Neuroscience & BiobehavioralReviews, Vol. 10, pp. 295-315, 1986. ©AnkhoInternationalInc. Printedin the U.S.A. 0149-7634/86$3.00 + .

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The Role of Glucose, Insulin and

Glucagon in the Regulation of
Food Intake and Body W e i g h t I
S E B A S T I A N P. G R O S S M A N

Committee on Biopsychology, The University o f Chicago, 5848 S. University Ave., Chicago, IL 60637

R e c e i v e d 4 M a r c h 1986

GROSSMAN, S. P. The role of glucose, insulin and glucagon in the regulation of food intake and body weight.
NEUROSCI BIOBEHAV REV 10(3) 295-315, 1986.--Glucose and related pancreatic hormones play a major role in the
metabolism of monogastric mammals yet their influence on hunger and/or satiety is, as yet, poorly understood. Glucose,
insulin and glucagon rise during a meal and gradually decline to baseline levels shortly after a meal. A sudden drop in
plasma glucose as well as insulinhave been reported just prior to the onset of a meal but the functional significance of this is
not yet clear. Systemic injections of glucose have no acute satiety effects but intraduodenal and intrahepatic infusions
r~duce food intake and free-feeding and deprived animals respectively. Treatments which decrease cellular glucose
utilization directly (2-DG) or indirectly (insulin) increase food intake while exogenous glucagon (which produces
hyperglycemia) decreases it. There is considerable evidence that some or all of these effects may be due to a direct central
action of glucose, 2-DG, insulin, and glucagon on brain mechanisms concerned with the regulation of hunger and satiety
although influences on peripheral "glucoreceptors" have been demonstrated as well. The functional significance of
glucoprivic feeding is, however, questioned. The feeding response to 2-DG and related compounds is capricious, and its
temporal course does not parallel the hyperglycemic reaction which presumably reflects cellular glucopenia. Moreover,
numerous brain lesions which increase, decrease, or have no effect on ad lib intake and often have no effect on the response
to deprivation have been shown to severely impair or abolish feeding responses to systemic injections of 2-DG that produce
severe central as well as peripheral glucopenia. Feeding responses to insulin are intact after most of these lesions,
suggesting that this hormone may influence food intake in a fundamentally different fashion. The mechanism of insulin
action is not understood--the classic feeding response is obtained only with doses that are pharmacological when compared
to normal plasma levels and there is increasing evidence that lower doses may have opposite, inhibitory effects on food
intake and body weight. Relatively small doses of glucagon decrease food intake (although opposite facilitatory effects have
been reported aider even smaller doses) but the effect does not appear to be due to hepatic mobilization of glucose as
initially assumed. Decreases in food intake after intracranial injections of very small doses suggest a direct central action.

Food intake Glucose Insulin Glucagon 2-Deoxy-D-glucose Glucoreceptors

ONE of the central issues in the contemporary behavioral
neurosciences is the relationship between basic biological
need states and corresponding corrective behaviors. Hunger
has served as a model of considerable heuristic value in this
field and there has been more empirical research on the
determinants of food intake than any comparable problem.
We nonetheless still do not understand the fundamental
e v e n t - - t h e translation of current energy need into the per-
ception of hunger or satiety. It is generally agreed that the
ebb and flow of nutrient ingestion, storage, and retrieval that
occurs in most species as a consequence of intermittent pat-
terns of ingestion must be monitored and evaluated in the
light of contemporary energy expenditures and the status of
various potential fuel reserves. But there is little consensus
as to the mechanisms which accomplish this feat.
J. Mayer [144,145] proposed 30 years ago that the prob-
lem might be solved, most parsimoniously, by "glucorecep-
tors" that are sensitive to their own rate of glucose utiliza-
tion. Mammalian tissues use glucose preferentially, and our
most important organ, the brain, cannot function unless at
least 30-40% of its energy needs are met by glucose. Mayer's
"glucostatic" theory is thus appealing even though most
contemporary investigators feel that other factors (such as
the quantity of fat stores, fat metabolism or energy in gen-
eral) may also influence regulatory mechanisms concerned
with food intake and/or body weight (e.g., [28, 69, 131, 166,
286]).
Mayer's proposal is supported by the fact that experi-
mental treatments which decrease glucose utilization di-
rectly (e.g., 2-deoxy-D-glucose and other nonmetabolizable
glucose analogues) or indirectly (e.g., insulin) elicit hunger in
man [82,260] and food intake in many species of experi-
mental animals [83, 107, 108, 159, 202, 203,233].
Treatments that increase glucose utilization (e.g., gluca-
gon which increases hepatic glucose output), on the other
hand, induce satiety in man [188] and reduce food intake in
experimental animals [75, 141,273].
These observations do not, however, compel acceptance
of the glucoreceptor hypothesis as Epstein, Nicolaidis and
Miselis [64] have argued cogently. Many contemporary in-

~Supported by PHS 2 S07 RR-07029-20.

295
 296
vestigators in this field are, indeed, disenchanted and dis-
satisfied with a model that has failed to produce more com-
pelling suppoi-t in spite of 30 years of intense empirical re-
search.
Some investigators in the field (e.g., [69,166]) have
suggested that a combination of (as yet unknown) peripheral
and central regulatory mechanisms may monitor available
" e n e r g y " (i.e., the total flux of metabolizable fuel) and ad-
just food intake accordingly. Others have proposed that var-
iables such as the total quantity of adipose tissue [190,291],
or the availability of free fatty acids or ketone bodies [286]
may play important regulatory influences on food intake and
body weight. As yet, none of these hypotheses has attracted
sufficiently consistent and persuasive empirical support to
warrant dismissal of the glucostatic theory.
Indeed, much relevant research has been published since
the glucostatic theory was last critically and comprehen-
sively reviewed more than a decade ago [64]. It therefore
seems appropriate, at this time, to take another look at the
role of glucostasis and related hormonal and neural proc-
esses in the genesis of hunger and satiety.
THE EBB AND FLOW OF NUTRIENTS
The principal metabolic fuels used by man and most
monogastric vertebrates are glucose, fatty acids, and ketone
bodies. Other nutrients such as lactate pyruvate and amino
acids also play a role in intermediate metabolism. The use,
storage, and subsequent distribution of these macronutrients
is tightly regulated.
Of all the metabolic fuels, glucose is used preferentially
by all tissues and exclusively (when available) by the brain.
The availability of glucose also determines, to a significant
extent, the metabolism of other fuels. This may account for
the fact that blood glucose levels are kept within surprisingly
narrow limits under a wide range of nutritional conditions.
When blood glucose levels rise after a carbohydrate-
containing meal, the excess is rapidly sequestered as glyco-
gen in liver and muscle and as triglycerides in adipose tissue.
When blood glucose levels fall between meals, the liver re-
supplies the organism directly from hepatic glycogenstores
and indirectly by gluconeogenesis, using amino acids,
glycerol, lactate and pyruvate.
During long-term starvation, the brain adjusts by using
ketone bodies (acetoacetate and beta-hydroxy-butyrate) for
as much as 50-60% of its energy requirements [182,183].
Ketone body utilization by brain is nonetheless not likely to
be a factor in the normal regulation of meal size and inter-
meal interval because the shift to ketones occurs only after
prolonged deprivation and requires extensive exposure to
substrate [40, 78, 79, 158]. (This should also be considered in
the interpretation of the results of experiments attempting to
demonstrate the efficacy (or lack thereof) of alternate
"brainfuels" in reducing food intake, glucopenia, etc.)
Starvation also causes the kidney to increase
gluconeogenesis to the point where it may account for nearly
half of the endogenously derived glucose.
The major storage site for metabolic fuels is adipose tis-
sue. During and shortly after a meal, fat cells remove fatty
acids and their substrates from the circulation and store them
in the form of triglycerides. When energy demands exceed
availability, during a fast, adipose tissue breaks down the
stored triglycerides and releases fatty acids and glycerol into
the circulation.
