Obesity 0025-712.5/89 $0.00 + .

20

Nutrient Balance and Obesity:

An Approach to Control of Food Intake
in Humans

George A. Bray, MD*

Obesity is an outward reflection of increased nutrients stored as fat. For young

men, a body fat level above 25 per cent is obcse; for young women, a comparable
figure is 30 per cent. Why does this positive nutrient balance occur? It implies a
disturbance in a system that normally is regulated. In the article by Keesey, the
concept of obesity as a disturbance in a body weight set-point was examined. In
this article, it will be argued that obesity, regardless of the cause, is associated with
decreased activity of that component of the sympathetic nervous system that
activates thermogenic systems in the body. When this system is operating at too-
low a level, food intake rises and fat tissue increases. For this failure of the
sympathetic nervous system to occur, adequate levcls of circulating corticosteroids
secreted by the adrenal gland must be reached. In animal experiments, obesity is
reversed or its progression attenuated by adrenalectomy. Thus, reduced activity of
the sympathetic nervous systcm and the development of obesity require minimal
levels of adrenal glucocorticoids. This metabolic disturbance can be analyzed using
a controlled-system approach.
A regulated or controlled system has several features (Fig. 1). First, there is a
controller located in the brain. Second, there is a controlled system consisting of
food intake, its storage, and metabolism. Third, there are feedback elements that
inform the controller about the controlled system, and, finally, there are the efferent
control mechanisms.
The regulatory system for body weight often is considered to be controlling
energy balance per se. ll. RO A more detailed analysis, however, suggests that each
individual macronutrient is regulated separately. "'Iany elements of the regulatory
systems for energy or nutrient balance appear to operate across species. Although
species variations obviously exist, the basic neurochemical and physiological mech-
anisms appear to apply to most mammalian species."
In analyzing a controlled or regulated system, we can begin at either the

'Professor of Medicine; Professor of Physiology and Biophysics; and Chief, Section of Diabetes
and Clinical Nutrition, Universitv of Southern California, USC/LAC School of ~edicine,
Los Angeles, California .

Supported in part by grants DK 32018 and DK 31988 from the '\'ational Institutes of Health

Medical Clinics of North America-Vo!. 73, :\10. 1, January 1989 29

30 GEORCE A. BRAY

BRAIN

ACTH
MSH

FAT F
... o
o
o
Heat
+ Work
+
Figure 1. Feedback model for the regulation of nutrient intake. The brain is depicted as
the central controller; the intake, storage, and oxidation of food is the controlled system; the
afferent and efferent signals (left and right side arrows) connect these systems.

controlled system, the controller, the feedback signals, or the efferent control
elements. This analysis will begin with the controlled system and end with the
efferent controls.

CONTROLLED NUTRIENT SYSTEM

The controlled or regulated system for nutrient balance is concerned with

maintenance of appropriate nutrient stores of each maeronutrient. In addition to
water, which is the major constituent of all living cells and is regulated closely, the
controlled system for macronutrients includes the intake, storage, and disposal of
protein, carbohydrate, and fat.
NUTRIENT BALANCE AND OBESITY 31

NUTRIENT INTAKE

NUTRIENT INTAKE INT AKE AS A PERCENT OF STORES

kcal/day MJ/d 'lIi

100%
2000 S.4 100
1600 6.7 so
1200 5.0 60
SOO 3.4 40

400 1.7 20
PROTEIN 1.67% 0.57%

t-"<.~
~()~
(QO-f.
vt-~
Figure 2. Nutrient intake in relation to quantities of each nutrient already in body stores.
The daily intake of carbohydrate approximates the total amount of carbohydrate stores. Protein
and fat intake are only a small portion of the body stores.

