisol with a 10-fold higher affinity than does removed completely. serum cortisol climbed from very low concen- regulate LHPA system activity. In this way the LHPA-system defines the setpoint for regulation of body mass.and high-affinity ATP-sensitive potassium channels as feedback signal. in ensuring that the LHPA system returns to homeostasis.g. Low-affinity ATP-sensitive potassium channels increase the cortical GABAergic tone and in so doing suppress the glutamate command signal. One known principle of supply and demand in a free market economy. in the We assume that cortisol-bound MR stimulates the LHPA hippocampus and in the amygdala.

Processes like We propose the following general principle to illustrate heterodimerization and autoregulation are so-called ‘non. However. One can see that the limbic system has to stimulate the underlying process is not a simple ligand – receptor the hypothalamic center continuously in order to prevent a interaction. Homeostasis: brain ATP and the LHPA model MR promotes and GR inhibits the release of cortisol system in balance via a range of intermediate steps. and that ‘heterodimerization’ (see above) or the rapid reduction in serum cortisol. and it is this very nonlinear property that makes an experimental analysis difficult. MR –MR homodimers stimulate the LHPA system (e. ACTH and cortisol are still literature [101. This concentration can be designated as a products. Cortisol bound MR and GR assemble into three the expression and transcription of a large number of genes. Here. Cortisol binds with high affinity to MR and lower Neurons of the limbic system are the starting point for the affinity to GR. from should also be encountered in other areas. i. patients determines the allocation of glucose to the brain and the with Addison’s disease. e. Pituitary ACTH is secreted and stimulates the adrenal release of cortisol. in humans is usually achieved during the evening. Peters et al. 4. It therefore represents a function for cortisol corresponds to an elimination of the first primary regulatory system. themselves. this drop-off rate is much slower than Pharmacological interventions with MR-inhibitors result that of the hepatic cortisol clearance. MR and GR modulate amongst other things balance-setpoint for the activity of the LHPA system. Netherlands. In hippocampus [98. The slow reduction in in elevated basal glucocorticoid concentrations. Ronald de Kloet and Marian Joëls at the University of Amsterdam/Leiden. in such individuals cortisol is removed from Thus. the cortisol circadian profile it falls continuously to a There is a debate as to whether limbic MR act in a minimum in the evening from a morning maximum after stimulatory or inhibitory way on the LHPA-system. can no longer produce any cortisol body periphery while the LH is essential for eating behavior. forms of dimers: MR –MR. and about 20 min and CRH a half-life of about 9 min. while GR interferes ligand-bound ion channels (e. of cortisol from the adrenal gland which slows the fall in it must be considered that with such interventions cortisol. This means that without adrenal investigators in numerous experiments investigating the production and secretion of cortisol more than 85% of the effects of cortisol on the excitability of neurons in the cortisol is already eliminated from the circulation after 6 h. cological inhibition may be erroneous. calcium channels). The hierarchical positions of brain ATP regulation and Circulating cortisol is metabolized in the liver and LHPA regulation are different. The Here we focus on the effects of MR and GR on reader will surely notice at this point that the regulation limbic neurons that stimulate the hypothalamic neurons.g.e. awakening. how the activity of the LHPA system is regulated: linear’ [24].e. which ACTH is cleaved. This primary regulatory system order. discovered These three simple rules regarding the interplay between many such corticosteroid effects and described them in a cortisol. a second gene group regulates and thereby cortisol secretion.g. the clearance rate of cortisol is proportional to its for brain ATP regulation operates with the glutamate concentration. that has proven its worth with one aspect of metabolism opiomelanocortin (POMC) peptide in the pituitary. However. the circulation according to its half-life: after 2. the two differing affinity receptors MR and GR and number of comprehensive reviews [98. MR and GR regulate 2. MR – GR or GR – GR.and heterodimers describe a the ability to influence the excitability of limbic neurons via control system that regulates cortisol secretion around the expression and transcription of a variety of gene a setpoint. 3b). Thus. (2) to the appetite-regulating LH. The clearance has the highest biological priority. the brain has two ways of fulfilling its demand . and 6 h it is analogous with a similar relationship found by other reduced to 1/2. 1. A. conclusions based on pharma.g. It would not be surprising pathways the hypothalamic release of CRH and vasopressin. One group of genes controls the behavior of ion channels 3. Thus.99]. ACTH has a half-life of regulatory subsystems. This signal is conveyed to its two higher is its hepatic elimination. stimulation of the LHPA system. if during evolution a reliable and simple regulatory principle The latter release-hormones activate the formation of pro.3.99]. The LHPA system Individuals who no longer have adrenal glands. The brain ATP regulation eliminated with a half-life of about 120 min. glutamate receptor coupled with this effect. subject to a GR-mediated feedback-inhibition (Fig. i. Therefore. MR has the various MR and GR homo.102]). principle underlying brain ATP regulation and LHPA The neurons stimulate via direct or indirect neuronal system regulation is the same. which glutamate-mediated signal input [103]. in this 2. The stimulatory effect of ‘autoregulation’ (see below) of MR and GR can cause the limbic system must be even greater if one considers that at paradoxical effects (as have clearly been demonstrated in hierarchically lower levels CRH. 1/4 and 1/8. but at the same time makes the LHPA-system particularly stable. The higher the cortisol is in the serum. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 153 dose-response relationship was shown for cortisol in humans.1. channels) and a third group influences G protein-coupled receptors. the command signal.: (1) to the LHPA system. possibly cortisol over the day therefore requires a continuous release suggesting an inhibitory effect of MR [100].

Inset on the upper right: Dependency of the energy balance of glutamatergic neurons on brain ATP is shown here: glutamatergic neurons stimulate glucose transport across the blood–brain barrier using the ‘energy on demand’ signal. The rate of change in brain ATP over time [dATP/dt] (ordinate) depends on the brain ATP itself (abscissa). (A) Setpoint for brain ATP regulation. a reduction of glutamatergic neuron activity occurs at higher brain ATP-concentrations (green function). High affinity ATP-sensitive potassium channels on glutamatergic neurons are closed at low brain ATP concentrations so that the neurons can become functionally active (green function). / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 Fig. Since the GABAergic neurons are inhibitory towards glutamatergic neurons. These neurons require . Low affinity ATP-sensitive potassium channels on GABAergic neurons permit functional activity only at higher brain ATP concentrations (red function). Peters et al.154 A. 3.

e. A special situation therefore occurs in which both high- This reciprocal relationship between allocation and and low-affinity ATP-sensitive potassium channels are in required food intake can be mathematically derived as a state of balance. b If brain ATP regulation and the LHPA system are in Allocation ¼ ð1Þ a state of balance. in times of starvation. 5a. 5a. and these neurons therefore appear to be ‘leptin resistant’. The setpoint for brain ATP regulation is found at the intersection point of the green and red functions (upper panel). The mass of the brain B is a 2.e. This resting vice versa. the required intake of foods is: equilibrium state. Eq. in which MR and GR required to satisfy the energy needs of the brain is are balanced for the LHPA subsystem. (3) is represented in Fig. graphically depicted in Fig. (2). the percentage of glucose transported across the blood – allocation. at moderate leptin concentrations the stimulatory a-MSH predominate. at high brain ATP-concentrations GABAergic neurons that only consume energy and thereby lead to a lowering of brain ATP-content are mostly active. The green function (D energy) shows how glutamatergic neurons provide energy for themselves and for GABAergic neurons depending on the brain ATP. (3) is regulated within very narrow limits and kept almost constant. Leptin stimulates the POMC neurons so that at moderate leptin concentrations they are activated. The combined output of both neuronal populations to the VMH is illustrated in the lower panel. The hepatic clearance rate of cortisol depends on the cortisol concentration itself (red function). The setpoint of the LHPA-system is found at the intersection point between the green and red functions (upper panel). represented graphically in Fig. Glucose uptake into the brain is b [g min21 kg21] constant and the MR and GR are in a state of balance. . NPY and POMC neurons are glucose responsive and feature ATP- sensitive potassium channels that are opened at high leptin concentrations. Does the newly proposed paradigm comply with our whereby the high. (1) into Eq. but it allocation to the brain the less food intake is necessary or always strives to return to its resting balance. This means that the greater the unusual crisis situations. the rate of change in brain ATP is equal to zero and the regulating system is at a state of balance (lower panel). the following superfluous. 5a. [g min21 kg21]. If B is designated as the mass of the brain [kg] and M that of the organism can remain stable in this metabolic the muscle/fat [kg]. The idea of an independent Necessary nutrient uptake ¼ bB þ mM ð2Þ system that regulates body mass therefore becomes If one inserts m from Eq. already adequately set by this balance. while m represents glucose uptake into muscle and fat meaning that the LHPA system is at a resting state.2. With low leptin concentrations the inhibitory NPY neurons predominate. i. The the brain can request energy via both regulatory subsystems LHPA system that determines allocation can be burdened in (i. The M organism is instead continuously exposed to stresses and the Necessary nutrient uptake ¼ b B þ ð3Þ Allocation nutrient supply is variable so that it must continually strive If one assumes that the brain keeps its ATP content constant. The neuronal activity of NPY and POMC neurons in the ARC (ordinate) depends on the leptin concentration (abscissa).e. channels are balanced. Load of the brain-supplying regulatory system constant parameter. Leptin inhibits the activity of NPY neurons so that at low leptin concentrations the NPY neurons are spontaneously active. All values of this function are characterized by the fact that the Loads can put stress on the brain-supplying regulatory brain ATP concentration is held at a constant concentration.and low-affinity ATP-sensitive potassium knowledge on how the organism reacts to these situations? R energy themselves for their excitation. It is worth noting that leptin at high concentrations can no longer activate the ARC neurons. The ratio between the two glucose uptake At exactly this intersection point the energy metabolism rates is defined as allocation: is in a state of homeostasis. Low-affinity glucocorticoid receptors (GR) are active only at high cortisol concentrations and inhibit the LHPA system so that adrenal cortisol production and secretion are decreased (green function). the rate of change of cortisol is equal to zero and the LHPA system is at a state of balance (lower panel).g. however. POMC neurons act inhibitorily while NPY neurons act in a stimulatory manner in the VMH. GABAergic neurons on the other hand are not able to promote glucose transport across the blood–brain barrier in this way. 5a all the points are reciprocal relationship between allocation and food intake represented in a second function. the the brain requires to fulfill its demand for energy.e. here. The body mass is. e. a certain required food intake m results from that. Depending on the magnitude of i. relationship between food intake and allocation results: Basically. Peters et al. A. to achieve this ideal balance state. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 155 for energy. At low brain ATP concentrations it is the glutamatergic neurons that mobilize glucose and increase brain ATP content that are mostly active. (B) Setpoint of the LHPA-system. allocation and appetite). for such reasons these neurons become deactivated at high leptin concentrations. i. If There is a substantial difference between the two sufficient energy resources are available to the organism. The corticosteroid balance. High-affinity mineralocorticoid receptors (MR) are active at low cortisol concentrations and stimulate the LHPA system and with that adrenal cortisol production and release. this balance-setpoint represents an ideal   equilibrium state which in fact is rarely achieved. regulatory subsystems for allocation and food intake. here. instead they only consume energy. (C) The leptin amplifier in the arcuate nucleus. the greater the amount of food consumed by the balance is designated as the so-called MR – GR brain organism the less allocation to the brain is necessary. If this food intake can be realized. On the one hand it can alter glucose allocation. and at high leptin concentrations both neuronal populations are inactivated. The ARC neurons project into the VMH. In Fig. The rate of change in cortisol over time ½dCortisol=dt (ordinate) depends on the cortisol concentration itself (abscissa). a food quantity arises from this relationship that brain barrier. whereby both the brain ATP is follows. and on the other it can alter food intake. the variable b in Eq. system. total amount of glucose available for distribution.