GROSSMAN
Hormonal Regulation
The utilization, storage and retrieval of glucose and other
nutrients is determined by availabilit (i.e., ingestion in re-
sponse to some need signal, or recruitment from existing
body stores) and by the interplay of several hormones. The
most important of these are insulin, secreted by the pancre-
atic beta cells; glueagon, secreted by the alpha cells of the
pancreas; somatostatin, released by pancreatic delta cells as
well as neurons of the hypothalamus; growth hormone from
the pituitary; and epinephrine and norepinephrine from the
adrenal medulla. The rate of release of these hormones is
directly and/or indirectly affected by blood levels of nutri-
ents, particularly glucose.
The secretory cells of the pancreas receive information
about the composition and quantity of a meal prior to the
absorption of nutrients from a variety of intestinal hormones
such as cholecystokinin (CCK), secretin, enteroglucagon,
vasoactive intestinal peptide, gastro-inhibitory peptide,
motilin and bombesin [61,247,265-267].
The secretion of insulin, glucagon and growth hormone
are also affected by neural inputs of hypothalamic origin
which are carried by vagal afferents (in the case of insulin) or
splanchnic nerves (in the case of glucagon) [70-73, 98, 242,
243,287].
The secretory activity of the pancreas is significantly
modulated by the direct, local interaction of its principal
hormones. Insulin inhibits the secretion of glucagon by the
pancreatic alpha cells while glucagon promotes insulin and
somatostatin release. Somatostatin, in turn, inhibits both in-
sulin and glucagon [6]. These " p a r a c r i n e " effects of the pan-
creatic hormones appear to fine-tune the pancreatic control
of blood glucose and, in general nutrient utilization, storage
and retrieval [21].
Pre-absorptive phase. The sight, smell, and taste of food
trigger a " c e p h a l i c " (centrally mediated) neural reflex which
results in the release of a considerable amount of insulin as
well as glucagon during the first minute of a meal [49, 132,
133,241,243, 251]. This pre-absorptive insulin and glucagon
release reaches a peak within a few minutes and declines to
baseline levels unless the animal ingests a significant amount
of food. The magnitude of the pre-absorptive insulin release
has been shown to be positively correlated with the palata-
bility of the available food as well as the size of the subse-
quent meal (the latter may, of course, be causally related to
palatability rather than insulin release per se) [135].
Steffens [242,243] has suggested that the anticipatory re-
lease of insulin and glucagon may serve to prepare the liver
for the arrival of nutrients from the gut, thus attenuating the
post-absorptive release of glucose and insulin. Such an in-
terpretation is supported by Shimazu's [225,226] report that
electrical stimulation of the lateral hypothalamus activates
liver mechanisms which convert glucose into glycogen
whereas stimulation of the ventromedial hypothalamus ac-
tivates liver mechanisms that convert glycogen into glucose.
The early, cephalic release of insulin in response to food-
related stimuli is prevented by vagotomy or systemic injec-
tions of atropine [132,133] indicating that it is mediated by
vagal efferents that act on cholinergic receptor cells. The
central representation of this system in the hypothalamus, on
the other hand, appears to be noradrenergic since microin-
jections of norepinephrine into the lateral hypothalamus
elicit a sustained release of insulin [49,243]. That the neural
influence on insulin secretion is mainly due to activation of
components of the vagus is further indicated by the fact that
G L U C O S E AND F E E D I N G
electrical stimulation of the caudal end of a transected vagus
nerve elicits insulin secretion in a variety of species [44, 73,
117, 118].
Glucagon release, on the other hand, appears to be prin-
cipally sensitive to neural inputs from the splanchnic nerve
(as well as increases in systemic catecholamine levels) [70].
Electrical stimulation of the splanchnic nerve releases gluca-
gon from the pancreas [24,156] and comparable effects are
obtained by systemic injections of epinephrine (E) or norepi-
nephrine (NE) [77]. In both cases, insulin levels are reduced.
The central origin of this aspect of control over pancreatic
secretory activity appears to reside in the ventromedial
hypothalamus since microinjections of norepinephrine into
this structure provoke glucagon release [49, 242-244].
Although the distinction between glucagon and insulin re-
lease in terms of sympathetic and parasympathetic control
is, in general, a valid one, the two branches of the autonomic
nervous system interact to a considerable extent so that
vagal stimulation can release glucagon as well as insulin [118]
and vagotomy may abolish the normal, glucagon-induced
suppression of feeding [142]. Conversely, the insulin secret-
ing beta cells of the pancreas have been shown to be sensi-
tive to catecholamines [189,191].
Absorptive phase. The arrival of nutrients in the stomach
and duodenum results in the release of a number of "gut
hormones" (e.g., cholecystokinin, gastrin, secretin) which
act on the pancreas to promote a second and far larger re-
lease of insulin that begins within a few minutes after the first
bite and peaks, in the rat, about 45 min after the onset of the
meal (i.e., quite some time after the rat has ceased feeding).
Insulin levels then decline, rapidly at first, to baseline levels
which remain essentially constant until the next meal [240,
251,254]. Blood glucose follows a similar time course [165,
238, 240].
During and after a carbohydrate containing meal, when
blood levels of glucose are high, the pancreas releases a
mixture of hormones that is high in insulin and low in gluca-
gon and somatostatin. Insulin is essential for the metabolism
of nutrients during the absorptive phase of digestion because
without insulin glucose cannot enter the cells of most tissues
of the organism (the brain and liver being the principal ex-
ceptions). Insulin also facilitates the conversion of glucose to
glycogen or fat (thus promoting the storage of nutrients that
are not required for current metabolic activity) and facilitates
the transport of amino acids into cells [259].
Post-absorptive phase. As long as the available energy
stores permit the maintenance of blood glucose above a
rather narrow range (75-100 mg/dl in the rat), insulin is re-
leased at a fairly low and steady rate [240,254]. When blood
glucose falls significantly below this level during periods of
food deprivation, the flow of insulin declines and glucagon
and somatostatin begin to be released in increasing quantities
[21,193].
In the post-absorptive phase when the nutrients from the
last meal have been used or stored, the pancreas releases a
mixture of hormones that is relatively low in insulin and high
in glucagon. This hormonal profile (supported by increased
release, of adrenal glucocorticoids and catecholamines) pro-
motes the release of glycogen and fats from storage and re-
sults in gluconeogenesis. It also results in increased produc-
tion of glycerol, free fatty acids and ketones [36, 65,102, 266,
267].
Glucagon is the principal hormone of catabolic metabo-
lism because it (along with growth hormone) promotes the
conversion of liver glycogen to glucose and facilitates the
297
production of free fatty acids, glycerol and ketones which
most tissues can metabolize in place of glucose [193, 266,
267].
Somatostatin exerts its influence on catabolic metabolism
at several levels: (a) in the gastrointestinal tract, where it
inhibits gastric acid and gastrin secretion as well as gastroin-
testinal motility thus decreasing nutrient absorption; (b) in
the hypothalamus where it provides an inhibitory influence
on growth hormone and thyrotropin release by the pituitary;
and (c) in the delta cells of the pancreas which release
somatostatin in response to decreasing concentrations of
blood glucose and other nutrients [6, 221,222].
GLUCOSTATIC THEORIES OF HUNGER AND/OR SATIETY
As we have seen, the utilization, storage and retrieval of
nutrients is under tight hormonal control. But how does the
organism regulate the essential periodic re-supply of nutri-
ents so as to avoid starvation or excessive storage? How do
we know when and how much to eat?
Glucose is the exclusive substrate of brain cell metabo-
lism under normal circumstances, and blood glucose levels
are tightly regulated. The brain can cover a significant per-
centage (50-60%) of its energy needs with ketone bodies dur-
ing periods of prolonged starvation [68, 182, 183] but there is
considerable evidence that the transport of ketones into
brain is quite slow and may require induction by prolonged
exposure of substrate [40, 78, 79, 158]. It thus seems likely
that ketones cannot nourish the brain during acute
glucopenia, forcing it to rely mainly on glucose except under
extreme conditions.