In a normal human being, total body fat stores are approximately 140,000 kcal
(588 MJ). This is some six times the quantity of energy that is stored in protein
(24,000 kcal or 100.8 MJ). By comparison, the quantity of carbohydrate available as
glycogen stores from liver, kidney, muscle, and other tissues, plus the glucose that
circulates in the blood, is minute, equivalent to only 800 kcal (3.36 MJ). Figure 2
shows the typical intake of 2000 calories (8.4 MJ) as protein (20 per cent),
carbohydrate (40 per cent), and fat (40 per cent). The adjacent bars represent the
percentage of the daily intake related to the pre-existing energy stores for each
component. 11 It is clear that carbohydrate intake at 800 kcal (200 g) per day is equal
to 100 per cent of the body stores of carbohydrate. On the other hand, protein
intake is only a little over 1 per cent of total stores and fat intake is less than 1 per
cent. It is not surprising, therefore, that in studies of nutrient balance in animal
experiments, Flatt30 has noted that changes in carbohydrate balance from day-to-
day influence changes in carbohydrate intake on the subsequent day. For fat
balance, on the other hand, the day-to-day relationship has a very shallow slope,
indicating that daily fat balance has much less effect on subsequent food intake.'l
A second feature of the regulatory system is shown in Figure 3. Energy
utilization by various tissues at rest is partitioned into the fraction utilized by
muscle, viscera, and brain. Muscle and skin account for approximately 18 per cent
of energy expenditure at rest, but this can increase to more than 50 per cent during
locomotion (physical activity). 21 Brain and visceral metabolism, on the other hand,
represent a much larger fraction of the basal or resting component of energy
expenditure and arc much less variable in absolute amounts.
The flow of nutrients through the controlled system is presented in Figure 4.
Nutrient intake is shown on the left, with the various components of tissue
metabolism shown below. Food entering the gut can send signals to the brain as
well as being digested for absorption. Two major pathways of absorption exist, one
through the lacteals for triglycerides packaged in chylomicrons, where clearance
prior to reaching liver or other tissues occurs by means of lipoprotein lipase. The
other pathway is for carbohydrate and amino acids, as well as short-chain fatty
acids, which are delivered in the portal vein directly to the liver.
The brain utilizes about 400 kcal per day; the viscera, 1000 kcal per day; and
32 GEORGE A. BRAY

NUTRIENT UTILIZATION AT REST

TISSUE NUTRIENT UTILIZATION

kcall d MJ/d RQ
2000 8.4 1.0 r-----'
I I
I I
I I
6.7 MUSCLE 0.9
1600

'11
.: ·: ·: ·: ·'
VARIABLE

•r---J-,•
1200 5.0 0.8
• I
800 3.4 0.7
400 1.7 0.6
0 0 0.5
llllllllllllllllll
BRAIN VISCERA MUSCLE
Figure 3. Nutrient utilization at rest. The partition of energy between the various tissues
is shown at the left, and the relative quantities of carbohydrate and fat, as the respiratory
quotient (RQ), is shown on the right. An RQ of 1 is a tissue that is oxidizing 100 per cent
carbohydrate, and an RQ of 0.7 is a tissue that is oxidizing 100 per cent fat. Viscera and
muscle are depicted as showing some adaptability in relation to diet.

BRAIN
FOOD SEEKING

VAGUS ... --~

;------------------------------------+--~
I VAGUS I
,,- - -':;J----- - - - ~-,--

II
I , I I

I I

11
11
11
PANCREAS i: I
I _____
- - ______ I1_1- 8NS / I
11 ADRENAL
11

"
"

.
1
:
1
--"'I
1
1
1

t ALANINE :
CHYLOS VLOL L______ ~~C!~~E________ ~~~P_A!~E!~C~_~
1
GLUCOSE f AMINO ACIDS 1
1
t

~
NEURAL
HORMONAL
NUTRIENT

Figure 4. A diagram of nutrient How. Food intake is indicated at the upper left. Within
the gut, food is digested and absorbed into the portal circulation directly to the liver, or as
chylomicrons that are cleared by lipoprotein lipase (LPL). Very low density lipoproteins
(VLDL) made in the liver are also cleared by LPL. Glucagon and insulin respectively from
the alpha- and beta-cells of the pancreas act on adipose tissue and liver that receive nutrients
from the fat cells and circulation. Amino acids, glucose, free fatty acids, and ketones from the
liver are utilized by muscle and other tissues or brain. The hypothalamus is indicated by the
semicircular part of the brain. (N = nucleus of the tractus solitarius; DV = dorsal motor
nucleus of the vagus; L = lateral hypothalamus; D = dorsomedial nucleus; V = ventromedial
nucleus; P = paraventricular nucleus; SNS = sympathetic nervous system; FFA = free fatty
acids; BAT = brown adipose tissue; CRF = corticotropin releasing factor.)
NUTRIENT BALANCE AND OBESITY 33