Never- the glucose uptake of these tissues [104. From ‘balance-setpoints’. ensures via a series of intermediary steps that the musculature utilizes fatty acids instead of glucose. With increasing body mass. 1 mus (VMH and PVN) [113].e. while the ATP deficit to the benefit of glutamatergic excitation (see body mass increases disproportionately [106]. On the 5th day he loses types of stress are possible: a pending energy deficiency in all his provisions through an accident. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 From the aspect of competition for energy resources. Leptin is formed and secreted in fat strictly regulated so that a marked reduction in ATP is not to tissue and musculature in a manner closely coupled with be expected during a 5 day fasting period [111]. In this chapter we basically various cortical regions (see Fig. only the low-affinity the metabolic stressors. There are 14 components (flow-chart arrows) in Fig. 4b) [73] (model a2 –b2). As already mentioned in the chapter stored energy. This functional feedback between intake reduction in brain ATP partly or even completely. inhibitory.g. Leptin of GLUT1 mRNA [112]. 4e) (model a2 – e2). stimulates glucose uptake.1.2.1. have been shown to affect . is the case with leptin receptor defects. Excitatory components include which are referred to.105]. a key stimulus is A minor activation of the low-affinity ATP-sensitive missing for the allocation of glucose to the brain. GLUT1 transports glucose both body mass? through the luminal and abluminal cell membranes of the The more food an organism consumes. the muscle and fat mass ATP-sensitive potassium channels react while the high- competing for glucose. the brain must be any intake of foods. the larger cerebral endothelial cells. with the transport of glucose via the blood – brain barrier Why is the regulatory system burdened by increasing (Fig. Leptin can Fig. as model a1 –a2 in the following the amygdala basolateral complex and the hippocampal text. as affinity ATP-sensitive potassium channels remain closed. the brain is able to measure even only a tiny conveys a signal describing the quantity of peripherally reduction in brain ATP. leptin can be under. and disinhibitory oriented towards the studies of Per Opstad [110]: components include the bed nuclei stria terminalis and the medial septal/diagonal band complex [113]. 4a). Peters et al. He manages to the brain and an excessive glucose-utilizing body mass. We also provide more insight into cerebral hemisphere organization. Its integrating camp before indulging in a heavy meal. stood as a ‘load signal’ that informs the brain of the size of With a tiny reduction in brain ATP. Glutamate therefore facilitates the stimulates the sympathetic nervous system in the hypo. The potassium channels reduces the GABAergic tone in the development of db=db mice expressing a leptin receptor entire cerebral cortex. and disinhibitory specific anatomical site to each component of the fishbone components—extending to specific parts of the hypothala- model. of foods and glucose allocation is mediated via the feedback In parallel a glutamatergic tone in the cerebral cortex effect of leptin (see Fig.and low-affinity the standpoint of the new paradigm. e. If this load signal is interrupted. Activation of the glutamate becomes the peripheral mass that must compete with the receptors has not only this rapid effect on GLUT1. inhibitory components include the amygdala are explained with the help of a case study on malnutrition central nuclei and the lateral septum. The balance between active gluta- defect has confirmed that the brain mass in the first postnatal matergic and GABAergic neurons is displaced with a slight weeks develops only slowly and inadequately. ATP-sensitive potassium channels play a decisive role. cortical high. while the feedback signal from muscle and adipose In healthy individuals the brain ATP concentration is tissue is leptin [12]. but it brain for glucose. Metabolic stressors. repeat the principles of the model while focusing on its According to Larry Swanson’s topographical model of dynamic behavior. i. Leptin theless. survive the remaining 5 day journey without practically According to the ‘selfish brain paradigm’. and this in turn is closely coupled stood as a load signal targeted towards the brain.1. Mechanisms and neuroanatomical structures involved CA1 – 3 fields. therefore be assigned as a class of cytokine due to its Glutamate is taken up by the astrocytes where it functional and biochemical properties and can be under. and arrives exhausted in the training stressors in the form of feedback-signals.2. 5b). which are transmitted via these wilderness expedition to the mountains of Norway as multiple descending pathways. leptin also exerts a prolonged stimulatory effect on the expression increases as an indicator of this ‘metabolic load’. although during this time he loses informed continuously about the magnitude of these two 4 kg in body mass. Gluta- 2. Signals from Case 1: The 25-year old Olaf goes on a 10-day hippocampus and amygdala. In the subsequent centers receive feedback signals for this purpose from all 2 weeks his food intake is also increased until his original brain areas as well as from the glucose-utilizing muscle and body mass returns. both hippocampus and biological details by assigning one representative specific amygdala pyramidal cells contribute to triple descending metabolic or neuroendocrine mechanism as well as one projections—with excitatory. two part of a ranger training exercise. The feedback signal from the brain itself is ATP.156 A. it is closely correlated with body mass. passage of glucose across the blood – brain barrier in a thalamus and in so doing the allocation of glucose to the number of cortical regions and can in this way correct a brain [107 – 109]. adipose tissues. Malnutrition mate stimulates the glutamate receptor on limbic neurons via projections that innervate the limbic system from 2.

The excitatory limbic pyramidal cells produce two important types of proteins in their cell nucleus: Under the influence of cortisol and its two receptors MR and GR they form proteins that define the excitability of these neurons. Under the influence of GR. They are subject to feedback-inhibition by brain glucose. Low glucose concentrations act permissively. They are stimulated by cortical glutamate that binds to the membranous glutamate receptors (Glu-R). Excitatory neurons produce the neurotransmitter glutamate and the neuropeptide brain-derived neurotrophic factor (BDNF). leptin directly accesses the VMH. At high cortisol concentrations GR are mainly active. however. In energetic homeostasis. MR also promote the synthesis of BDNF receptors (trkB). BDNF stimulates via its high-affinity trkB receptors the CREB gene. The glucose-sensitive neurons of the lateral hypothalamus release orexigenic peptides and in so doing stimulate food intake. The sympathetic nervous system regulates glucose uptake into muscle and adipose tissue by inhibiting pancreatic b-cells. Peters et al. 4. thereby stimulating the POMC-neurons. Both neuronal glutamate release and activation of the sympathetic nervous system lead to an allocation of glucose to the brain. The neurons of the VMH measure the difference between the peripheral (leptin) and central (brain-glucose) feedback signals and generate the VMH output from this result. the stimulatory influence of NPY and the inhibitory influence of a-MSH are at a state of balance. and these also downregulate their own production. which as a result release GABA and act inhibitorily on the excitatory VMH neurons. while it inhibits the CREB gene via its low-affinity BDNF receptors (p75). At low cortisol concentrations MR are primarily active and these downregulate their own synthesis. These excitatory limbic neurons are subject to the influence of presynaptic GABAergic glucoresponsive neurons. These channels are themselves closed at low glucose concentrations and ensure the functional activity of the excitatory neurons. and inhibiting the NPY-neurons. These neurons project with their neuronal pathways into the ventromedial hypothalamus or into the paraventricular nucleus. In addition. Neuronal glutamate is taken up by the astrocytes and stimulates glucose uptake across the blood– brain barrier. A. In this way glutamatergic transmission is subject to modulation by cortisol and BDNF. and this can be stabilized over the long-term by LTP. At very high leptin concentrations the ATP-sensitive potassium channels which are localized on both ARC-neuron types are opened so that these neurons become hyperpolarized and deactivated. (C) Ventromedial hypothalamus. and high glucose concentrations inhibitorily on the activity of cortical excitatory neurons. Ventromedial hypothalamus-(VMH)-neurons stimulate the CRH-neurons in the paraventricular nucleus (PVN) and with that both the sympathetic nervous system and ACTH-release from the pituitary. BDNF-receptors (p75) are produced. (D) Lateral hypothalamus. In these two core regions the POMC neurons release a-MSH and the NPY neurons NPY. These neurons project into the limbic system where they release glutamate and BNDF. Glucose is transported by the insulin-sensitive GLUT4 across the membranes of muscle and fat cells. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 157 Fig. ATP-sensitive potassium channels on presynaptic GABAergic neurons are closed. Both neuronal populations project into the VMH and the LH. . leptin binds to the leptin receptor (LR). At high leptin concentrations the same ATP-sensitive potassium channels on the presynaptic GABAergic neurons are opened so that the neurons release less GABA and a stimulatory effect on the excitatory VMH neurons results. CREB-proteins lead to LTP and a durable alteration in the number of membranous glutamate AMPA receptors. (E) The blood–brain barrier and the cell membranes of muscle/adipose tissue. (F) Arcuate nucleus. (B) The limbic system. They are permanently under feedback control: (1) Postsynaptic high-affinity ATP-sensitive potassium channels are localized on these neurons. With high brain glucose concentrations their sodium/potassium ATPase is activated so that these neurons become hyperpolarized and stop releasing orexigens. (2) Low affinity ATP-sensitive potassium channels are localized presynaptically on GABAergic neurons. while NPY from the ARC decreases the leptin effect. Excitatory neurons are localized in the core regions of the limbic system. thereby limiting the insulin-receptor (IR) mediated glucose uptake into peripheral tissues. Glucose is transported by glucose transporter 1 (GLUT1) across the blood–brain barrier. Under the influence of BDNF and its two receptors trkB and p75 they form so-called CREB-proteins which determine the number of membranous glutamate receptors during the process of long-term potentiation (LTP). The orexigenic neurons are stimulated by glutamatergic neurons and inhibited by GABAergic VMH neurons. These excitatory VMH neurons also mediate GABAergic output to the lateral hypothalamus. The glucose-responsive neurons of the arcuate nucleus produce POMC and NPY. neuropeptides from the ARC also exert a modulatory influence. (A) Cerebral cortex. These channels are closed at high glucose concentrations so that the nerve endings release the inhibitory neurotransmitter GABA that inhibits the excitatory neurons. In addition. whereby both processes restrict peripheral glucose uptake. In the ARC. Limbic neurons stimulate VMH neurons. a-MSH from the ARC amplifies the stimulatory effect of leptin on the excitatory VMH neurons. These excitatory VMH neurons are also subject to a dual feedback-control: At high brain-glucose concentrations.