In the rat, blood glucose remains in a range of 75-100
mg/dl under ad lib feeding conditions [238, 240]. At concen-
trations below 50 mg/dl the brain cannot extract enough glu-
cose from blood to cover routine metabolic needs and there
is some evidence that blood glucose levels of 200 mg/dl and
above can produce tissue damage [269].
In view of the significance of glucose for normal brain
functions and the pervasive role of glucose in all phases of
metabolic activity it is tempting to suggest that a measure of
the availability or rate of utilization of this important fuel
would provide the most useful index of the organism's ever-
changing fuel needs.
J. Mayer formally postulated such a glucostatic theory of
hunger more than 30 years ago. It proposed, in essence, that
the organism's energy needs are monitored by special
"glucoreceptors" which are sensitive to their own rate of
glucose utilization and directly affect hunger-related brain
mechanisms accordingly [144,145].
In the context of current controversies, it is important to
remember that Mayer did not deny the potential importance
of other metabolic variables and did, indeed, suggest that
while glucostatic mechanisms might regulate meal size and
intermeal interval in the short term, "lipostatic" signals, re-
lated to the state of the body's adipose tissue might well
provide overriding signals that control body size in the long-
term.
Since the brain uses glucose exclusively except after pro-
longed food deprivation Mayer suggested that the
glucoreceptors might be located in the brain, most likely in
the ventromedial hypothalamus which contemporary inves-
tigations implicated in the control of satiety and body weight
regulation [30,101].
 298
Russek [207-211] has proposed a glucostatic theory of
hunger and satiety which postulates receptor cells in the
liver. According to Russek, pre-absorptive satiety is due to
the activation of chemoreceptors in the gut which hyper-
polarize liver glucoreceptors via sympathetic nerves. Post-
absorptive satiety, according to this " h e p a t o s t a t i c " theory,
is due to a direct action of glucose on the liver receptors.
The liver is a likely place for feeding-related glucorecep-
tots because it is a major storage depot for glucose (in the
form of liver glycogen) which can be readily used under the
influence of pancreatic glucagon. Nerve cells which appear
to be uniquely sensitive to glucose have been found in the
liver [168] and there is evidence that these cells communicate
with feeding-related portions of the hypothalamus via the
hepatic branch of the vagus nerve [169, 218,227]. Russek's
interpretation receives support from the fact that electrical
blockade of vagal activity inhibits feeding in hungry dogs
[207], whereas electrical stimulation of the vagus elicits feed-
ing [187] as well as insulin secretion [73,287]. That the vagus
carries information about systemic glucose availability
and/or utilization is further indicated by the fact that vagot-
omy attenuates the feeding response to 2-deoxy-D-glucose
(see below). Russek and associates [200, 208,214] have also
shown that intraportal injections of glucose produce
anorexia in hungry animals while systemic injections of
comparable quantities had no effect. Russek and Stevenson
[212] further supported the notion of liver glucoreceptors by
demonstrating a strong negative correlation between food
intake and the concentration of hepatic reducing sugars.
Although there is considerable support for the notion that
liver glucoreceptors may play a significant role in the regula-
tion of hunger and/or satiety, they may not be an essential
component of the neural control of hunger and/or satiety
since total liver denervation has been reported not to affect
food intake or body weight regulation in the dog [18] or rat
[16], even when a detailed analysis is made of meal-size and
intermeal interval ([20,136], but see [211]).
Even human and animal recipients of liver transplants
show no persistent deficits in food intake and weight regula-
tion [114,237].
As we will discuss in more detail below, liver denervation
also does not significantly alter the feeding response to
glucoprivic challenges such as insulin or 2-DG [17,261,263].
Novin [171,172] has suggested that liver glucoreceptors
may play a role in satiety only when an animal feeds after
prolonged deprivation while glucoreceptors in the gut may
be responsible for satiety when food is available ad lib. The
theory relies on the fact that the ingestion of glucose causes
the release of glucagon. In the freefeeding animal which has
high glycogen reserves, this can directly increase cellular
glucose levels. In the starved animal, liver glycogen stores
are low and this mechanism is not effective. Instead, glucose
must reach the liver in significant quantities and the arrival of
glucose in the liver becomes part of the satiety signal.
Novin's theory is based on the observation [174,272] that
intraportal infusions of glucose reduce food intake in 22 hour
deprived rabbits but not in freefeeding rabbits while
intraduodenal infusions of glucose significantly reduce the
food intake of freefeeding animals but have no effect in 22
hour deprived rabbits. These observations may explain why
some investigators [58] have reported that intragastric or
intraduodenal infusions of glucose do not reduce food intake
in deprived animals while others [27,297] report positive ef-
fects.
GROSSMAN
BLOOD GLUCOSE, GLUCOSE UTILIZATION,AND HUNGER
Arterio-Venous Glucose DifJ~,rences
Much of the early empirical work in this field was de-
signed to relate hunger and/or food intake to measures of
glucose utilization such as arterio-venous (A/V) differences
in glucose levels. Although some of the early clinical reports
[144,278] were encouraging, subsequent experimental work
has generally failed to demonstrate significant correlations
between A/V glucose differences and hunger and food con-
sumption in man [74, 192,201].
Because A/V differences were an important component of
the early writings about the glucostatic theory, the failure to
find consistent effects continues to be cited as evidence
against the theory. It is only fair to point out, however, that
at any point in time, the rate of glucose utilization varies
greatly in different parts of the organism as well as within
individual organs. Crude estimates of total body- or whole
brain-glucose utilization could thus not be expected to detect
even major changes in glucose uptake in small populations of
cells such as the hypothesized glucoreceptors in the ven-
tromedial hypothalamus (or elsewhere).
Plasma Levels o f Glucose andh~r Insulin
Most investigators have failed to find a significant rela-
tionship between plasma glucose or insulin (the two varia-
bles that primarily control glucose utilization) and the pat-
tern of food intake (i.e., meal-onset, -duration and intermeal
interval) (e.g., [238,240, 252, 254]). Glucose levels are typi-
cally steady during the intermeal interval [238,252] although
a sudden drop has been reported when a meal was prevented
[238]. Plasma insulin falls more gradually from its prandial
elevation [240] and a significant decrease in plasma insulin
levels (which may result in lowered glucose utilization) has
been observed five minutes before the onset of a meal [254].
Two recent investigations, using on-line continuous
measures of blood sugar [37,134] have shown that a small
(6-11%) and brief drop in blood glucose may occur just prior
to the onset of a meal. LeMagnen [130] has suggested that
this may be a critical signal for feeding in the rat but the
extensive peer commentary on this article suggests that
many investigators in this field are not willing to infer caus-
ality from these correlative data. Campfield et al. [37] have,
however, recently provided some data which argue in favor
of LeMagnen's hypothesis. When a glucose infusion de-
signed to compensate for the pre-meal drop was adminis-
tered when blood glucose began to drop at the expected time
of a new meal, the latency to the anticipated next meal was
markedly increased.
An interpretation of the observed pre-meal drop in blood
glucose is further complicated because its magnitude appears
quite small when compared to the enormously elevated
levels seen after glucose injections that do not affect feeding
[252] or to the size of the glucose drop seen after insulin
injections that are minimally effective in increasing food in-
take [239]. Further research is clearly needed to elucidate the
functional significance of the slight rise in blood glucose that
does appear to precede the onset of a meal in the rat.
Systemic Glucose Infusions
Attempts to induce satiety by intravenous infusions of
glucose have not met with success. Some early investigators
[146] reported significant effects but others [111,112], includ-
GLUCOSE AND FEEDING
ing a number of recent studies [18, 245, 252] consistently
report that infusions which increase blood glucose levels far
beyond the levels normally attained during a carbohydrate-
rich meal fail to reduce food intake in a variety of species
unless large, calorically significant amounts are infused.
EXPERIMENTALMANIPULATIONSOF GLUCOSEUTILIZATION
A vast body of empirical research has shown unequivo-
cally that experimental treatments which result in central
and/or peripheral glucoprivation provide a reliable stimulus
for hunger and food intake. However, the results of recent
experiments (to be discussed in detail below) suggest that the
ability to respond to experimentally-induced glucoprivation
may not be essential for the meal-to-meal or day-to-day regu-
lation of food intake and body weight. Moreover, it has been
argued [64,69] that increased eating during glucopenia does
not, by itself, constitute a convincing case for glucostatic
regulation of hunger because a variety of non-specific
metabolic events (which might themselves be "metered")
occur during glucoprivation.