muscle, approximately 600 kcal per day, with considerable variation in the fraction
of carbohydrate-to-fat oxidized by muscle, based on the degree of training of the
muscle. 80 The quantity of fat used by muscle depends on its state of training and
the intensity and duration of exercise. During short bouts of intense exercise,
carbohydrate provides the major fuel and is mobilized in large part from glycogen
stores within muscle. During prolonged aerobic exercise, the percentage of fatty
acids oxidized by muscle increases and the respiratory quotient (carbon dioxide
produced/oxygen consumed) falls . One major difference between muscle in a
physically trained person and muscle in an untrained individual is its ability to
oxidize fatty acids during exercise and at rest. In general, the brain utilizes only
carbohydrate, although, clearly, different regions of the brain have differing sensi-
tivities to carbohydrate need. One major limitation in fatty acid oxidation by the
brain is its transport across the blood-brain barrier.
Obesity occurs when the controlled system fails to maintain balance and excess
fat is stored. These basic facts about the nutrient control system can be summarized
in the following equation:
Nutrient Balance - ~ [(6 Carbohydrate Balance) + (6 Fat Balance) + (6 Protein Balance)]

Several concepts are suggested by this equation:

1. The balance of each major nutrient may be regulated separately.
2. The time required to achieve balance varies for each nutrient as a function of the
amount ingested each day in relation to the total body stores. Becoming obese by eating a
high-carbohydrate diet therefore would appear to be more difficult than with a high-fat diet30
because the body storage systems for carbohydrate are limited. Although excess carbohydrate
can be converted to fatty acids, this is an energetically expensive transformation. Body fat
stores, on the other hand, are many times larger than fat intake, implying a much greater
capacity for fat storage and a much longer time constant to achieve balance. 34
3. Achievement of nutrient balance requires that the net oxidation of each nutrient equals
the average composition of the nutrients in the diet.
4. Ingestion of a high-fat diet requires greater fat oxidation than a low-fat diet.
5. Because physical training can increase the oxidation of fatty acids by muscle, regular
aerobic exercise might reduce the tendency to become obese on a higher-fat diet.
6. The regulation of nutrient stores is subject to positive and negative feedback elements
for each component that operates through the central controller.
Nutrient intake plays a variable role in the development of experimental forms
of obesity l4. 72 and probably in human obesity as well. This is presented graphically
in Figure 5, a three-dimensional representation to show, along the X-axis, the
dependence of obesity on dietary composition, whether hyperphagia is present or
not, and whether that hyperphagia is essential for the development of obesity. It
can be seen that the animals with lesions in the paraventricular nucleus (PVN)36. 49. 75
are hyperphagic and that this appears to be essential for the development of this
syndrome. 78 The other forms of hypothalamic obesity, produced by lesions in the
ventromedial hypothalamus (VMH) or by injecting gold thioglucose, are not more
nutrient-dependent than PVN-lesioned animals. 13 They also have hyperphagia, but
this hyperphagia is not essential for the development of these syndromes. 24 • 33. 40
Two other syndromes with hypothalamic injury that caused by injection of bipiper-
idly mustard or monosodium glutamate (no. 5 and 6) are not hyperphagic and will
become obese on any diet. s The genetic obesities (no. 10-12) are all hyperphagic,
but this hyperphagia is not essential for the development of obesity in these
animals. 14. 22. 23 Moreover, animals with genetic obesity will become fat on high or
low carbohydrate diets. Of syndromes caused by peripheral manipulations, ovariec-
tomy shows modest hyperphagia that is not essential for development of this
syndrome, but these animals are more susceptible to a high-fat diet" and therefore
have a hi h nutrient de endence for the develo ment of obe sit . 72 Of the t es of
34 GEORCE A. BHAY

CENTRAL
1. PVN LESION
2. VMH LESION

•1
3. GTG LESION
+ 4. BIPIPERIDYL MUSTARD

t
HOW ESSENTIAL
5. GLUTAMATE
HYPERPHAGIA
GENETIC

DEGREE OF 10. OB/OB

11. FA/FA
HYPERPHAGIA +
12. DB/DB
+
PERIPHERAL
20. OVARIECTOMY
21. HIGH FAT DIET
NUTRIENT DEPENDENCE _ 22. SUCROSE SOLUTIONS
23. CAFETERIA DIET
Figure 5. Diagram of the relative nutrient dependence of various animal models of
obesity. Also shown is the dependence and presence in these models of hyperphagia for the
appearance of obesity. (PVN = paraventricular nucleus; VMH = ventromedial hypothalamus;
GTG = gold thioglucose; OB = obese; FA = fatty acid; DB = diabetic.)