Peters et al.158 A. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 Fig. 4 (continued ) .

4 (continued ) . Peters et al.A. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 159 Fig.

and this also decreases the and the ‘glutamate command’ signal normalizes.160 A. Replenishment. A subsequent forms ketone bodies from free fatty acids. The brain ATP is normal. It is transported via activates glucose allocation to the brain. Upon intake of food a large amount of glucose is stimulation of PVN neurons. 5b the characteristics for low the presynaptic VMH-neurons so that the VMH neurons are body mass and additional ketone formation are graphically not just stimulated by the limbic system. VMH neurons project towards the PVN. metabolize these ketone bodies as an alternative substrate. the glutamate activated in the VMH [133. During minutes (model c1 – c2). a specific transport mechanism across the blood – brain How does ketone body formation on the one hand and a barrier. 4c). the main glucose transporter for these peripheral tissues. (3). inhibit appetite. lowers drastically due to the reduced allocation of glucose to tions have been shown to activate both VMH neurons [117] adipose and muscular tissue [140]. can stimulate CRH and vasopressin release [131. bound to any specific one. It is beyond question that on the 5th day and cortisol from the adrenal gland as well as a stimulation of fasting Olaf in case 1 suffered an extreme feeling of of the sympathetic nervous system coincide with the hunger. but the competition between brain and 130]. Leptin binds to its leptin receptor in the VMH [141.135] where the After a few minutes the raised substrate supply results in stimulation of a2-adrenergic receptors suppresses the more glucose reaching the brain across the blood – brain secretion of insulin [68.139]. At the same time. less glucose until the setpoint is achieved for ATP (model a3 – a2). The decrease in body mass on the other that although these structures and functions are understood hand occurs far more slowly than does the leptin reduction.69]. These hypothalamic KATP channels body mass M is included into the calculation of this belong to the network of hierarchically organized ATP characteristic according to Eq.132]. This hypothalamic neuronal activity. However. while the leptin concentration and In conclusion. The brain ATP increases further during food intake on muscle and adipose tissue [70]. The closed and the GABA-ergic tone increases. glutamatergic cortical mass. circulating Leptin is a 5-day fasting period. and in so doing request entails a certain disburdening for the regulatory system and mobilize circulating fuels. which is already burdened by a threatening state of ATP A minor reduction in ATP opens the KATP channels in deficiency in the brain. The sympathetic nervous then available for allocation to the brain and the periphery. and antagonizes insulin effects barrier. but they are also illustrated. On the 5th day of fasting the brain’s energy supply glucoprivation increases signal output from the VMH [129. His brain at the end of the fasting period therefore had signals can activate limbic structures that enhance to compete with a reduced glucose-utilizing organ mass. corticosterone.134] which project to the LH and command signal acts on the appetite controlling LH (Fig. remains critical. a latent brain ATP deficit therefore subject to only slow changes over time. Peters et al. a raised glutamatergic tone in the cerebral the body mass are still noticeably reduced. reduction in body mass on the other alter the burdening of 142] which is localized on presynaptic GABAergic neurons the regulatory system? [143] (Fig. 4 kg in final mechanisms. The KATP channels in the VMH and the Glucose is therefore guided past the peripheral tissues and is pancreatic b cells play key roles during the replenishment instead available for uptake by the brain [138. the brain is already optimally supplied in the model. and they lie below the normal characteristic. epinephrine. Since the brain can rise was observed in the hormones ACTH. a Only in the next step is the allocation of glucose to the decreased peripheral glucose uptake is seen during fasting. 5b).and BDNF-containing neurons are 2. GABA. 4e). where it can open KATP channels. Mike Ashford’s research group from . small body mass M. We want to emphasize alleviated (Fig. serum leptin concentration (model b2 – c2).124].1. 4c). Glutamatergic sympathetic nervous system also innervates the musculature and GABA-ergic activity return to a state of equilibrium. periphery regulated. norepinephrine [121 – 123] and in the substrates the loading of the regulatory system for glucose allocation is blood glucose and lactate [122. This means that with a sensors that maintain glucose homeostasis [125 – 128]. Again. As a result. Immediately after the each particular mechanism identified here can fulfil its role start of food intake.2.137]. Both a release of ACTH from the pituitary 4d) (model a2 – d2). Hippocampal stimulation or microinjec. Local or systemic of foods. In summary. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 the hypothalamus-pituitary – adrenal system [114 – 116] During the first day of fasting. During this phase the liver and PVN neurons [118 – 121] (see Fig.2. The insulin-mediated glucose uptake [136. phase for the periphery (model c3 – c2). During fasting. The locally disinhibited. as potential candidates they do not represent the absolute and At the end of the fasting period Olaf had lost approx. The transporter 4 (GLUT4) is translocated onto the cell KATP channels on the GABAergic cortical neurons are membranes of muscle and adipose tissue (Fig. In Fig. cortex activates allocation of glucose to the brain by How does this pattern of events influence the functional promoting GLUT1-mediated glucose transport across the state of the KATP channels in the VMH? blood – brain barrier and restricting GLUT4-mediated Leptin can open KATP channels directly and within glucose transport into muscle and adipose tissue. less glucose allocation suffices in order The VMH governs glucose allocation by limiting to supply the brain with adequate energy for the same intake peripheral glucose uptake (model c2 – e2). system innervates the pancreatic b cells [66. where they periphery has shifted somewhat to the benefit of the brain. Since GLUT4 is energy supply to the brain returns to an optimal state. although the whole theory is not necessarily again while the peripheral energy depots are still depleted.

. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 161 Fig. If there is adequate energy supply of the brain. Peters et al. Glucose allocation is described as the ratio between the glucose uptake rate of the brain and the glucose uptake rate of the muscle and adipose tissue. The food intake required for brain nourishment (ordinate) depends on glucose allocation to the brain (abscissa). A.and low-affinity ATP-sensitive potassium channels are in equilibrium. (A) Balance and Setpoint. the effects of high. The reciprocal relationship describes how much food intake is necessary in order to achieve an adequate energy supply to the brain with a given glucose allocation to the brain. The higher the allocation. 5.

If the setpoint of the LHPA-system is chronically too low. expect such a dual input for a sensor controlling allocation During the replenishment phase. shows an apparently ‘normal’ activity. the tone of status dominates (i. The modulated feedback signal [Leptin þ l(Leptin)] at high leptin concentrations produces an amplified stimulation of the sympatho-adrenal system and as such an increased glucose allocation to the brain. (C) Feedback amplification. The way in which the feedback signal l (leptin) is generated in the ARC is illustrated in Fig. the food intake required for brain energy supply is smaller (compare equation 3). a loading of the brain-supplying regulatory system is due to the continuous increase in body mass. (2) Consequently. brain’s hypothalamic allocation regulator. Leptin stimulates the allocation centre (VMH) in the hypothalamus. With very high glucose allocation the glucose is assigned almost exclusively to the brain so that food intake almost exclusively covers the energy needs of the brain (dashed line). At low leptin concentrations it attenuates the sympatho-adrenal system and with that the glucose allocation to the brain. the the sympatho-adrenal system increases and allocation of hypothalamic KATP channels are closed and glucose is glucose to the periphery is curbed (Fig. assigned to the periphery. Replenishment of the stores due to glucose allocation to the muscle and adipose tissue. however. The KATP channel in the tone (that stimulates the sympatho-adrenal system) and via VMH has a dual input: an inhibitory input for ATP and a vagal stimulation lead to a secretion of insulin from the beta stimulatory input for leptin. a rise in blood glucose. The setpoint of the LHPA system (vertical straight line) is determined by the MR-GR balance. Leptin and melanocortins both stimulate the LHPA system. Insulin enables glucose allocation to energy. If the KATP channels are opened. The ‘normal’ activity of the LHPA-system does not suffice. glucose allocation to the brain also decreases. lead to a disburdening of the regulatory system. but also during the further course of disease to a loss in body mass (yellow area). [The deep red areas describe situations in which body mass has a tendency to increase. Disburdening of the regulatory system through ketogenesis and body mass reduction. The intersection point of the reciprocal function and the vertical straight line characterizes the setpoint for homeostasis: here. Food intake. ATP is sufficiently available). The extent to R the more glucose is assigned to the brain. and in extreme cases to glucosuria. The principle of allocation control can be blood and increasingly opens the KATP channels in described briefly as follows: if the signal for brain energy the VMH. succeeded in Immediately after starting food intake the inhibitory determining the key facts surrounding this process. whose setpoint is reduced but whose load is increased. alternative substrates that provide a portion of the brains energy supply. Peters et al. a-MSH and NPY. the hypothalamic KATP channels can be balanced over the long-term with the aid of the are opened and glucose is assigned to the brain. Obesity can develop in three stages: (1) A setpoint-reduction of the LHPA-system leads to an inadequate glucose allocation to the brain (with increased allocation to muscle and adipose tissue) and makes it necessary to increase the uptake of nutrients. The reciprocal function describes the forward signal path of the regulatory system. (3) An amplified feedback-effect of leptin from melanocortins. (E) Development of obesity. The feedback signal path therefore describes the association whereby an increased food intake leads to increased glucose allocation to the brain. Closed KATP KATP channel via an intracellular signal cascade (via channels in the VMH lead to a decrease in noradrenergic phosphoinositide-3-kinase) [25]. United Kingdom. The LHPA system determines glucose allocation to the brain and strives to achieve a balance state (setpoint) under the influence of the corticosteroid feedback loop. This KATP-sensor with a dual cells [135. The leptin signal can be modulated by neuropeptides from the ARC. From a regulatory-theoretical viewpoint. Normalization of body mass. the brain ATP concentration is sufficient and the LHPA system is at a state of balance. (B) Loading of the regulatory system. . if the signal for peripheral energy The energy needs of the brain and the entire organism status (leptin) dominates. Extreme loading of the LHPA system can lead to a pathological change in the MR-GR balance. while the yellow areas describe situations where it tends to decrease. 3c. In parallel to that the LH is disinhibited. leptin increases in the to two organs. The feedback signal-path (diagonal straight line) describes the reverse effect of the food intake on glucose allocation. The LHPA-system is influenced by the MR–GR balance which determines the system’s balance state (setpoint). and input measures the difference between a signal representing these neurons stimulate insulin secretion via direct efferents brain ATP and one representing the peripherally stored to the beta cells [145]. The numbering describes the chronological sequence of events provided in the first case study (ranger training): 1.e. With a reduction in body mass (M). / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 the University of Aberdeen. to supply the brain with energy so well that a reduction in food intake can be enabled. Correspondingly. With very low glucose allocation the greater proportion of the glucose is assigned to the musculature and adipose tissue so that a larger food intake is necessary in order to ensure that the brain is supplied. The loss of glucose via the kidneys represents an additional load on the regulatory system. The more food that is consumed. becomes greater as a result. With a lowered setpoint the brain supply is therefore maintained more by intake than by allocation of nutrients. With a given glucose-allocation to the brain the required food intake is controlled according to the reciprocal function. At extremely high leptin concentrations the amplifier mechanism is ineffective ½lðleptinÞ ¼ 0 and leptin only exerts its own. An amplified glucose allocation to the brain may lead not only to a type 2 diabetes mellitus. (3) Under the feedback influence of leptin the LHPA system is stimulated in the burdened regulatory system and glucose allocation to the brain is increased.162 A.e.The lower reciprocal function describes the forward signal path when load on the regulatory system is alleviated. Therefore the LHPA-system. unmodulated effect on glucose allocation. In this way the feedback function is complemented by the feedback signal l(leptin). Such an overactivity of the LHPA-system leads to an increased glucose allocation to the brain. 3. Increased glucose allocation to the brain due to stress from fasting. 5. 2. such as ketones. (2) A loading of the regulatory system due to increase in body mass. i. one can the muscle and adipose tissue. 4. necessary for an adequate brain supply. Return of the LHPA system to a state of balance (setpoint). Individuals of a certain genetic background with an especially strong melanocortin system can amplify the leptin-effect on the sympatho-adrenal system in such a way that the burdened LHPA system is hyperactive.] (f) Development of a type 2 diabetes mellitus. (D) Setpoint-change. the more glucose enters into the musculature and adipose tissue so that the leptin concentration increases. 4c). The signal of brain ATP dominates over the stimulatory leptin leptin receptor activated in the VMH opens the cells own signal and the KATP channels are closed.144]. The development of type 2 diabetes mellitus can occur in 3 stages: (1) A setpoint- reduction of the LHPA system. Glucose allocation to the brain is determined by the LHPA system.