Increased Feeding After Insulin
The principal clinical and experimental observation that
led to the postulation of the glucostatic theory is the fact that
the administration of large doses of exogenous insulin elicits
hunger sensations and eating in man [82] and feeding in every
monogastric species tested to-date including dogs [83], cats
[203], rats [137,159], hamsters [52, 53,194], gerbils [202] and
mice [206].
The stimulatory effects of insulin on food intake are de-
layed by about 30--90 rain in most species but even longer in
others such as hamsters. During this initial period, insulin
promotes the rapid uptake of glucose from extracellular fluid.
Eventually, this produces hypoglycemia which, in turn,
causes cellular glucoprivation. According to the glucostatic
theory, it is this reduced cellular utilization of glucose which
gives rise to the sensation of hunger. The alternative hypoth-
esis that the hypothesized glucoreceptors might be sensitive
to the absolute level of glucose in the blood was rejected by
Mayer because hunger coexists with high blood glucose
levels (but low utilization because of insufficient insulin) in
patients afflicted with diabetes rnellitus.
A detailed analysis of the time course of the metabolic
and behavioral effects of exogenous insulin in the rat [239]
has shown that single injections of insulin sharply reduce
blood glucose to a low level of about 50 mg/dl within a few
minutes of the injection but do not elicit feeding until about
30--60 min later. In the hamster, the normal pattern of nearly
constant nibbling delays the blood glucose fall until about 2
hours after exogenous insulin and significant increases in
food intake occur as late as 3 hours after the injection
[52,53]. The puzzling delay of the feeding response to single
injections of insulin may simply be due to the fact that signif-
icant cellular glucopenia develops only after the observed
delays [130]. Steffens [239] has suggested that the delay may
be further prolonged because the sudden induction of hypo-
glycemia may release epinephrine which may act as a tran-
sient satiety signal [214].
Continuous intravenous (IV) infusions of large doses of
insulin result in a significant increase in the number of meals
consumed (their size is affected little or not at all) because
the animals (rats) initiate meals promptly whenever blood
glucose levels fall to 50 mg/dl [239].
299
Slow IV infusions of very low doses of insulin, on the
other hand, have been reported to reduce rather than
enhance food intake and body weight in the rat [274]. A
failure to replicate this potentially important observation has
been noted [131] but inhibitory effects on sham-feeding have
recently been reported even after single small doses of
short-acting insulin [176]. It is possible that this apparently
paradoxical inhibitory effect of insulin might be related to a
direct central action of insulin, to be discussed below.
The feeding response to exogenous insulin appears to be
independent of parasympathetic or sympathetic feedback
since neither vagotomy [82, 83,261,263] nor surgical [83] or
chemical [264] sympathectomy significantly impair the ef-
fectiveness of insulin.
Just where and how insulin exerts its effects on food in-
take has been the subject of debate. Infusions of glucose
prior or during the insulin injection prevent feeding but so do
manose, ketone bodies and, at least at low doses of insulin,
fructose which cannot nourish brain [204, 248, 250]. These
findings argue for a peripheral site of action although the
observed pattern of effects clearly does not exclude the
possibility that insulin may have feeding-related central as
well as peripheral sites of action. Indeed, it is possible that in
these studies, the availability of alternate fuels to peripheral
tissues might free sufficient glucose to ameliorate brain
glucopenia secondarily.
The Satiety Effect of Glucagon
The second major pancreatic hormone, glucagon, has
been shown to decrease food intake in man [188,220], rat [48,
75, 76, 141,142], rabbit [273], and dog [213]. Intraperitoneal
injections of antibodies to glucagon conversely have been
shown to increase food intake in rats [122].
Glucagon stimulates hepatic glucose output via
glycogenolysis, decreased glycogen synthesis and
gluconeogenesis. The suppressive effect of glucagon is
prominent only in free-feeding or mildly deprived animals
[142, 217, 273] possibly because longer periods of depriva-
tion deplete liver glycogen stores.
The apparent dependence of the suppressive effects of
glucagon on liver glycogen stores suggests that it may not,
under normal circumstances, play a major role as a 'satiety
hormone.' However, its explosive release during the first
minutes of a meal [251] and the fact that it appears to
lengthen intermeal intervals when administered in large
doses [11] suggests that it may play an as yet poorly under-
stood role in the regulation of food intake and body weight.
That the mode of action of this hormone may be far more
complex than anticipated is suggested by a recent report of
increased food intake (in the presence of significant
hyperglycemia) following IP injections of very low doses of
glucagon [97].
The effect of glucagon on food intake is abolished by
vagotomy in rats [76, 141, 142] as well as rabbits [273].
Splanchnicectomy but not vagotomy abolishes the release of
glucagon due to electrical stimulation of the lateral hypothal-
amus [98].
Effects of Nonmetabolizable Glucose Analogues
2-Deoxy-D-glucose. The glucostatic theory (as well as the
more modest hypothesis that glucoprivation induces hunger)
appeared handsomely supported when Smith and Epstein
[233] reported in 1969 that systemic injections of the glucose
 3O0
analogue 2-deoxy-D-glucose (2-DG) elicit feeding in sated
rats and monkeys.
2-Deoxy-D-glucose is a structural analogue of glucose
which inhibits intracellular glucose utilization in brain, liver,
and other tissues [32]. The effect of 2-DG is not uniform,
glucose utifization being decreased more in brain than in
striated muscle [32].
2-DG stimulates the release of epinephrine from the ad-
renal medulla and promotes hepatic glycogenolysis and
gluconeogenesis [32]. The adrenal response to 2-DG results
in severe hyperglycemia [103] accompanied by overt symp-
toms of hypoglycemia due to reduced cellular utilization
[123]. The hyperglycemia can be prevented by adrenalec-
tomy [235].
2-DG also inhibits insulin secretion [121,191] and releases
free fatty acids from adipose tissue, thus reducing glucose
uptake by fat and muscle cells. This alters the normal distri-
bution of glucose so that more of it is available to the brain.
Feeding during 2-DG-induced glucoprivation not only pro-
vides exogenous glucose from the ingested foods but also
tends to normalize the distribution of glucose because insulin
secretion is stimulated [234].
Although it is generally assumed that the feeding response
to 2-DG reflects cellular glucoprivation, the relationship be-
tween feeding, blood glucose levels and cellular glucopriva-
tion is, as yet, poorly understood. The first report of 2-DG
feeding in the rat [233] describes such classic signs of central
glucoprivation as stupor and ataxia within minutes after the
injection of 2-DG, yet feeding occurred only after a delay of
124 min on the average (the range extended from 24 to 360
min). Blood glucose levels were highest in this experiment 60
min after the injection of 2-DG (no earlier samples were
taken). A comparison of the blood glucose levels of 4 rats
that were allowed to eat and those of 6 others that were
deprived after the injection of 2-DG failed to show significant
effects of the food ingested during the first 6 hours after
2-DG. The same report describes data from one monkey that
did not eat after 300 mg/kg of 2-DG even though blood glu-
cose was severely elevated as in other monkeys that did
increase their food intake two- to fourfold over saline control
levels.
A later report [235] describes large and reliable increases
in blood glucose after 100,200, and 400 mg/kg of 2-DG but no
reliable increases in food intake in most of the rats tested. In
monkeys, blood glucose was significantly elevated 5, 15, and
30 min after injections of 80 or 100 mg/kg of 2-DG but reliable
feeding responses were obtained only with 320 mg/kg.