dietary obesity, cafeteria-fed rats are the most hyperphagic,63 while the other two
show only limited degrees of hyperphagia. 46.70.71 In conclusion, nutrient dependence
and hyperphagia are separate dimensions in the equation for obesity.

AFFERENT OR FEEDBACK SIGNALS

The brain receives information for regulating energy balance from several
sources. These afferent signals can be transmitted over the somatic sensory system,
through the bloodstream, or via the autonomic nervous system, and have been
summarized briefly in Table I.
Sensory Signals
The sight and smell of food are important signals for initiating food-seeking
behavior and identifying potential sources of food. Along with the taste and texture

Table 1. Afferent Signals Affecting Food Intake

FOOD I:\TAKE

SIGNAL Increased Decreased

Environmental
Ambient temperature Cold Hot
Smell of food Appetizing Repugnant
Taste offood Pleasant Unpleasant
Gastrointestinal "Hunger cramps" Distension
Cholecystokinin
Bombesin
Metabolic signals
Glucose Insulin Hepatic portal
2-deoxyglucose glucose
Fatty acid oxidation Decreased Increased
Hepatic redox potential Reduced Oxidized
NUTRIE'\IT BALAt\CE At\D OBESITY 35
of food in the mouth, these sensory eues about the availability and quality of food
can serve both as positive feedback signals, initiating continued food ingcstion, or
negative signals to slow down, terminate, or abort an eating incident. The ability
of most animals to avoid fC)Qds that previously have made them sick, a phenomenon
known as bait shyness, is an example of these afferent sensory signals, integrated
with a central learning system.
Gastrointestinal Signals
Information from food in the gastrointestinal tract can be initiated by one of
two mechanisms. The first is gastric distension and the second is release of
gastrointestinal hormones by nutrients acting directly on neural receptors in the
richly innervated enteric plexus. Gastric and intestinal distension are both mecha-
nisms for terminating meals by negative neural feedback systems. The vagus nerve
is the principal afferent sensory relay for this type of information. One mechanism
by which cholecystokinin, a gastrointestinal hormone that can reduce food intake,
may work, is by constricting the pylorus and delaying gastric emptying, thus
increasing the duration and intensity of signals from gastric distension. '" The satiety
produced by cholecystokinin is blocked by sectioning of the gastric vagal nerves.
The relays from vagal afferents have been traced from the gastrointestinal tract and
liver to the nuclcus of the tractus solitarius (NTS) and from there through the
parabrachial nucleus to the lateral hypothalamus and to the PVN.38 In addition to
cholecystokinin, a bombesin-like peptide, also released from the gastrointestinal
tract, may serve as an inhibitory signal for food intake.:l8
Nutrient and hormonal signals also may act on the liver to initiate vagal afferent
messages. Glucose injected into the portal circulation decreases vagal afferent firing
rate, probably through hepatic glucose receptors. 59 Glucagon may act on the liver
and other intestinal receptor systems to initiate satiety, and this effect is partially
abolished by vagotomy." These data suggest that the afferent vagal circuitry may
be one way in which changes in glucose balance might modulate food intake through
the PVN. A second possible mechanism is through direct effects of glucose on the
central nervous system.'" Hauger and coworkers 41 have demonstrated that glucose
regulates the binding of amphetamine to the sodium pump (Na+ -K+ ATPase) in the
hypothalamus, and that this effect is modulated by nutrient intake, specifically
glucose. Thus, at least two mechanisms may be involved in the regulation of glucose
balance.
Nutrient and Hormonal Signals
Nutrient and hormonal signals may act on both the liver and the brain. The
hepatic mechanisms clearly involve the vagal afferent nerves. In addition to the
effects of glucose and glucagon, it is clear that fatty acid metabolism" and hepatic
redox potential may also serve as afferent vagal signals. Injection of beta-hydroxy-
butyrate or lactate will change the redox potential in liver and produce satiety.
Increased fatty acid oxidation by the liver is associated with a decrease in food
intake. 4'
The potential role for serotonin in the regulation of protein intake and/or
carbohydrate balance is suggested by the relationship between tryptophan and food
intake. 9. 82 Tryptophan, 5-hydroxytryptophan, and drugs like fenfluramine and
fluoxetine, '9 which increase serotonin concentrations at neuroeffector junctions, are
known to alter the preference for carbohydrates and moderate the preference for
protein, while those that influence the noradrenergic system, specifically amphet-
amines, alter the preference for protein. 64
Fat balance provides a more complicated problem. Increasing the percentage
of fat in the diet will increase body fat stores in most animal species. 27 7() Within
36 GEOHGE A. BHAY