With increased release of lactate from the musculature. the allocation of glucose to the brain and the muscle/adipose tissue had returned to a state of equilibrium. There are KATP channels [146] and leptin the musculature. An amplification mechanism of the leptin-feedback effect allows at times of nutrient intake a formed in the liver. Both ketones and the reduced body mass sympatho-adrenal activity which is associated with an led to a disburdening of the regulatory system. Numerous periphery energy balance and the LHPA system returned to reports have suggested that such canoe rides sometimes a state of calm. spared by the lactate. contrary to expectations.e. These findings indicate that the limbic system during critical nutritional states over particularly long plays a supraordinate role over the hypothalamus in periods it can utilize central adipose tissue stores (Fig. After 2 days the brain is supplied in part by ketone ment of the leptin effect works as a kind of servo- bodies. during this phase of fasting the brain lized. 2. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 163 which the limbic system also represents a center that The central adipose tissue is an energy depot for the brain. 6). ketones eral adipose tissue) gain access to the liver. As a result. cover a portion of the brain’s energy.152]. In order to safeguard its energy needs [148 – 150]. With food surplus it leads to an increase in mass decreased.4. it can operate in ‘save mode’ and used as substrates for cardiac and skeletal musculature. balancing the energy needs of the brain and the entire organism (compare chapter ‘sleep and the consolidation of Case 2: The natives of the pacific island of Nauru often setpoints’). for retention in central brain supply returned to an optimal state so that adipose tissue. During the replenishment phase the body mass renorma. in the brain allows a reduction of sympatho-adrenal tone 5. i. The brain can optimize its energy supply receptors [142. As a result. Immediately after the start of the replenishment phase the glucose. The brain’s ‘strategy’ of efficiently using lactate or ketones for its energy needs may shed new light on the pathogenesis of type 2 diabetes (see Chapter 3. Ketones are Fig. With long-term fasting. lasted several weeks and. and load on the free fatty acids arising from peripheral adipose tissue are sympatho-adrenal system is alleviated. Peters et al.2. Lactate and ketones pass the blood –brain barrier with the help of specific monocarboxylate transporters. released from central adipose tissue and converted to 4. The increasing leptin concentrations activated utilizes glucose and ketones. when peripheral stores are replenished. Lactate arises in the muscle tissue from the glycolytic. diabetes mellitus).147] in the limbic system that also play a by maintaining lactate and ketones during phases of food role in memory formation and long-term potentiation supply and deficit. Thus. . free fatty acids from central adipose tissue can be employed for ketogenesis in the liver. glucose allocation to the There is a neuronal network in the hypothalamus that brain was activated because of a threatening state of reinforces the effect of leptin during nutritional surplus and cerebral energy deficiency. The LHPA system returned to its resting state with an equilibrated MR-GR balance. and purposes these are not available for ketogenesis. 6. can maintain brain supplies economically over a long period of time. The metabolization of ketones glucose allocation to the brain more and more. In case 1 a homeostasis gradually appeared over undertook long canoe journeys from one island to the the ensuing three weeks during which both the brain/ next before the era of European colonization. lactate instead of glucose can central adipose tissue and reach the liver via the portal vein. tissue stores. The glucose spared in this way can be Contrastingly. were Fig. the brain the brain was somewhat reduced.3. only a small proportion of the free fatty acids stored instead under the influence of insulin and cortisol in central adipose circulating in the general circulation (arising from periph. curbs its effects during undernutrition [12]. 5b summarizes the five different constellations that frequently survived [19]. and can protect the brain against hypoglycemia [153 – 157]. During the further course of fasting the body mechanism. A. During falling leptin concentrations the allocation of glucose to this phase. integrates the feedback-signals brain ATP and leptin is not while the peripheral adipose tissue is an energy depot for yet clear. The liver utilizes free fatty acids for particularly strong activation of the sympatho-adrenal system that promotes ketogenesis that are lipolytically released from visceral lactate release from the muscle. can be directly metabolized by neurons as energy substrates [151. employs glucose and lactate. Economics of alternative brain-specific substrates.3. At the beginning of fasting. Economics of the alternative brain-specific sub- strates. This reinforce- 2. and to all intents instead of glucose can cover a portion of the brain’s energy needs. In this process it leaves the 3. ketones in the liver. The Therefore less glucose-allocation to the brain is required. free fatty acids are allocation of glucose to the musculature was restored. anaerobic breakdown of glucose.1. appeared in case 1 during fasting and replenishment of nutritional stores: How can an organism maintain its brain supply over extremely long periods of undernutrition? 1. With prolonged fasting.

after long-term fasting. The brain can employ lactate directly as an the stimulating influence of leptin a neuronal population of alternative substrate [151 –157]. With cerebral ATP deficiency or peripheral promotes central adipose tissue growth while maintaining leptin surplus the KATP channels are opened and the POMC adequate supply to the brain. is second signal pathway emanating from the ARC. i. A certain proportion of the the ARC synthesizes the precursor molecule pro-opiomela. to the brain. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 and consequently a reduction in glucose allocation to the While the body energy stores are being replenished the brain. In the same way an appetite VMH with the aid of a-MSH after conversion in the POMC suppressing effect of a-MSH is possible without the brain neuron. 2c). Peripherally stored masses can neuropeptide Y (NPY). so that less energy is MC4 receptor on the appetite-inducing orexigenic neurons. 4f). it KATP channels that are closed by ATP and opened by leptin or mobilizes lactate and glucose for the brain and in this way insulin [26. In this way. From Fig. stored in peripheral adipose tissue.162]. produces less leptin than peripheral fat [167]. unrestricted mobility. with moderate leptin concentrations melanocortin system. This means that the leptin-amplify- In times of prolonged fasting these accumulated central ing melanocortin system is only fully functional with a fat depots can ensure a long-lasting supply of ketone bodies balanced cerebral ATP content and a normal body mass.e. In contrast. Under [163 –165]. 4c). The axons of these POMC neurons innervate storage of glucose in exactly this fat compartment. a powerful appetite stimulator considerably restrict physical mobility (larger inertial (Fig. as such the leptin effect on particularly effective hypothalamic leptin amplification. Here. 4f) [160]. It responds to undernutrition . from which the melanocortin a-MSH is visceral central adipose tissue. glucose allocation to the brain. Here a-MSH acts inhibitorily via its store replenishment is taking place. POMC neurons are glucose-responsive.e.159]. Cortisol also favors the cleaved [12]. e. In conclusion.164 A. Peters et al. Our above-described (a-MSH) is released by the ARC while with low leptin views on how an effective melanocortin system can allow a concentrations NPY is mostly secreted. In conclusion. One such the VMH. where unlike a. The central (visceral) adipose tissue MSH they act in a stimulatory manner [12]. i. The melanocortin system CRH (which promotes glucose allocation to the brain) and increases the role of allocation and decreases that of food thereby attenuates food intake [158].g. 3c provides an overview of the activity of POMC allows more energy uptake. Fig. From a biomechanical standpoint the storage of Leptin amplification can also be accomplished through a energy in certain strongholds. 4c) (model d1– c2). Catecholamines and cortisol Leptin amplification is provided by the melanocortin favor the increased build up of lactate in the musculature system in the hypothalamic ARC (Fig. neurons are inactivated. whereby a mass at the body’s center of gravity also into the VMH. they possess the melanocortin system amplifies the leptin effect. adrenal activity [161. One can only receives an additional energy supply from lactate—as distinguish a primary leptin signal that sends information described above—but also an additional share of glucose. 3c it should also be noted that with nutrients and improves the survival chance of their carriers moderate leptin concentrations mainly melanocortin in situations of long-term starvation. from an The increased allocation under these conditions enables the amplifying secondary leptin signal. The melanocortin system can also increase allocation to described primary leptin signal which directly acts on the the brain. glucose allocation in the VMH is amplified. leptin inhibits a neuronal population that synthesizes particularly favorable. This signal pathway runs parallel to the above. a-MSH amplifies the leptin effect on supply being endangered. Thus. and they project to the LH. which only acts on the organism to take in less food. (Fig. and NPY neurons depending on leptin concentration. Under the influence of melanocortin. 5c summarizes the behavior of a brain equipped with glucose allocation in the VMH is reduced during fasting a leptin amplification system in the ARC: It responds to an (with low leptin concentrations). Under the influence of the melanocortin projects with its axons directly into the appetite-controlling system a somewhat reduced intake of foods occurs while LH (model d1– d2). while with high leptin hypothesis’ [168] postulated that a combination of genes concentrations both the POMC and NPY neurons are might exist that allows an especially efficient utilization of inactivated. where a-MSH is released and stimulates cortisol effect with central fat accumulation is known to noradrenergic neurons via its melanocortin (MC4) receptor clinicians in the form of Cushing’s disease. the long-lasting brain supply allows us to assume that the melanocortin system is activated with nutrient surplus (with natives of Oceania do indeed carry genes that allow moderate leptin concentrations). where unlike a-MSH they act (smallest inertial momentum) [166] permits an almost inhibitorily. The POMC neuron also intake (Fig. the utilization of ketones as an alternative melanocortin system is able to amplify the sympatho- substrate for the brain allows a ‘saving mode’ to be entered. the brain not KATP channels in the VMH (Fig. directly from the periphery to the VMH (allocation). glucose is therefore available for other tasks: to be stored in nocortin (POMC). 2c shows that the increased intake of foods with an especially effective melanocortin system is able to amplify glucose allocation loading of its stress system that coincides with an increased and decrease the intake of foods. in the core of the body. and therefore Fig. The NPY neurons project with their axons momentum). At low Currently it is not known whether the natives of Oceania leptin concentrations. James Neel in his ‘thrifty gene the POMC neurons are active. Fig. the NPY described in case 2 have a supranormally effective neurons are activated.