More recently, significant feeding responses to systemic
as well as intracerebroventricular (ICV) injections of 2-DG
have been observed at a time (6-8 hours after the 2-DG in-
jection) when blood glucose levels had returned to normal
[196]. Further research from this laboratory [170] has shown
that 6 hours after 2-DG two measures of glucose uptake and
utilization (glucose oxidation and uptake of C-14 labelled
2-DG in brain) were significantly affected during the first 1.5
or 3.5 hours after 2-DG but not 6-7 hours after the injection
when rats displayed significant eating in the previous exper-
iment. These results suggest that the feeding response to
2-DG may reflect a metabolic event that persists after cellu-
lar glucoprivation has abated.
This conclusion is supported by the results of an earlier
experiment [67] which demonstrated that the hyperglycemic
response to intracerebroventricular injections of 2-DG was
suppressed by fumarate and glutamate as well as pyruvate
and d-fructose but not by d-xylose, d-ribose or aceto-acetate
GROSSMAN
or hydroxybutyrate ~the latter actually potentiated the
hyperglycemia significantly). The authors of this report
concluded that the brain cells believed to be responsible for
the 2-DG induced hyperglycemia may not be specifically re-
sponsive to glucose or glycoprivation but react, instead, to
changes in the rate of oxydative metabolism. Several inves-
tigators (e.g., [68,69]) have supported such an interpretation.
The feeding response to 2-DG appears to be permissive
and not essential for survival. It differs in this important
respect from the feeding response to exogenous insulin
which appears to be essential to survival in monogastric ver-
tebrates. (Ruminants such as goats and sheep fail to increase
feed ingestion to exogenous insulin and do not respond to
IV or intragastric infusions of glucose [7-9, 41, 104, 138]).
Although 2-DG is a potent stimulus for eating in man
[260], monkeys [233-235], cats ([203], but see also [110]),
rats [233,235], rabbits [108], house mice [206], goats and
sheep [107], some species such as hamsters [194, 202,230],
deermice [206], and gerbils [202] which increase food intake
in response to exogenous insulin, do not feed in response to
2-DG, even though significant hyperglycemia develops.
Moreover, even in species which do, generally display
significant feeding responses to 2-DG, the response of indi-
viduals is often unpredictable. It is not at all uncommon to
find individual animals that do not eat in response to a wide
range of doses of 2-DG even though they become severely
hyperglycemic and display overt signs of central glucopriva-
tion (see, for instance, [235]).
The feeding response to 2-DG is also highly dependent
upon the palatability of the diet, being blocked by the addi-
tion of small doses of quinine to the diet which do not inter-
fere with ad lib intake [I 15,279], and enhanced when a palat-
able high-fat diet is offered [298].
We might note here that 2-DG does not increase and may
even depress food intake in deprived animals [108, 113,235].
Jones and Booth [113] found that 2-DG increased food intake
in deprived animals if glucose had been administered within
2 hours of the 2-DG injections. The authors suggested, on the
basis of this information, that 2-DG might increase food in-
take in free feeding animals by blocking the satiating conse-
quences of glucose absorption.
The efficacy of ICV 2-DG injections at doses far smaller
than those effective in the periphery (below) clearly implies a
central site of action. This widely accepted interpretation is
supported by the observation that 2-DG feeding is blocked
by infusions of glucose but not fructose (which cannot re-
verse glucopenia in brain tissue) [248]. Infusions of ketone
bodies which should not reverse brain glucopenia acutely,
apparently do not suppress 2-DG feeding [205], although
positive effects have been reported in an earlier publication
[248].
The feeding response to 2-DG is attenuated, but not
abolished by complete subdiaphragmatic vagotomy [26,173],
suggesting that it may affect peripheral as well as central
glucoreceptors. In the rabbit, the liver, in particular, appears
to be implicated by the observation that intrahepatic portal
infusions of 2-DG produce more feeding more rapidly than
comparable intrajugular injections [173,219]. In the rat, the
two infusion sites are equally effective [248]. Selective hepa-
tic vagotomy does not reduce the feeding response to 2-DG
in rats even when combined with celiac vagotomy or a more
extensive denervation of the stomach and duodenum
[261,263]. Intact feeding responses to 2-DG have even been
reported after complete denervation of the liver [17].
Surgical visceral sympathectomy reduced the feeding re-
GLUCOSE AND FEEDING
sponse of the rabbit to intraportal 2-DG but actually in-
creased food intake after intrajugular injections [219]. Chem-
ical (i.e., guanethidine-induced) sympathectomy attenuated
the feeding response to intraperitoneal 2-DG (but not insulin)
in the rat [264].
It is interesting to note in this context that intracerebro-
ventricular injections of very small quantities of alloxan
block the feeding response to systemic 2-DG but not the
hyperglycemic reaction to it [199,292].
Other glucose analogues. In order to shed more light on
the cellular mechanisms that are responsible for the effects
of 2-DG on feeding and glucostasis, other glucose analogues
have been tested. There is some controversy about the effec-
tiveness of 3-O-methyl glucose (3-O-MG), a glucose
analogue that freely enters cells but is not metabolized. At
high concentrations, 3-O-MG competes for the transport
mechanisms of d-glucose in cell membranes.
3-O-MG elicits gastric acid secretion [39], and produces
hyperglycemia [103] but affects food intake only slightly
even when extremely high doses are used [26,64]. Since
3-O-MG, unlike 2-DG, is not metabolized, it passes rapidly
out of cells so that its intracellular concentration is far lower
than that of 2-DG after injections of equimolar doses.
Whether this explains the weak feeding response to 3-O-MG
is not clear.
5-Thio-D-glucose (5-TG) is a glucose analogue in which
sulfur is substituted for the pyranose ring oxygen [66]. Very
low doses of this compound, administered intravenously,
have recently been shown to elicit dose-dependent increases
in food intake and blood glucose concentration in the rat
[195]. In other species, such as hamsters, which do not feed
in response to 2-DG, 5-TG elicits hyperglycemia but fails to
increase food intake reliably [51,54].
T H E R O L E O F T H E C E N T R A L N E R V O U S SYSTEM
Effects of lntracerebroventricular (ICV) Injections
2-Deoxy-D-glucose and other glucose analogues. The
hypothesis that central glucoreceptors may play a significant
role in hunger and/or satiety is supported by the results of
experiments that have demonstrated feeding as well as
hyperglycemia and hypothermia after intracerebroventricu-
lar injections of doses of 2-DG that were smaller, often by
nearly an order of magnitude, than those needed to produce
feeding when administered systemically.
Miselis and Epstein [157] have reported significant feed-
ing after ICV injections of 2.9 to 5.0 rag/rat, the magnitude of
the effect being comparable to that elicited by systemic in-
jections of far larger doses of 2-DG (2.5-2.7 g over saline
baseline). Eating began after 6-53 minutes and was com-
pleted, usually as a single meal, no later than 1.5 hours after
the injection. Control injections of d-glucose or sucrose did
not affect food intake. The ICV injections of 2-DG also
produced symptoms of central glucopenia such as ataxia and
stupor that are typically seen after much larger doses of
2-DG given systemically.
Mueller and associates [67, 160, 162] have shown that
ICV injections of 1.0 to 5.0 mg/rat of 2-DG resulted in signifi-
cant hyperglycemia and concomitant fall in body tempera-
ture. Both effects peaked 60 minutes after the injection and
gradually disappeared in the course of the following 120 to
180 minutes. Even small doses (0.06 to 0.5 mg/animal) elic-
ited significant and persisting hyperglycemia in mice. The
effects of ICV 2-DG on blood glucose was significantly di-
minished but not abolished entirely when 2-DG was adminis-
301
tered to mice pretreated 6 days earlier with gold thioglucose.
Mueller and associates [161] have implicated central
alpha-adrenergic pathways in the mediation of 2-DG feeding.
ICV injections of alpha-adrenergic blockers such as phen-
tolamine and azapetine in doses (50-100/xg/rat) that did not
affect ad lib food intake, reliably reduced the feeding effect
of a large (750 mg/kg) systemic injection of 2-DG, ICV injec-
tions of beta-adrenergic blockers such as propranolol or MJ
1999 in comparable doses did not interfere with 2-DG eating.
Inhibitory effects were obtained by systemic pretreatments
with 50 mg/kg of the catecholamine synthesis blocker
alpha-methyl-p-tyrosine and by repeated ICV injections of the
catecholamine neurotoxin 6-hydroxy-dopamine, adminis-
tered 12 days before the 2-DG test.