each species, however, there are some members that are considerably more resistant
to developing obesity when eating a high-fat diet than others.
In our studies of sensitive and resistant variants of rats fed a high-fat diet, we
have observed that resistant rats have a number of important differences from
sensitive rats in their response to a high-fat diet. Changes of food intake in response
to insulin and anorectic drugs differed significantly.2' Blood levels of ketones were
inereased in the resistant rats and may be a reflection of changes in insulin
concentrations. b3 Ketones are the metabolic product of fatty acid metabolism by the
liver, and are secreted for transport to other tissues, where they provide an
important metabolic fuel. Ketones also may provide a signal to the liver or brain
about the state of fatty acid oxidation. We have observed that the transport of 3-
hydroxybutyrate across the blood-brain barrier is significantly higher in the rats
that are resistant to dietary obesity than in those that are sensitive to high-fat
diets. '6 When animals are fed a high-fat diet, there is an increase in blood-brain
barrier transport mechanisms but the resistant animals still transport significantly
more than the sensitive ones. In other studies from our laboratorv, we have
observed that the infusion of ketones into the ventricular system ~f the brain
enhances sympathetic activity, as reflected by the increased thermogenic properties
of brown adipose tissue (BAT)6 and increased sympathetic firing rate of nerves to
BAT when ketones are microinjected into the ventromedial hypothalamus.'i7 This is
in harmony with the observations of Davis and colleagues 23 and suggests that the
ventromedial hypothalamus plays a pivotal role in producing resistance to obesity
in rats eating a high-fat diet.
The importance of the VMH in the resistant rat is underlined by the fact that
VMH lesions convert the resistant rat into one that is sensitive to a high-fat diet. 62
Resistant rats also show an altered pattern of response to drugs that att~nuates food
intake,28 but not to castration or sucrose-induced obesity.71
Differences in efferent controls also exist between resistant and sensitive rats.
The resistant animal has a higher activity of its sympathetic nervous system than
the animal that is sensitive to a high-fat diet. 29. 81 Because the concentration of
ketones available to the brain tissue is a function of the rate of transport across the
blood-brain barrier, the resistant strain should, and does, have increased activity of
the sympathetic nervous system. It is of interest that the response to ketones
infused into the cerebroventricular system does not appear to vary with the diet. A
higher blood-brain barrier transport of ketones following exposure to a high-fat diet
therefore would lead to greater quantities ofketones in the brain and, subsequently,
to greater activation of the sympathetic nervous system by this mechanism.
Circulating nutrients and hormones also may act directly on the brain at the
areas where there are openings through the blood-brain barrier, on receptors in
the blood-brain barrier, or after transport across the blood-brain barrier. Changing
amino acid concentrations, particularly the amino acids that are precursors for
neurotransmitters, such as tyrosine or tryptophan, may play important roles in
signaling the adequacy of protein intake. Although ketones and glucose in the
circulation may provide information to the brain about the state of gluc~se availability
or fatty acid oxidation, demonstrating direct effects on the brain has been more
difficult than demonstrating effects' mediated through afferent neural systems
involving the autonomic nervous system.
Ambient temperature and heat production play a role in regulation of food
intake. '8 High ambient temperature tends to reduce food intake and low ambient
temperature to increase it. It also has been suggested that endogenous heat
production from BAT or other sites may act as an afferent satiety signal ..19

THE CONTROLLER
A number of signals influence food intake by acting within the central nervous
system; they are summarized in Table 2.
NUTHlE]'\T BALANCE AND OBESITY 37