serum cortisol climbs from sensation during hypoglycemia. Peters et al. Cortical deficiency or leptin excess the postsynaptic KATP channels glutamate via receptors in the limbic system stimulates of the ARC neurons are opened [25. even in situations where an 15 to 25 mg/dl [179]. stress is resolved immediately. restful sleep. 4d) Sascha expresses euphorically that he wants to learn to [173–175] (model d3–d2). The leptin resistance of the melanocortin system is 2. Since in tissue. This hypothalamus-pituitary system [177. There is a signal-filter in the ARC that controls glutamatergic neuron population provides the glutamate whether the leptin signal should be relayed. hypoglycemia is not mediated via signals from the ARC [176]. Contrast. obtaining energy. shaking. During the evening he falls a cerebral energy deficit. while the LH neurons depolarize. while those in the LH are designated as tandem jumpers experience 45 s of freefall before the ‘glucose-sensitive’ [171. orexins. the brain.1. and inner unrest.159] so that these projections activating the LHPA system [73]. VMH (KATP channels) and the LH (Naþ/Kþ ATPase) differ the plane ascends to a height of 3500 m. He senses ingly. by blood cortisol concentrations. allocation and food intake. signals from the periphery are only were dominant. the stimulatory effect of leptin on ‘palpitation’) and with the release of hormones from the the melanocortin system has been lost as a rule. The Case 3: Sascha. Cortisol and insulin also . the release of orexigenic neuropeptides (e.m. The neurons in the jump’ to the front of an experienced trainer. What mechanisms therefore a necessary condition to maintain the ‘primacy of underlie the primacy of the brain regarding energy supply? the brain’ regarding energy supply.4.2. exhausted but satisfied into a deep. With cerebral ATP across the blood – brain barrier is increased. The cortical balance between glutamater- leptin-signal can reach the VMH at any time unhindered. During the fundamentally. who have sympathetic nervous system (leading to symptoms such as high leptin concentrations. as This neuroprotective mechanism permits a ravenous hunger in the above described example. i.m.2. a 22-year-old architectural student. In this state. the KATP channels 2. In conditions of psychological stress the brain is neuroglucopenia the brain is dependent on all possibilities for adequately supplied with energy in this way. Correspond. activation of the stress The melanocortin system suppresses appetite and food systems promotes glucose allocation to the brain and intake and can therefore theoretically induce a serious reduces the uptake of glucose into muscle and adipose conflict in a life threatening neuroglucopenia. Sascha was exposed to a strong psychological stressor The brain has yet another mechanism to guarantee its and put into a state of great tension. One such situation What effects does psychological stress have on glucose occurs for example with insulin-induced hypoglycemia metabolism? which is frequently seen in individuals with type-1 diabetes.26.178]. the brain. With ATP deficiency the VMH neurons 15 min ascent and particularly during the seconds before hyperpolarize. The GABAergic neuronal activity in this conveyed in a restricted way to the regulatory centers of the situation took the back seat. With a parachute jump. Although the command signal. Naþ/Kþ-ATPase is a molecular structure that is ATP. As described above. Many new experiences had to be dealt with. A. In the parachute- sensitive and which can activate the appetite-stimulating school beginners are strapped for a so-called ‘tandem orexigenic neurons in the LH [169.e.00 p. As described above.e. the gic and GABAergic activity prevailing during exposure to melanocortin signal from the ARC is transmitted only under psychological stress resembles that observed during meta- certain conditions: i. Psychological stress act as sensors for the regulation of glucose allocation.g. excitement. Fig. At 10 a. Catecholamine.2. during the ingly. undertakes his first parachute jump. cortisol and insulin excessive peripheral body mass provides a ‘satiety’ signal to play a role in allocating glucose. the jump Sascha appears somewhat excited. cortical excitatory are critical constellations regarding the competition for activities. and primacy regarding its energy supply. depolarization of glucose-deprived LH neurons leads to subsequent communal lunch with the other beginners. The responsive’. The ‘primacy of the brain’. deficit or a peripheral energy surplus occurs (both of which selected. Activation of neurons are hyperpolarized and stop releasing melanocortin the LHPA system coincides with stimulation of the (a-MSH) at their synapses. With cerebral ATP deficiency parachute opens and 5 min coasting under the opened the hyperpolarization of presynaptic GABAergic neurons in parachute.172]. it The degree of activation of the LHPA system is indicated deactivates the melanocortin system in such crisis situations. As already phenomenon is often described as ‘leptin resistance’. The psychological the VMH allows glucose allocation to the brain. A safe landing follows. In obese individuals. Two independent mechanisms are available to the brain for measuring cerebral ATP content: the KATP channels and the Naþ/Kþ-ATPase. If a cerebral energy attentiveness. with sufficient brain ATP and at bolic stress such as neuroglucopenia. also known as neuroglucopenia. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 165 with a highly effective restriction of its stress systems. At 1. In the life-threatening situation of parachute at any cost. Glucose transport physiological leptin concentrations.170]. both the allocation mechanisms as well as hunger are activated independently of one another. and judged. especially of glutamatergic neuronal populations energy resources). severe palpitations. the VMH neurons are also known as ‘glucose. It has indeed been shown that hyperphagia during enabled by an economically effective utilization of ketones. shown in the chapter ‘malnutrition’.

Under the inhibitory underlying the formation of memory. During a period of amplify the glutamate command signal from the limbic minimum reactivity towards environmental stimuli. refers in this case to a fundamental function of controlled Cortisol binds to MR and GR in the limbic system and to biological systems whereby a memory is formed for the GR in the hypothalamus. contextual learning of familiar during the slow wave sleep phase. The LH in turn releases Cortisol easily crosses the blood – brain barrier as a appetite-stimulating orexigens. i. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 feedback to the brain [98. in the pituitary stabilization of setpoints and with that a lasting ‘strategic’ CRH receptors [188] and POMC [189]. These GR-dimers of an adaptive interaction between the organism and its with their feedback effects control the excitability of the environment. Sascha’s serum cortisol concentrations the NMDA receptors increases the calcium concentration . In addition. the limbic system can use serves to consolidate memory. At this time-point the adrenal cortisol inadequate energy request might be harmful to the brain. The energy request is only a crude—but necess. Learning chapter. and on glucose. Unlike the (model b3– b2). and disinhibitory) continuously. As we shall explain in the following signal on the basis of previous experiences. The triple descending projections 2. inhibitory. cortisol inhibits wake phase. melanocortin (MC2) receptors [190]. Now the LHPA synaptic plasticity. the pituitary. as long as the psychological cerebral cortex communicates with the limbic system via a stress persists. Sites of cortisol feedback appear to presses CRH in the PVN which also has an appetite include the limbic system. sleep also functionality [113]. VMH neurons that inhibit how strongly the organism reacts to stressor exposure. MR – MR homodimers increase excitability of limbic neuron populations.g. serum cortisol concentrations reduced concert via triple (excitatory. existing (inborn as well as learned) setpoints limbic neurons that determine activity of the LHPA system are subject to destabilizing influences (stressors). sleep system to the body periphery: in the PVN CRH [185] and allows the reorientation of an inner homeostasis through the vasopressin [186]. Under the influence of CRH and ACTH. complex information processing system. and the are no longer present. During primarily GR –GR homodimers and MR – GR that form in the wake phase setpoints are newly acquired (learned) as part the pyramidal cells of the limbic system. in terms of emotional or the limbic neurons that control the LHPA system (model declarative memories. An nadir of about 3 mg/dl. suppressing effect aside from its function as a releasing and the adrenals. in the ARC POMC [187]. Because of this Sascha is able to eat food limbic feedback action can be traced by lesion studies to the again after his successful landing.194]. and contextual learning of aversive content potentiates [184]. Before sleeping the cortisol concentrations reach a amount of energy that will actually be utilized. sleep represents a phase during which the the mRNA of those peptides and receptors that convey or consolidation of memory is optimized. Cortical excitation normalizes. During may be harmful to the body (catabolism). Accordingly. Peters et al. There is a debate as to whether the locus of hormone [192]. that optimises the energy request b1– b2). The rise in cortisol indicates fall off according to their half-life. There are two by widespread cortical glutamatergic input.e. Glutamate receptors are necessary for conveying the responsive cells high-affinity ATP-sensitive potassium glutamate command signal to the body periphery [73].3. the less binding there descending pathways to exert corticosteroid feedback. and MR– MR homodimers In our opinion. it is the information stored within these predominate. released from the adrenals sufficiently to prevent further arily—anticipatory estimate of the energy need. the LHPA system continues to be stimulated glutamate-mediated synaptic transmission.180].e. the LH [84. cortisol sup- lipophilic hormone. The limbic system modulates the glutamate command trations that then prevail. so-called long-term potentiation system is subject to the dominant inhibitory feedback (LTP) [195]. LTP is thought of as the basic neuronal process influence of the GR-dimers in particular. activity [193.134] decline in activity. e. inhibi- tory. It is therefore slow wave sleep in the first half of the night the MR-MR adaptive to match the energy request closely with the energy homodimers are mainly active at the low cortisol concen- need. as does NMDA receptor that specifically modulates a form of the stimulatory input to the LHPA system. production is approximately as large as the hepatic cortisol An excessive energy request mediated by the LHPA system elimination so that cortisol concentrations stabilize. The lower the cortisol is. Interestingly. the decline. Sleep and the consolidation of setpoints described by Swanson which consist of excitatory. the hypothalamus. in the adrenal gland adaptation to stressors. the ingestion hippocampal formation [181 – 183]. Activation of feedback influence. as described in are also essentially involved. main types of ionotrophic glutamate receptors: the AMPA After a safe parachute landing the psychological stressors receptor involved in basal synaptic transmission. content attenuates. is to GR in the limbic system. With long-lasting stressors. the amygdala. and they can act in In the evening. i.166 A. However. The definition of memory memories to make the most economic energy request. The stores are replenished. a consolidation of memory and metabolic setpoints modifies limbic signal transduction in three ways: fear can occur under the influence of MR – MR homodimers conditioning enhances. The channels [191]. Such controversial of glucose may additionally suppress the LHPA system findings suggest that other brain regions. At high cortisol concentrations it is purpose of consolidating and stabilizing setpoints. and disinhibitory components precisely reflect this In addition to its general restorative function. The limbic neurons belong to a detail in the chapter ‘malnutrition’. cortisol is signal.

/ Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 167 in the postsynaptic neuron and thereby activates a range of gene activation and protein synthesis. It has now become apparent that BDNF exerts its effects This interaction of a ligand with two receptors also on LTP and LTD via two different membrane receptors: the reminds us of a general principle which we have already high-affinity trkB receptor and the low-affinity p75 receptor illustrated with the brain corticosteroid receptors (MR and [200. their slow effects on neuronal survival or differentiation (h or days). BDNF mediates its effect on LTP as 2. antiapoptotic and proapoptotic) effects of (trkB) receptor synthesis depends on cortisol. In the counteracting process. and p75-p75. modulation of synaptic transmission is much faster (s to min). The neurotrophin receptors form three kinds of dimers: trkB – trkB homodimers. long-term the CREB protein a transcription factor [209]. With the assistance of high-affinity and low-affinity at the cell membrane stabilizes over the long-term. After a few hours the synthesis of glutamatergic AMPA receptors intensifies. The receptor dimers bind in each case one BDNF molecule. In this way the effects of BDNF (as an nuates LTD [206] via its trkB receptor. are trophic proteins necessary for the 3. BDNF- Opposing (e. the Max-Planck-Institute in Martinsried/Munich [198]. In LTP. Induction and maintenance of long-term potentiation (LTP) involves induction of CREB mutual phosphorylation of the two cytoplasmic tyrosine proteins. The p75-containing dimers do not transmit bell-shaped dose-effect relationship. Autophosphorylation indicator for the scale of the stressor effect) and cortisol (as an indicator for of the trkB receptor activates a cascade of kinases leading to the scale of the stress reactions) are integrated. stabilize synaptic modification and help to form new synapses: amongst these include structural proteins for new synapses. and [196. within a few hours.3. trkB – p75 heterodimers and p75 – p75 homodimers [202 – 204]. BDNF receptors and In summary. Genes like LTP? CREB activate a genetic chain reaction by activating diverse As an answer we propose: ‘later’ genes. trkB-p75.e. Unlike prevent these. LTP induced during wakefulness is maintained during slow wave sleep only if both cortisol and BDNF mediates the induction of LTP [199.205] and atte.and low-affinity ATP-sensitive potassium receptor displays a cytoplasmic domain with a tyrosine channels. 7. CREB is a so-called ‘early’ gene. again with a bell-shaped trkB and p75 receptors have indeed been demonstrated [203]. through Fig. element binding’ (CREB) gene produces exactly the proteins AMPA receptors are recruited in greater numbers to the cell that appear to be essential for neuronal plasticity and long- membrane so that synaptic signal transmission is increased term memory [207. Optimal conditions for long-term potentiation. BDNF-bound trkB and p75 receptors form three BDNF and other neurotrophins. That means that the p75-receptor competes with the trkB-receptor to prevent trkB-induced activation of cellular processes. tyrosine kinase mediates on the production of CREB-protein results from the autophosphorylation of the trkB receptor as the first step of behavior of BDNF and its two receptors (Fig. CREB protein expression depends on BDNF concentration. A bell-shaped dose-effect-relationship for BDNF kinase. 4b). 7).1. The p75-receptor on the other hand lacks the intracellular tyrosine kinase domain. BDNF lie within optimal ranges. i. . After a stressful event. BDNF binds with high affinity to the trkB receptor neurotrophin BDNF by Yves Barde and Hans Thoenen at and low affinity to the p75 receptor. After binding BDNF. These intracellu. The number of AMPA receptors 1.201]. Consequently trkB – trkB homodimers are predominantly active at low BDNF concentration. Stressors and the limbic system receptors for the cell membrane. 2. The complete effect of BDNF is mediated in this case via the homodimer trkB –trkB. BDNF-(trkB) receptors must be the signal because of their lacking cytoplasmic domains. In addition they effects on LTP while the p75 containing dimers modulate synaptic transmission and plasticity [199]. The trkB-trkB homodimers mediate the BDNF differentiation and survival of neurons. Peters et al. dose-effect relationship. 2. A major breakthrough was the identification of the 1. Like most growth factor receptors the trkB GR) and the high.208]. as well as kinases and How do limbic neurons find the optimal conditions for proteins that maintain vital functions of the neuron. A. With LTP the depression (LTD). with this effect fading intracellular biochemical signal pathways. intracellular signal transduction.g. such as the formerly known types of dimers: trkB-trkB. while at high BDNF concentrations p75-containing dimers are. present in sufficient numbers for the complete BDNF effect.197]. nerve growth factor. with the assistance of high-affinity and low-affinity follows: brain corticosteroid receptors. Alcino Silva and Eric Kandel of Columbia lar signals modify both the number and the activity of the University in New York showed that the ‘cAMP responsive postsynaptic AMPA receptors with lasting effect. AMPA receptors are endocytosed so CREB protein controls production of effector proteins that that synaptic transmission is reduced [196] (see Fig. with a kinase residues.

various groups found that cortisol-bound MR during prior wakefulness [226]. Stress reactions and the limbic system the storage of which relies essentially on the functions of the Cortisol also modulates synaptic transmission and plas. hints that BDNF concentrations in limbic regions such as BDNF and cortisol responses with stress coincide.e. has been proposed to enhance the formation of declarative types of memory [224.225]. hippocampal formation. induction of immediate early genes as the basis of memory Here we present the view that BDNF and cortisol formation. mRNA was highest with low corticosteroid concentrations. Ronald reactivated during slow wave sleep. Low but balanced cortisol concentrations. induced by the process of LTP and the production of BDNF receptors [222]. glutamate command signal. There are of an organism’s stress response. Recently it was shown that GR activation enhances not be associated with a return to homeostasis. they both suppressed their own production. It is assumed that the memory ticity.e. Because of the tight association between BDNF to a sufficient number of trkB receptors and allows for and cortisol in their effect on LTP. In this way a stable and effective information in memory would be favored especially if a communication between the brain cortex and the body state of balanced cortical activity and balanced stress periphery is present which ensures the conveyance of the reaction would prevail after stressor exposure. For this reason BDNF can be considered as a MR and GR are in equilibrium. not associated with a return to homeostasis were to be The effect on CREB gene transcription is maximal if BDNF deleted.2.3. setpoints. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 2. temporal pattern of excitation within limbic neuron net- tion’. within an optimal concen. glutamate. Under these conditions BDNF binds response. cortisol is an indicator for the magnitude adequate number of trkB receptors to be produced. allowing for [227 – 229].3. Both excessively high and low cortisol during the and cortisol are ‘balanced’. the production of p75 receptors [223]. LTP and associated consolidation of memories. MR– general indicator of metabolic or psychological stress. curves regarding corresponding gene products: cortisol on It would be just as beneficial if programs whose activation is the BDNF-(trkB) receptor. maximum numbers of trkB receptors to be formed. Extending these findings.3. these BDNF and cortisol jointly regulate LTP. Fig. strategies taken by experimental rats to find food in a maze) Limbic neurons modulate and mediate the cortical glutamate . a stressor) during wakefulness becomes GR attenuates it [219–221]. while hippocampus. i. 2. Bruce works associated with a particular behavior solution to a McEwen and colleagues showed that MR activates LTP while problem (i. Cortisol concentrations are optimal during the and potentially disrupt the consolidation of memories nadir of the circadian cortisol profile. and the respective behavior would receptors.e. i. a certain spatio- [210–213] and GR [214–218] were subject to ‘autoregula. 7). Pathological glucose regulation of nocturnal sleep. period of sleep replay activation would fail to enhance dominant MR activation is critical for the production of trkB present memory [227]. Peters et al. Thus. The effects of cortisol in the limbic system are enhancing effect of sleep is generated by a ‘replay’ of the influenced by the interaction between MR and GR. these If specific behavioral programs are activated during the findings lead us to conclude a bell-shaped dose-effect curve stress of the wake phase day and the organism returns to for corticosteroids on trkB receptor production (Fig. Thus. Memory formation during sleep Slow wave sleep. These The limbic system plays a decisive role in the communi- are memories for facts and episodes (including the survival cation between the cerebral cortex and the body periphery. In this constellation. BDNF on the CREB protein.168 A. during this period. This that both BDNF and cortisol have bell-shaped dose-effect strategy appears beneficial towards the organism’s survival. occur only if both BDNF and cortisol are within furthermore regulate the consolidation of metabolic their optimal concentration range. If cortisol is too high during the early This dose-effect relationship supported the idea that pre. The such as those established during slow wave sleep periods number of trkB receptors is the limiting factor for the effect of the early night provide conditions optimal for the of BDNF on the CREB gene. This eventually results de Kloet and coworkers showed how cortisol modulated LTP in strengthened synaptic efficacy and enduring memory for when they confirmed that corticosteroids influence the this behavior. homeostasis (MR – GR balance) during the evening. memory representation newly acquired in a learning phase Originally. In healthy individuals. This means that storage of hypothalamic networks. MR homodimers are present in sufficient numbers to allow an Complementarily. 7 shows programs are consolidated during slow wave sleep. evening hours have unfavorable effects on slow wave sleep tration range. A success of this replay for enhancing memory can be while at high corticosteroid concentrations it was barely predicted from the balanced cortisol concentration achieved evident and not different from the vehicle injected controls. Together. Expression of trkB– expression of immediate early genes discussed above. which is dominant during the early part 3. required for the this context that the magnitude of a ‘stressor’ might be presumed stabilization of glucose setpoints in limbic- balanced by the ‘stress reaction’. it might be speculated in optimal expression of LTP and CREB. If the LHPA system returns to its setpoint at the BDNF is released upon cortical excitation together with beginning of the night with balanced cortisol concentrations. are maintained during sleep and thus remain in pathological states may selectively impair the cortisol an optimal range [230].