Viewed in conjunction with Miselis and Epstein's [157]
observation that ICV 2-DG reliably elicits feeding, these ex-
periments leave little doubt that all three of the principal
effects of 2-DG (hyperglycemia, hypothermia, and increased
food intake) can be produced by central injections.
Another nonmetabolizable glucose analogue,
5-thioglucose (5-TG) administered intracerebroventricularly
(as well as intravenously) has been reported to be an even
more potent stimulus for feeding and hyperglycemia than
2-DG [195,231].
The feeding response to ICV 5-thioglucose is severely
impaired by microinjections of very small quantities (200/zg)
of alloxan (a toxin which selectively destroys pancreatic beta
cells) into the fourth ventricle [163]. ICV alloxan did not, in
this experiment, block the hyperglycemic response to ICV
5-TG.
Insulin. Brain metabolism is, in general, insulin inde-
pendent and the hormone does not readily cross the blood-
brain barrier except at a few circumventricular 'windows' in
the brainstem. However, specific insulin receptors have
been demonstrated in brain parenchyma [96, 275-277],
especially in portions of the ventromedial hypothalamus
[276] that are readily accessed by systemic insulin. Elec-
trophysiological responses to iontophoretically applied insu-
lin have been reported from medial as well as lateral hypo-
thalamus [178-180] (see section on hypothalamus, below, for
detail).
LeMagnen [130] has suggested that insulin-sensitive
glucoreceptors in the ventromedial hypothalamus control the
diurnal rhythm of alternating lipogenesis (during the dark
portion of the cycle in the rat) and lipolysis. If these insulin
receptors are "downregulated" like insulin receptors on
adipocytes and other tissues, a persistent hyperinsulinemia
(such as one finds during the night when the rat ingests most
of its food) will reduce the density and affinity of the insulin
receptors and thus sensitize the glucoreceptors to
glucopenia. This is thought to provide the signal for neurally
induced lipolysis. Upregulation of the insulin receptors dur-
ing the light portion of the diurnal cycle (when rats feed
little), on the other hand, would desensitize the glucorecep-
tors and give rise to lipogenesis.
Woods and Porte [190, 289, 292] have suggested that the
long-term regulation of body weight might depend on brain-
insulin receptors which are sensitive to the concentration of
insulin in cerebrospinal fluid (CSF). The hypothesis is based
on the fact that CSF insulin levels are proportional to body
fat content both within and between individuals [22, 183,
293] and the observation that insulin is transported from
blood to CSF, the rate of exchange being sufficient that CSF
insulin tends to be proportional to basal plasma levels (with-
out, however, being subject to the rapid fluctuations that
302
occur during and immediately after a meal) [183,288, 290].
Intracisternal or intracerebroventricular infusions of in-
sulin have been shown to modify plasma glucose and insulin
levels in the dog [38,288].
Small doses of insulin (4.2 /zU/hour) infused ICV con-
tinuously for 20 days have been reported to decrease food
intake and body weight in baboons without affecting plasma
glucose or insulin levels. The effects of these chronic infu-
sions were not very large (the average weight loss over the 20
day experiment did not exceed 0.75 kg) but the effect ap-
peared to be repeatable [294]. Small but statistically reliable
decreases in food intake and body weight have also been
reported, more recently, after chronic infusions of 7.5 or 10
mU per day of insulin into the third ventricle of the rat [29].
It is interesting to recall in this context that Vander-Weele
et al. [274] have reported that insulin administered slowly
and continuously into the peritoneal cavity by means of an
osmotic 'minipump' also decreased food intake by reducing
meal size and limiting weight gain.
Walls and Wishart [282], on the other hand, have reported
that a single ICV injection of 600 mU of insulin into the third
ventricle increased the food intake of 21 hour deprived rats.
The effect was not affected by ICV injections of the glucose
uptake blocker phlorizin but was reduced by the alpha-
adrenergic blocker phentolamine (15 mg/rat), and blocked
completely by the beta-adrenergic blocker propranolol (60
mg/rat).
Glucagon. Injections of very low doses of glucagon (5-25
ng) into the third ventricle of rats have recently been re-
ported [109] to suppress food intake with a relative potency
that was more than 1000 times greater than that of systemi-
cally administered glucagon. Similar ICV infusions have
been shown [ 143] to produce persisting hyperglycemia which
might be responsible for the suppressive effects on food in-
take. The effect of ICV glucagon on blood glucose was
blocked by systemic injections of atropine or phentolamine
(but not the beta-adrenergic blocker propranolol). These re-
cent findings contradict several earlier reports. Herberg [99]
failed to observe reliable effects on food intake in the rat with
ICV injections of up to 1 /zg/kg. Woods et al. [294] did not
observe significant effects on food intake or body weight
after slow and long-continued infusions of 2.35 ng/kg/day in
the baboon.
Sugar acids. Recently two short-chain sugar acids have
been identified in the blood of fasted rats [216]. When the
first of these, 2-deoxytetronic acid (DTA), is injected into the
third ventricle of rats in small quantities (2.5 /xmol), food
intake and neuronal activity in the lateral hypothalamus are
suppressed [229]. When a comparable dose of the second
sugar acid (3-deoxypentonic acid or 3-DPA) is infused via the
same route, feeding is elicited and lateral hypothalamic
neuron activity increased [228].
lntrahypothalamic Injections o f Glucose and Glucose
Analogues
Most investigators have been unable to modify food in-
take by intrahypothalamic injections of glucose [62, 88, 157,
281].
The main exception is a report by Balagura and Kanner
[10] which describes very small but statistically significant
effects of intrahypothalamic placements of glucose or 2-DG
in crystalline form. In free feeding rats, glucose as well as
2-DG increased food intake during a 30 rain test when
applied to the lateral hypothalamus. Both compounds also
GROSSMAN
increased the food intake of deprived animals when applied
to the dorsomedial hypothalamus. In both cases, the abso-
lute magnitude of the effects was very small and attempts to
replicate these potentially interesting effects with more phys-
iological injections of glucose or 2-DG in solution have had
limited success.
Gonzales and Novin [80] injected 1/zl of a 5% 2-DG solu-
tion into the hypothalamus of free feeding rabbits. Injections
into the ventromedial hypothalamus had no effect on feed-
ing, similar injections into the lateral hypothalamus resulted
in very small but statistically reliable increases in food in-
take.
Miselis and Epstein [157] obtained robust and repeatable
increases in food intake after ICV injections of 2-DG but
could not obtain significant effects after injections of a wide
range of doses into the lateral hypothalamus.
Panksepp and Nance [186] injected glucose or glucose
mixed with insulin into the VMH 10 or 30 min before a 1 hour
test period. The rats were then food deprived for 2.5 hours
and another 1 hour test begun immediately afterwards. Food
intake was not affected by glucose or glucose mixed with
insulin on either of these tests. However, in the 19 hour
period following the last test, food intake was significantly
decreased by both injections. When glucose or 2-DG were
administered into the VMH at 12 a.m. and again at 6 p.m.,
the daily food and water intake were depressed. The effect
was large and statistically reliable for glucose and relatively
small and statistically not significant for 2-DG.
Panksepp and Meeker [185] gave 3 intrahypothalamic in-
jections of either d-glucose or 2-DG, spaced 7 hours apart
and observed a large decrease in the daily intake after glu-
cose injections. The effect was statistically reliable in normal
controls as well as alloxan-diabetic rats. 2-DG also produced
a statistically significant decrease in the food intake of the
diabetic animals but increased the daily intake of controls
(the effect was sizeable but not statistically reliable).
Finally, Booth [25] reported that microinjections of 1.1/zl
of isotonic glucose into the lateral hypothalamus signifi-
cantly reduced the normal feeding response to 20 U/kg of
insulin. He noted, however, that the glucose injections also
eliminated drinking and appeared to make the animals
drowsy, suggesting that the effects of the glucose injections
were not specifically related to an effect on feeding-related
neural mechanisms.