Table 2. Central Signals Affecting Food Intake

FOOD Ir\TAKE

SIGNAL Increased Decreased

Cognition Meal time Unpleasant thoughts of
Pleasant thoughts of food food
Monoamines Norepinephrine Serotonin
(PVN) Norepinephrine
(alpha-2-receptor) (perifornical) (heta-
receptor)
Histamine (H-l receptor)
Metabolites 2-deoxyglucose 3-hydroxyblltyrate
I-deoxyglucose 3,4-dihydroxybutyrate
Gamma aminobutyric acid Gamma amino butyric acid
(VMH) (LH)
Peptides Dynorphin Bombesin
Beta-endorphin N eurotensin
Neuropeptide Y Anorectin
Galanin Corticotropin-releasing
Growth hormone-releasing factor
hormone Calcitonin
Thyrotropin-releasing
hormone (Cyclo-His-Pro)
Cholecystokinin
Electrical stimulation Lateral hypothalamus
Drugs Amitriptyline Amphetamine
Cyproheptadine FenRuramine
Clonidine (rats)

Anatomy
Several anatomic regions of the brain appear to play an important role in the
control of energy balance. 52 Destruction of the VYlH is associated with hyperphagia
and obesity in most homeothermic species that have been studied. 14 Destruction of
the lateral hypothalamus, on the other hand, is associated with a decrease in food
intake and a reduction in body fat. 45 Ylore recently, the PVN has been shown to be
a particularly important region for stimulation of food intake following topical
injection of norepinephrine, acting through alpha-2-adrenergic receptors,4' and of
neuropeptides such as dynorphin" and neuropeptide-Y.74 The primacy of the
ventromedial nucleus in the regulation of body fat stores is suggested by the fact
that the chronic infusion of norepinephrine into the V~1H produces obesity, whereas
comparable infusion into the PVN does not. 73
N eurotransmitters
Norepinephrine, serotonin (5-HT), histamine,"9 gamma-aminobutyric acid, and
a number of peptides may be involved in the transmission of information that
regulates food intake and nutrient stores. 7. " Infusion of norepinephrine into the
VMH can increase food intake and fat stores. 71 Serotonin also plays an important
role in the regulation of food intake and nutrient stores. 9 Tryptophan and 5-
hydroxy tryptophan, two precursors of serotonin, both decrease food intake. Drugs
that block the effect of serotonin can increase body weight and those that stimulate
release of serotonin or inhibit its re-uptake from nerve endings will result in a
reduction in body weight release. 79 Thus, both norepinephrine and serotonin play
important, but usually reciprocal, roles in the regulation of food intake through
structures located in the medial and lateral hypothalamus. 48
38 GEOHCE A. BHAY

Several peptides also modulate food intake." Neuropeptide-Y, beta-endorphin,

dynorphin, growth hormone-releasing hormone, and galanin all stimulate food
intake when applied to the ventromedial or PVN."" On the other hand, a variety
of other pep tides, including bombesin, cholecystokinin, anorectin, calcitonin, neu-
rotensin, thyrotropin-releasing hormone, and corticotropin-releasing factor (CRF),
can inhibit feeding when injected topically in the region of the ventromedial nucleus
or when infused into the third ventricular system. 1 4." In addition to these
neuropeptides, there also is evidence to suggest that infusing either insulin or
glucagon into the ventricular system of the brain can decrease food intake in several
species, but the physiological importance of this remains unclear. 17, 4:1