1. reduced [239]. Catecholamines later. With mild. He attends a company intra-cerebroventricular infusion of cortisol also decreases function where the best-working employees are being the hormonal hypoglycemia response on the following day honored. but in fact by ambulance. Only Stephen Davis’s group could confirm this presumed effect [243]. Upon arrival his plasma-glucose value is they also have the capacity to store information on a long. In such a constellation disrupted hypoglycemia awareness. sweating or palpitations. at which both the energy supply of the brain and episodes of hypoglycemic coma [237. such an What diseases arise when the setpoint of the LHPA attenuation is barely evident [240]. Hypoglycemia unawareness (type 1 diabetes mellitus) the following day [243.238]. and falls to the floor disrupted hypoglycemia awareness has not yet been . In addition. The research group employed different concentrations fall in line with the counterregulation [236]. So-called ‘glucose counterregulation’ is the physiologi- A unique traumatic experience can lead for example to cal mechanism that normally prevents hypoglycemia very persistent modifications in the LHPA system. but can be altered by experiences in hypoglycemia unawareness [178]. Patients at risk to severe hypoglycemia have more cations in the MR–GR balance. periphery. A week after stressor exposure. limbic neurons are in principle able to ‘memorize’ Asymptomatic hypoglycemia represents a major pro- experiences and using these to persistently change the blem in the modern treatment of diabetes mellitus. results in a lower glucose Recurrent hypoglycemia plays a key role in the origin of allocation and a higher food intake. With moderate hypo- system is altered and glucose allocation to the brain changes glycemia. A. podium and conducting his thanksgiving speech. Peters et al. 5d shows the consequences that result from an duration. anorexia nervosa. the attenuation lasts for up to 5 days [241]. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 169 command signal to the muscle and adipose tissue. insulin stress paradigm [234]. obesity basis [242]. these changes also broad agreement that severe hypoglycemia arises from an persisted for 14 days after the stressor exposure. This MR-GR balance is development of a severe neuroglucopenia is known as genetically programmed. He had already suffered a hypoglycemic coma term basis with the help of the molecular mechanisms a year previously. wobbles on his feet. without quences for glucose allocation to the brain and the body noting any earlier warning symptoms such as shaking. can not lower their serum insulin concentrations at the MR–GR balance was examined post mortem one week short notice through suppression of b cells. stressors in animal experiments during a single extended Individuals with type-1 diabetes mellitus. a change in the MR – GR while during recurrences these reactions are quite clearly balance leads in the long-term to a change in body mass. One such LHPA system Approximately a third of people with type-1 diabetes setpoint alteration entails considerable long-term conse. He is brought immediately to the hospital not just control the activity of the LHPA system. other. must compensate for this lacking insulin reaction. 25 mg/dl. or have already suffered setpoint. They do unconscious. likely type-1 than type-2 diabetes mellitus. The dinner is served about one hour too late. Thus. the postnatal period [231–233] as well as in later life [65]. These findings support the notion that episodic of insulin. There is GR ratio was revealed in the hippocampus. who must inject session. With these properties. the LHPA system are balanced. setpoint of the LHPA system. a reduction in the MR. Israel Liberzon effectively and corrects it wherever necessary [235]. and then allowed a stress-free period to pass before insulin. short hypoglycemia. mellitus suffer severe hypoglycemia with comas. They supported Case 4: Walter. as observed with post-traumatic stress the sympatho-adrenal system with the associated increase in disorder. During a hypoglycemic the brain increases the intake of foods and in so doing episode the counter-regulatory hormones increase strongly. a low concentration of glycosylated hemoglobin. infusion of a high cortisol dose results in a reduced increase in the counter-regulatory hormones with hypoglycemia on 3. a 50 year-old plumber. Before he leaves home he injects his usual dose [245]. a longer diabetes Fig.244]. as a consequence? whereas amongst patients with recurring hypoglycemic Considering this question we shall now discuss the origin coma the counter-regulation is decreased on a long-term of hypoglycemia unawareness. alteration in the MR – GR balance: the pathologic balance an autonomous neuropathy. Two research groups have studied whether the and type-2 diabetes mellitus. This and coworkers of the Mental Health Research institute in Ann counter-regulation is based mostly on the activation of the Arbor were able to show that an amplified negative cortisol LHPA system. The inability to sense such warning The MR–GR balance can be seen as an indicator for the symptoms or the absence of such symptoms before the setpoint of the LHPA system. involved in long-term potentiation (LTP). cortisol excess plays a key role in the pathogenesis of Walter notices that he has difficulties going to the hypoglycemia unawareness. safeguards its energy supply. has suffered from their first results by verifying in animal experiments that type 1 diabetes for 25 years. can be induced by application of a single prolonged serum catecholamines and cortisol. This activation includes the stimulation of feedback effect. He goes The role of the limbic MR– GR balance in the origin of back to his table. possibly even permanent modifi. It is certainly interaction between absolute and relative insulin excess on remarkable that a single stress-intensive episode is able to the one hand and an impaired counter-regulation on the lead to such long lasting.

and every brain with its falling ATP content is dependent on an afternoon she goes to the sport’s club where she trains for immediate intake of foods. KATP channels. Thus.250]. She has good grades at school. Because of this a stronger allocation of glucose to the brain is increased while that to neuroglucopenia can develop. Furthermore. the her life.and low- Susumu Seino and Nabuya Inagaki at the Akita and Chiba affinity ATP-sensitive potassium channels in balance). the body periphery is decreased.65 m (BMI of recurrent hypoglycemia [83]. the brain then competes system is also reduced. Even a relatively short-lasting stimulation of the with disrupted detection only an inadequate time period is LHPA system has effects on glucose allocation: the available for food intake. Anna and her younger brother have to the brain can be considered to be inadequate with type 1 already been hit very frequently. but Anna feels the correction of an energy deficiency in the brain through lively and active. If one assumes a setpoint reduction of the LHPA system Both parents are alcohol-dependent and get very violent after one or several hypoglycemic comas. In result of this is that neurons over the entire neocortex addition. With critically low ATP. we shall show in the current chapter that state of knowledge it can be hypothesized that hypoglycemic a chronic stress can instead lead to a hyperresponsiveness of comas. leads to a loading of the LHPA system and glucose allocation to the brain. two uptake and peripheral glucose uptake. it still remains to be checked whether a single stressor load. Anorexia nervosa receptors. strated by the reduced morning cortisol concentrations [239]. While in the previous chapter we showed that episode of a hypoglycemic coma can lead to a lasting setpoint hypoglycemic comas can lead to a hyporesponsiveness of reduction of the LHPA system in humans. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 examined. it also predicts that the number of inadequate glucose allocation to the brain. The adjusting LH and inhibits it (forward signal pathway). When she comes back to school her neuroglucopenia there is often insufficient time to allow friends are shocked by her appearance. employed by Liberzon.248]. Our model nigral. Case 5: The 15 year-old Anna lives in permanent stress. one involving cortical. In such individuals. As a Universities in Japan showed recently that KATP channels result.e. both VMH and LH are subject to inhibition by become hyperpolarized and deactivate [55]. presynaptic low-affinity ATP-sensitive potassium channels on inhibitory cortical Chronic exposure to various psychological stressors. With type-1 diabetes [249. Both a BDNF and a glucocorticoid coma. With our current the LHPA system. As a result of AMPA receptors on the limbic neurons that control the LHPA episodic. glucose allocation when they are drunk. and the other involving excess occur with severe hypoglycemia [247. continues her fasting. there is a decrease in body mass brought protection mechanism against generalized seizures at about by a centrally defined ratio between brain-glucose critical brain ATP-concentrations.2. Overall. a smaller amount of glucose is available for glucose localized in the substantia nigra can also support neuropro. Because of the autoregulation of the brain corticosteroid 3. Peters et al. whereby neurons employ their last influence of the limbic system. The and adipose tissue. allocation. food intake is curbed so far remaining energy merely for structural maintenance. another. the ratio of MR to GR decreases and the circadian cortisol profile stabilizes to a lower concentration.5 kg/m2) to 45 kg. sleeps well. Unlike the sympatho-adrenally 2 h. With mild neuroglucopenia. With rapidly progressing 16. similar to the ‘single prolonged stress paradigm’ the LHPA system. hunger is not attenuated with and diets. regular loading with mid-level stressors can the essential steps of this sequence of events have been lead to a completely different reaction pattern of the demonstrated by various individual experiments elsewhere organism compared to a single short-term overwhelming (see chapter 2). Since the VMH is subject to a lasting stimulatory tive mechanism. Despite this burden- diabetes and as a result the sympatho-adrenally mediated some situation she is very ambitious and has set goals for alarm symptoms are less marked. During a summer camp Anna intensifies her training mediated alarm symptoms. and does not care for itself sufficiently. . The activated allocation- concentrations in the brain the high-affinity ATP-sensitive controlling VMH is hierarchically superior to the appetite potassium channels are also opened (model a1 –a2). From this viewpoint it would appear of brain ATP regulation predicts that the coincidence of that the syndrome of hypoglycemia unawareness is based on BDNF and glucocorticoid excess in the limbic system induces a ‘learned’ setpoint reduction of the LHPA system and an an LTD.170 A. which causes an increase in food intake described with Anna. body mass decreases over the long research groups showed that KATP channels activate a nigral term. does more sport and food intake. In conclusion. An initial study on the MR–GR balance suggested neuroprotective mechanisms appear to be mobilized at that the ratio of MR and GR in the hippocampus is reduced in critical brain ATP concentrations leading to a hypoglycemic acute hypoglycemia [246]. metabolic insults. Her weight falls from 54 kg at 1. can lead to persistent alterations in the limbic MR–GR balance. as neurons are opened. that the brain ATP concentration is balanced (high. Although A long-term. A hypocortisolism then results on the inadequately with the body periphery for energy resources day after the hypoglycemic episode which can be demon. and glucose uptake is reduced in the muscular tection at critical brain ATP concentrations [35]. This resting brain ATP (feedback signal pathway) independently of one state of the neocortex can be understood as a neuroprotec. i.