Insulin-Sensitive Central Mechanisms
Controversy concerning brain insulin. Binding sites indi-
cative of insulin receptors have been demonstrated in many
regions of the brain in a variety of species [96, 275-277].
What has remained controversial is the source of the in-
sulin that may act on brain receptors. Some investigators
have observed brain insulin concentrations comparable or
even larger than those found in plasma and suggested that
brain insulin may be produced by brain cells [96]. This hy-
pothesis is supported by immunocytochemical evidence that
insulin is found in some CNS neurons [56,57]. However,
Baskin et al. [12] have recently failed to obtain im-
munocytochemical staining for immunoreactive insulin (IRI)
in the .hypothalamus of the rat when antiserum at high dilu-
tions was used. These authors have argued that some of the
earlier results may reflect cross-reactivity with other CNS
molecules possessing insulin-like antigenic properties.
Other investigators [59,60] have consistently reported
lower insulin concentrations in brain (and other tissues) than
GLUCOSE AND FEEDING
in plasma. They have therefore argued against extrapancre-
atic synthesis of insulin and proposed, instead, that brain
insulin is taken up from plasma and concentrated onto insu-
lin receptors. Attempts to demonstrate such transport di-
rectly have provided evidence for regional uptake, confined
mainly to circumventricular organs lacking a blood-brain
barrier, and to tissues surrounding the third ventricle espe-
cially in the postero-medial hypothalamus [12, 81,276, 277].
Attempts to provide indirect evidence for a role of plasma
insulin in brain by studying the effects of exogenous insulin
on brain glucose transport or metabolism have produced
conflicting results that have been difficult to interpret be-
cause most of the experiments were done under metabolic
nonsteady state conditions [45, 81, 105] and/or relied on
methods which do not permit the assessment of regional ef-
fects [100].
A recent report by Grunstein et al. [94], however, does
not appear to be subject to these limitations. These authors
examined the effects of insulin infusions on regional glucose
utilization in the brain of rats undergoing englycemic clamps
that maintained steady glucose levels at increasing plasma
insulin concentrations. The results of these experiments
demonstrate reduced glucose utilization in the medial basal
hypothalamus (as well as several other regions of the rat
brain) during insulin infusions that were within the normal
physiological range. These observations appear to confirm
earlier reports of in vitro studies that have shown decreased
glucose utilization in medial hypothalamus in the presence of
insulin [124].
Pancreatic insulin as a modulator of hypothalamic func-
tion. Baskin et al. [12] have suggested that plasma insulin
may be transported preferentially to periventricular brain
parenchyma, so that pancreatic insulin may reach hypotha-
lamic receptors via cerebrospinal fluid (CSF). They pro-
posed, more specifically, that: "CSF insulin may be a pep-
tide signal in the brain, modulating feeding behavior and
body weight gain."
This hypothesis is supported by several earlier studies
which have shown that (a) CSF insulin is proportional to
body fat content both within and between individuals [22,
183,293], and (b) insulin is transported from blood to CSF,
the rate of exchange being sufficient that CSF insulin tends
to be proportional to basal plasma levels (without, however,
being subject to the rapid fluctuations that occur during and
immediately after a meal) [288,290]. The effects of intraven-
tricular injections of insulin on food intake and body weight
(see above) support the general notion that this hormone
may complete a feedback loop concerned with food-intake
regulation.
lntrahypothalamic injections of insulin. There are, as yet,
few reports of physiological or behavioral effects of insulin
injections into the hypothalamus. Several investigators
[246,255] have reported decreased blood glucose levels after
insulin injections into the VMH. Similar injections into
neighboring areas of the hypothalamus had no effect [246].
The hypoglycemic effect of intrahypothalamic insulin is
blocked by vagotomy or atropine pretreatment [255]. Hat-
field and associates [95] implanted bovine or porcine insulin
in crystalline form into the VMH of normal or diabetic rats
and observed statistically reliable reductions in the food in-
take of 12 or 24 hour deprived animals. Unfortunately, this
interesting report contains no data from a control test con-
ducted after the insulin implantation so that one cannot rule
out explanations in terms of non-specific irritation of the
VMH.
303
These reports do, however, complement the results of a
technically competent experiment reported by Strubbe and
Mein [253] who found increased feeding after microinjec-
tions of very small doses (0.5 to 1.5/~U) of insulin antibodies
into the VMH.
There are also a number of reports of experimental find-
ings that provide indirect evidence in support of the hypoth-
esis that glucose uptake in feeding-related neurons in the
medial basal hypothalamus, unlike other CNS cells, may be
insulin dependent. Microinjections of 3 mU of insulin into
the VMH restore the destructive effects of gold thioglucose
on VMH neurons in diabetic mice (which normally are not
subject to GTG lesions presumably because the toxic gold
compound is not taken up into nerve cells) [46,47]. Similarly,
implants of GTG directly into the VMH result in overeating
and obesity in intact animals but not in diabetic animals
[232].
Lastly, we have a brief report of significant inhibitory
effects on food intake and body weight following long-term
continuous infusions of low doses of insulin into the perifor-
nical hypothalamus [167]. The author suggests that the hypo-
thalamus may represent a 'microcosm' of peripheral tissue
and that the lipid content of at least some of its cells in-
creases as peripheral adiposity develops. It is suggested that
the presence of a lipogenic agent such as insulin should be
able to 'fool' these cells and thus lead to reduced food intake
and a loss of body weight.
Iontophoretic application of insulin to a significant
number of neurons in the medial hypothalamus modifies
their electrical activity in predictable fashion [177-180]. On
the basis of extensive studies of this phenomenon, Oomura
and Kita [180] have suggested that insulin may act as a neu-
romodulator in hypothalamic neuron systems concerned
with the control of food intake, body weight, and related
metabolic events. The reports from Oomura's laboratory
indicate that insulin exerts powerful effects on the response
of some medial hypothalamic neurons to glucose. This is
consonant with the recent suggestion by Grunstein et al. [94]
that insulin may influence brain neural activity by lowering
glucose utilization in some areas.
Pharmacology of Feeding- and Glucostasis-Related Brain
Mechanisms
It is well established (see [126,244] for review) that cate-
cholamine neurons in the hypothalamus mediate many, if not
all, of the region's influences on food intake, body weight,
and related metabolic functions such as pancreatic insulin
and glucagon release.
Microinjections of norepinephrine (NE) into the ven-
tromedial hypothalamus (VMH) elicit feeding in sated rats
[84,125] and stimulate pancreatic glucagon release in unfed
animals [226,242]. Epinephrine (E) has similar but smaller
effects [85,226]. The effects of NE and E on feeding as well
as glucagon release have been shown to be selectively
blocked by local pretreatment with alpha-adrenerglc
antagonists such as phentolamine, phenoxybenzamine and
tolazoline but not by beta-adrenergic antagonists such as
propranolol, alprenolol or haloperidol [86, 126--128].
Microinjections of epinephrine or beta-adrenergic
agonists such as l-isoproterenol, dl-salbutamol, and dl-
terbutaline into the perifornical and adjacent ventrolateral
hypothalamus suppress feeding in deprived rats [127]. This
effect is selectively blocked by beta-adrenergic antagonists
such as l-propranolol, l-alprenolol, and dl-butoxamine but
 304
not by alpha-adrenergic antagonists such as phentolamine or
tolazoline [128]. Dopamine antagonists such as haloperidol,
and pimozide also block the feeding-suppressive effects of
periventricular E and various beta-adrenergic agonists [129].
Microinjections of dopamine agonist and antagonists into
the periventricular and lateral hypothalamus reproduce (and
block respectively) the inhibitory effects of beta-adrenergic
compounds but Leibowitz [126] has presented considerable
evidence in support of her conclusion that " E P I and DA act
directly on distinct, functionally independent beta-
adrenergic and dopaminergic receptors, respectively."
Microinjections of NE or E into the lateral (perifornical)
hypothalamus provoke sustained release of pancreatic insu-
lin, NE being more effective than E [226,242]. The effects of
beta-adrenergic or dopaminergic compounds and their
antagonists on pancreatic secretory activity are, to the best
of my knowledge, unknown.