EFFERENT CONTROLS

The efferent controls include the motor activities involved in seeking and
ingesting food, as well as the efferent effects produced by the autonomic ne'rvous
system and circulating hormones. The complex sequence of motor activities that
leads to the initiation of food seeking, the identifieation of food, and the killing and/
or ingestion of the food is integrated in the lateral hypothalamus, given the fact·
that electrical stimulation of this area will lead to food seeking and ingestive
behavior. Detailed description of this system is beyond the scope of this review.
Autonomic Nervous System
Both the efferent sympathetic and parasympathetic nervous systems are in-
volved in the development of obesity. 15 In animals where obesity follows hypotha-
lamic lesions, there is evidence for increased activity of the efferent vagus nerve. 24
This provides part of the explanation for the increase in insulin that characterizes
this svndrome. 44
Reduction in sympathetic activity is characteristic of the obese state and may
enhance insulin secretion. 11. 1.1 In animal experiments, there is an inverse relationship
between the activity of the sympathetic nervous system and food intake.!. 2.' 6. 68
Throughout the 24 hours, there is a negative correlation between basal activity of
the sympathetic nervous system and spontaneous food intake (r= -0.91). In addition,
almost all of the experimental maneuvers we have tested that increase food intake
(V"1H lesions, genetic obesity)66 7[i result in a decrease in the activity of the
sympathetic nervous system. Conversely, those that decrease food intake (lateral
hypothalamic lesions or fenfluramine)1. 2. 503. 84 increase sympathetic activity. Two
apparent exceptions to this relationship are observed in fasted animals'6. 87 and in
animals eating a cafeteria or supermarket diet." In fasted rats, the activity of the
sympathetic nervous system declines. This reduction in sympathetic activity,
however, may be consistent with the negative correlation between food intake and
sympathetic activity, if one views the level of food intake of the fasted animal by
asking how much the animal would have eaten if food were available. With our
mode't of a negative correlation between food intake and resting sympathetic activity,
the low sympathetic activity observed with fasting would predict an increased level
of food intake when food first becomes available (Fig. 6). Van Itallie and Kissileff'7
have observed precisely this relationship, with a higher initial level of food intake
as the degree of fasting is prolonged. The increased food intake of the cafeteria-fed
rat" or the animal drinking sucrose solutions'6 may represent positive feedback
signals that override the normal reciprocal relationship between food intake and
the sympathetic nervous system.
Insulin
Increased levels of insulin are characteristic of obesity.14 ~Ol'eover, insulin
injections can increase food intake, probably by lowering glucose concentrations,
NCTRIENT BALA~CE A~D OBESITY 39

tACTIVITY
SNS

t INTAKE
FOOD t INTAKE
FOOD

t ACTIVITY
SNS
Figure 6. Relationships of food intake and sympathetic nervous system activity. When
food intake increases (left) there is a rise in activity of the sympathetic nervous system. This
may in turn be a signal to decrease food intake through the thermogenic effects of the
increased sympathetic activity. As food intake falls, so does sympathetic activity, which may
then serve as a signal for the subsequent initiation of a meal.

given that injections of 2-deoxy-D-glucose, an analogue of glucose that inhibits

glucose metabolism, also will stimulate food intake. 5 Insulin has been proposed as
a signal to the brain about the state of peripheral fat stores. bl The major problem
with this hypothesis is that insulin falls rapidly following caloric restriction and long
before there are significant changes in the quantity of body fat. Y!oreover, there
are some experimental types of obesity that occur with little or no rise in the
concentration of insulin. Thus, the rise in insulin appears to be a reflection of a
high level of nutrients, and is influenced by hypo thalamic control in insulin
secretion, modulated by the autonomic nervous system.
Adrenal Steroids
The development or progression of experimental obesity is reversed or atten-
uated by adrenalectomy. w. 12. 13.20.26..'6, 65 In clinical medicine, Addison's disease with
adrenal insufficiency is associated with leanness, whereas Cushing's syndrome is
associated with obesity. This striking observation requires special consideration.
The fact that almost all defects in the genetically obese animal are reversed by
adrenalectomy 13. 42. 55, 89 suggests that glucocorticoids play a key role in the develop-
ment of this syndrome. Adrenalectomy produces two effects on food intake": First,
food intake returns nearly, if not completely, to normal levels after adrenalectomy
in genetically obese animals, 55. 65 in animals with ovariectomy-induced obesity, 56 and
in animals with hypothalamic obesity.20 Feeding patterns also revert to normal.
Leibowitz" has described one way in which feeding may be influenced by
adrenalectomy. She has shown that adrenalectomy almost completely abolishes the
stimulation of food intake when norepinephrine is injected into the PVN. Treatment
40 GEORCE A. BRAY

ADRENALECTOMY MODEL

I ADRENALECTOMY I-LI CORTICOSTEROIDS I

FOOD INTAKE
I.--_----'~~ ~f
I' 1
~
~_s_N_s_A_c_T_,V_,T_y~lt-----
Figure 7. Model of the effects of adrenalectomy in the control of sympathetic nervous
activity and food intake. The central factor in this system is corticotrophin releasing factor
(CRF), which can modulate the reciprocal changes in food intake and sympathetic activity.
(SNS = sympathetic nervous system.)