65 m. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 171 The model of brain ATP regulation predicts that under We shall now explain how secondary metabolic conse- chronic stressor exposure there is not just a loading of the quences can burden the LHPA system.254]. If the withdraws socially. in body periphery for energy resources. Ketones allow that at least a glucose allocation to the brain is inadequate amongst such proportion of the available glucose is assigned to the traumatized individuals. Peters et al. contrast. ketones therefore assume an important available for taking food. Clara never left stress [251. and avoid If one assumes a setpoint increase of the LHPA system social contact. In the Canadian increase of the LHPA system with inadequate glucose Twin Study it could indeed be shown that low plasma allocation to the muscle and adipose tissue. BMI of 27. As a result of cortisol is a predictor for a substantial increase in body this chronic stress. As a result. glucose allocation to the brain decreases. sleep patterns remain ties and travel. patients with a setpoint alteration function for supplying energy to the brain and in so doing after a traumatic experience have sufficient time to ensure enable the body mass to be maintained and stabilized. setpoint reduction of the LHPA system [255. hypersomnolent. hyperphagic. If ketone body paradigm (see above) [234]. a depression are consistent with a decreased MR to GR ratio ketone-induced inhibition of the sympatho-adrenal system and can therefore be considered to represent a setpoint in the hypothalamus occurs during this late stage of disease reduction of the LHPA system. A. results in opposite effects on body mass. [153]. If one assumes a setpoint reduction of the LHPA system Up until now no effect of ketone bodies on hunger has been after a single traumatic experience.256]. supply to the brain by increasing their food intake (see Fig. This prediction is 1. After the death of her boyfriend decreases due to autoregulation of the brain corticosteroid she refused to speak. With chronic fasting. Such a A setpoint-reduction of the LHPA system may result setpoint change entails considerable metabolic consequences. ketone body [258].e. In hypercortisolism. After a year she becomes increasingly and unchanged for the most part. anxiety-like behaviour. glucose allocation to the typical depression. this can lead to an an atypical depression. In its clinical presen- If the glutamate command signal of the brain is very large or tation and neuroendocrine status atypical depression shows is amplified by the limbic system. The neuroendocrine modifications resemble those formation occurs in the liver. Patients with atypical depression are increase in the system setpoint. The findings with atypical formation in progressive anorexia nervosa is activated. and is very sensitive and feels there is an increased influence of MR leading to LTP. Clara developed LHPA system is stimulated chronically. wind accident her boyfriend became a quadriplegic and and hypothalamo-pituitary-adrenal responses to behavioral died after a 3 month treatment in hospital. eats a lot and number of AMPA receptors on the limbic neurons that has already gained 20 kg in weight (current weight 74 kg at control the LHPA system increases. In and well-protected circumstances. exposure due to maternal deprivation leads to a persisting hyper-responsiveness of the LHPA system [233]. lethargic. patients with atypical depression show a brain was increased while that to the body periphery was less active LHPA system. After a the central amygdaloid nucleus. it can be understood that confirmed [253. She sleeps regularly for 12 h. tired. During slow wave sleep continuously depressed. Her fasting plasma glucose consistent with the observation that an early postnatal stress (102 mg/dl) and cholesterol (180 mg/dl) are normal. from a wide spectrum of conditions and disorders that . characterized by CRH deficiency decreased in Anna’s case. LHPA system. Unlike the situation with progres- musculature and adipose tissue. Unlike the endocrine modifications with with chronic psychological stress. anorexia nervosa is based on a ‘learned’ setpoint marked increase in peripheral body mass. Experiments in mice with inactivated GR in the nervous 3. long-term muscle and adipose tissue results over the long term in a changes. The easily offended. A setpoint elevation of the LHPA-system. Conversely. These ketone bodies can be caused by Liberzon in the ‘single prolonged stress’ metabolized by the brain in place of glucose. As such the strength of the and hypocortisolism [255]. the brain competes excessively with the weight [259]. increased MR/GR-ratio and elevated setpoint) showed increased activity of the LHPA-system and A short-term load with a traumatizing stressor can cause a decreased peripheral fat accumulation [260]. but there is in fact also a limbic amplification of the glutamate command signal. associated with low cortisol [257]. a loss in body mass many common features with ‘posttraumatic stress disorder’ critical to survival results. but receptors. the number of MR increases. After her school- animal experiments it has been shown that corticosterone leaving examinations she traveled with her boyfriend delivery to the amygdala increases CRH mRNA in who was an enthusiastic surfer to the Atlantic coast. The combination of increased glucose allocation to From this new way of looking at limbic. A chronic stimulation of Case 6: The now 23 year-old Clara grew up in prosperous the LHPA system typically leads to hypercortisolism. sporting activi- hypercortisolism is only mild. She starts her law studies.2 kg/m2). If the After the traumatic loss of her partner. the number of GR his side during this time.252].3. In the progression of sing hypoglycemia whereby only a few minutes are anorexia nervosa. Dissociative behavior is also glutamate command signal determines the low body mass. 5d). avoiding friendships. Obesity system (i.

Diabetes mellitus arises from an attenuation of the stimulatory input from the occurred frequently in Pedro’s family. however. 5b and e). Also ‘endocrine hospitalization. Individuals with a marked . disrupting chemicals’ [261]. brain-specific substrates’ we discussed that some groups A larger peripheral adipose tissue mass is then able to with genetic peculiarities (Nauruans. Higher metabolic syndrome (hyperglycemia. exercise. Pima Indians) can absorb more glucose. Peters et al. can development of obesity. recovered only sluggishly. The organism leptin amplification. As predicted by the model.4. insult and cortisol excess. Leptin periphery for energy. / Neuroscience and Biobehavioral Reviews 28 (2004) 143–180 disrupt or alter the ‘glutamate command’ signal and the various fractures. a-MSH and NPY act as system. For the last four weeks Pedro alter the endocrine system. We presume brain for energy resources. it can be expected that such individuals therefore reacts to the body weight increase by indirectly react to obesity in a special way. periphery (e. Pedro in the MC4-receptor level would produce a predominance of NPY subsequent period developed obesity. more forceful competitor in the periphery. traumatization. In an impressive experiment. may displace the limbic is feeling weak. A setpoint change of the LHPA system can lead to the via the hypothalamus and its sympathetic efferents. course of disease differed fundamentally.263 – 266]. Disturbances of the LHPA may also be located at treatment for angina pectoris the doctors diagnose the hypothalamic level.262]. That means in reverse that leptin background [268]. After he finally seeks hospital the body. VMH diabetes mellitus (blood glucose 350 mg/dl) as well as and PVN lesions induce obesity [87. had the melanocortin system can amplify this leptin feedback suffered a severe accident at work 10 years previously. the brain ATP [269 –271]. 5b and e). a renormalized insulin secretion was shown. It was recently shown that Case 7: Pedro.172 A. the development of obesity occurs in two increase in serum leptin by increasing glucose allocation to stages: (1) an initial setpoint reduction and (2) a compensa. or the hypothalamus. In other words. centrally applied melanocortin agonists was in a coma for five days. In the chapter ‘economics of the alternative regulatory system is burdened secondarily (Fig. People with a leptin amplifier mechanism react to the In conclusion. a 40 year-old Mexican factory worker. The organism can respond to this that this adaptation is made possible by a leptin amplifier metabolic load by increasing either food intake or mechanism. treated vagotomized animals with leptin and examined so that ultimately it has to compete even more with the body their insulin production under glucose loading. If obesity develops activation of glucose allocation to the brain (see the amongst people with specific genetic background allowing feedback characteristic in Fig. The feedback effect of leptin mediates an one such leptin amplifier mechanism. healthily and athletically built. as The genetic background of people with a Mexican- expected. or infectious diseases. Selective disruption of the a-MSH pathway at the tone of the LHPA system. representing a larger competitor to the survive particularly long periods of starvation. suppressed insulin secretion almost completely. the further neurons and their attenuating action on the leptin signal. In our model. The way in which the organism suppress insulin secretion and with that glucose allocation to reacts to this metabolic load depends greatly on its genetic muscle and adipose tissue. obesity does indeed develop in MC4 deficient American origin differs from those of a European origin mice [267]. However. Obesity also arterial hypertension (200/100 mmHg). concentrations increasing with body mass can promote glucose allocation to the brain. hyperlipoproteine- brain structures and functions have therefore found a new mia. Pedro suffered a physical trauma. fat-derived leptin or muscle-derived inter- leukin-6) into these hypothalamic nuclei [6. the limbic system.g. The melanocortin system fulfills the criteria for allocation. These conditions may include extreme work only a year later. In the time after his starvation.e. Type 2 diabetes mellitus also sympathectomized. and loses 2 kg. he puts on 15 kg in weight. tory feedback-response of the LHPA system. the brain (see Fig. hypertension and abdominal obesity) is increased role in the pathogenesis of obesity. i. and resumed MR – GR balance. a serious physical regions is reduced in melanocortin (MC4) condition can lead to a setpoint alteration in the LHPA receptor deficiency. The team then carried out the same experiment with animals that were 3. In the second phase it feedback-effect on glucose allocation. respect. The prevalence of type 2 diabetes mellitus and the neocortex. has resorted to drinking large amounts of MR – GR balance and in so doing influence the mass of water. Similar to Clara. etc. Hypothalamic stimulatory input would be attenuated and. was operated on repeatedly for inhibit insulin secretion [272]. 5f).). the stimulatory input into these hypothalamic psychological trauma suffered by Clara. Common to both situations is the coincidence of an leptin-amplifying and leptin-attenuating signals. The experiment showed that leptin. which can lead to a decreased ively. increasing the burden on the LHPA system. Akira Mizuno and coworkers of the Takushima University the brain in the first phase competes too little for energy in Japan were able to demonstrate the leptin-mediated resources with the body periphery. here. amongst individuals of a Mexican-American origin With increasing body weight ðMÞ. Such disruptions may be localized in the [19]. environmental agents that mainly around the abdomen. Before the accident Pedro was stress situations (neuroglucopenia. Similar to the Similarly. The researchers sees a growing. He effect even further.

10 g/l glucosuria). Berlin: There are four basic tenets of the theory: First. . but we cannot rule out increased allocation to the brain coincides with both that another factor was more involved. A. For example. bodies prevent the body mass from falling below a certain Attempts to prevent or treat obesity can be successful only critical mass. An inhibited new theory: refutal of any of these tenets should lead to a glucose uptake into the peripheral tissues results in an major questioning of the validity of the theory. Third. The ‘flowing through’ (in Greek ‘diabeinein’) of energy prevents the body exceeding a References certain critical mass. Friedman JM. editor. The selfish brain: learning from addiction. With certain of a biological feedback control system. Proenca R. Alternative strategies lactate for the brain allows the body to reduce food intake of the brain to safeguard its energy needs can result in while still guaranteeing the energy supply of the brain. 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