with corticosterone rapidly reverses this effect. This loss of sensitivity after adren-
alectomy could explain the return of food intake to normal after adrenalectomy.
Energy expenditure also is increased after adrenalectomy. 35. 63, 76 We 76 and
others 42 "," have shown increased activity of the sympathetic nervous system following
adrenalectomy, as measured by increased norepinephrine turnover in nerve endings
in BAT76 or by increased binding of guanosine 5' -diphosphate to mitochondria from
this tissue, as an index of thermogenic activity. 42 The effects of corticosteroids on
thermogenic activity can be observed in normal, as well as obese, animals.
Because efferent systems for food intake and sympathetic activity are both
affected by adrenalectomy, the removal of glucocorticoids would appear to act at a
site different from those involved in genetic obesity, dietary obesity, or hypo thalamic
obesity. After adrenalectomy, the negative feedback signal produced by corticoster-
one is absent and CRF will be synthesized in the PV/Ii and released into the
hypo thalamic portal circulation to stimulate increased ACTH output from the
pituitary. This increased CRF also may reduce food intake and stimulate sympathetic
activity following adrenalectomy. Injections of CRF into the cerebral ventricle of
the rat decrease food intake 4 51 and body weight 4 and increase circulating levels of
epinephrine and norepinephrine. 19 Because adrenalectomy attenuates obesity in
genetically obese animals, this would suggest that the mechanism by which CRF
works is different for both food intake and sympathetic activity from those mecha-
nisms associated with any of the other neurotransmitter systems involved in the
syndromes of hypo thalamic, genetic, or dietary obesity. This hypothesis is presented
schematically in Figure 7. Recent studies in our laboratory have shown that chronic
infusion of CRF into the third ventricle of genetically obese fatty rats or obese rats
with VMH lesions will lower body weight and activate the thermogenic component
of the sympathetic nervous system that supplies BAT.
This description of the controlled system for regulation of nutrient intake has
implications for therapy of obesity. Figure 8 shows a summary diagram of the three
types of obesity that we have been dealing with. In each type, there is a lowered
NUTRIENT BALANCE AND OBESITY 41

Control Hypothalamic

BRAIN
UU--
~

~
~
+ +
.
Heat
·-rn
. Work

Genetic Dietary

--I ,- ...c::JRAIN --
I I I
I I I

i
I

(LJ)
I
I
I
I
i
I
I ~ I
I

~:i i§] FAT

_ + 0
D

+
Heat
+
Work + +
Heat Work
Figure 8. Feedback models for the control situation and for possible sites where defects
might produce dietary, hypothalamic, and genetic forms of obesity. In all three types of
obesity, there is a suggested reduction in activity of the sympathetic nervous system.
42 GEORCE A. BRAY

level of sympathetic activity. It is particularly interesting that the activity of the

sympathetic nervous system can be increased, and food intake and body weight
lowered, by CRF infused into the third ventricle, because this implies that this
component of the controlled system still can be activated, but the nature of the
V~H lesion or the genetic obesity has prevented the normal activation of this
system, which should reduce body weight. Any therapeutic maneuver that will
activate the sympathetic nervous system, with its influence on thermogenic systems,
therefore should have an influence on the storage of nutrient as fat. The recent
evidence that beta-adrenergic agonists that work on beta-adrenoreceptors can
repartition nutrients in farm animals by lowering body fat and raising lean body
mass is consistent with the ideas that have been proposed, namely, that obesity is
a condition with reduced activity of the sympathetic thermogenic nervous system
in the face of adequate concentrations of adrenal glucocorticoids.

SUMMARY

This article has examined the regulated systems that control nutrient balance.
From this analysis, the following conclusions may be suggested:
1. Each nutrient is regulated separately in a feedback system.
2. The control of glucose is regulated by the size of the glycogen stores; the size of the
fat depots, by the rate of hepatic fatty acid oxidation; and protein, by the size of the protein
depots.
3. Obesity can occur as a result of hyperphagia or from repartitioning the deposition of
nutrients. In either case, there is a relative or absolute reduction in the activitv of the
sympathetic nervous system, requiring adequate levels of circulating corticosteroids ..

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