An interaction between pancreatic hormones, food in-
take, and hypothalamic catecholamine metabolism is also
indicated by other lines of investigation. Systemic insulin
injections increase hypothalamic N E " t u r n o v e r " (NE con-
centration after alpha-methyl-p-tyrosine) in the rat [13,14]
and the effect persists after plasma glucose levels have re-
turned to normal levels until nutrients such as glucose or
beta-hydroxybutyrate (which can be used by brain) are ad-
ministered, Nutrients such as fructose which are excluded
from brain do not normalize hypothalamic NE turnover after
exogenous insulin [198]. This persistence of the increased
NE turnover, at a time when acute glucoprivation has
abated, is significant in view of the well-established fact that
stress per se appears to increase NE release and/or turnover
in the brain [259].
In a related experiment, McCaleb and Myers [148], using
a push-pull cannulation technique demonstrated that sys-
temic 2-DG increased NE effiux from medial hypothalamus
but had no effect on the LH whereas peripheral insulin in-
jections had no consistent effect on medial hypothalamus but
reliably decreased the effiux of NE from the lateral hypo-
thalamus.
In mice (but not rats or hamsters) Rowland et al. [205]
have reported increased NE turnover in medial as well as
lateral hypothalamus following systemic insulin. 2-DG af-
fected NE turnover only in the medial hypothalamus in this
study.
Increased hypothalamic NE release or turnover have also
been observed during and following a meal [140, 149, 270,
271]. The role of endogenous insulin release in this phenom-
enon has not yet been examined.
Intracerebroventricular (ICV) injections of the alpha-
adrenergic antagonists phentolamine or azapetine which had
no effect on ad lib food intake have been reported to inhibit
the feeding response to IP injections of 2-deoxy-D-glucose.
The beta blocker propranolol produced no effects in this
paradigm [161]. The feeding response to 2-DG was also
blocked, in these experiments, by systemic injection of the
synthesis blocker alpha-methyl-p-tyrosine and by ICV injec-
tions of 6-OHDA at doses that produced little or no effects on
ad lib food intake.
Electrophysiology of Feeding- and Glucostasis-Related
Brain Mechanisms
A number of investigators have reported changes in the
EEG, multiple unit, or single unit activity of hypothalamic
cells in response to systemic injections of glucose,
2-deoxy-D-glucose, or insulin [2-4, 33, 50, 181].
GROSSMAN
In most of these studies, cells in the ventromedial hypo-
thalamus were affected most strongly although exceptions to
this rule have been reported [33]. Hyperglycemia generally
activates the E E G or increases the activity of cells in the
medial hypothalamus and decreases neural activity in the
lateral hypothalamus. Hypoglycemia or 2-DG induced
glucoprivation produce opposite effects in both regions.
Although this literature is generally internally consistent
and in agreement with the hypothesis that the ventromedial
as well as lateral hypothalamus may contain hunger or sati-
ety related glucose-sensitive cells, other interpretations are
possible. Severe systemic hypo- or hyperglycemia is un-
doubtedly stressful and it is possible that some or all of the
observed changes in hypothalamic activity may reflect stress
reactions rather than hunger-related reactions to changes in
the availability of glucose.
In some of the earlier studies attempts were made to
demonstrate the relationship between feeding and the hypo-
thalamic E E G [2,3] or between hypothalamic unit activity
and arteriovenous differences in blood sugar which
presumably reflect glucose utilization [4]. The results of
these studies are, however, generally not persuasive.
Oomura and colleagues [181] have reported increased
neural activity in the medial hypothalamus and opposite de-
activation of cells in the lateral hypothalamus during and
after feeding, and activation of lateral hypothalamic cells
when food was withheld at the customary feeding time.
Oomura and colleagues [17%180] have also reported re-
sults from an extensive series of experiments which demon-
strate specific and apparently unique single neuron re-
sponses to electrophoretic applications of glucose, insulin,
or glucose-insulin mixtures. Although the detailed results of
these studies are complex, they consistently show that a
significant number of neurons in the lateral and ventromedial
hypothalamus appear to be specifically sensitive to glucose.
Approximately 313% of the neurons of the lateral hypothala-
mus are glucose-sensitive. These cells decrease their firing
rate when glucose is applied to them iontophoretically and
are excited by direct application of insulin and/or 2-DG.
Neurons in the ventromediai hypothalamus show a pattern
of responding which suggests that they may act specifically
as insulin-sensitive glucoreceptors. These cells increase their
discharge frequency in a dose-dependent manner in response
to iontophoretically applied glucose in concentrations that
are within the normal physiological range. When insulin is
applied to these cells their firing rate tends to decrease but
when a mixutre of glucose and insulin is applied simulta-
neously, the facilitatory effects of glucose are greatly en-
hanced.
Effects of Hypothalamic Lesions
Ventromedial hypothalamus (VMH). M a y e r ' s proposal
that the VMH may contain feeding related glucoreceptors
was based, in part on the results of experiments [139,147]
which demonstrated that systemic injections of gold thioglu-
cose (GTG) produced lesions in the ventromedial hypothal-
amus of mice and resulted in hyperphagia and obesity.
Mayer concluded that nerve cells in this area must have a
special affinity for glucose and thus accumulate the toxic
gold compound.
Mayer's interpretation received support from a series of
studies by Debons and colleagues which demonstrated that
GTG did not destroy the ventromedial hypothalamus in dia-
betic mice or in mice pretreated with an anti-insulin serum
[46,47]. Intravenous as well as intra-VMH injections of insu-
G L U C O S E AND F E E D I N G
lin restored the region's susceptibility to GTG promptly.
Intrahypothalamic injections of insulin were effective even
in the presence of insulin antiserum in the general circulation
[47]. The latter observation is a particularly important one
since it has been suggested that the effects of GTG may not
be due to a direct toxic action on glucosensitive neurons in
the VMH but, instead, to ischemia brought about by de-
struction of capillaries in the region [5]. It also addresses a
controversy which arises as a consequence of the observa-
tion that VMH lesions can be produced by systemic injec-
tions of toxic compounds such as bipiperidyl mustard [34,35]
and 4-nitroquinoline l-oxide [296] which have no known
special affinity for glucoreceptors.
Smith [232] implanted cannulae containing GTG directly
into the hypothalamus of normal and alloxan-diabetic rats.
Cannulae placements in the VMH increased food intake and
rate of body weight gain in intact but not in diabetic animals.
The latter did increase body weight when insulin was added
to the GTG plug, suggesting that glucose-uptake in this area
might be insulin-dependent. Cannulae placements in the lat-
eral hypothalamus produced a significant decrease in food
intake and body weight in both normal and diabetic animals.
This effect was blocked by the addition of 2-DG to the GTG
plug providing some support for the hypothesis that the GTG
effects were due to the cellular uptake of the toxic substance
rather than non-specific damage.
Muller and associates [162] have reported that rats in the
dynamic phase of VMH obesity did not eat in response to a
high dose of 2-DG (750 mg/kg) or a moderate dose of insulin
(4 U). Very high doses of insulin (8 U) produced a delayed
and reduced feeding response. When the tests were repeated
80 days after the lesion (e.g., during the static phase of VMH
obesity), 750 mg/kg of 2-DG produced a delayed increase in
food intake that was, however, significantly smaller than that
seen in controls.
Panksepp and Nance [186] reported that rats which
were tested shortly after VMH lesion with 2, 4, 6, and 8 U of
insulin given on consecutive days did not overeat and died in
coma. When this experiment was repeated with increasing
doses of insulin administered twice daily for 21 days, rats
with VMH lesions displayed little or no overeating (the con-
trols consumed more than the experimental animals on the
last 8 days of the insulin treatment).
Other investigators have reported normal feeding re-
sponses to insulin as well as 2-DG in mice with gold thioglu-
cose induced lesions of the VMH [64] as well as rats with
electrolytic lesions [63, 119, 120] or parasagittal knife cuts
lateral to the VMH [106, 223,224].
My associate and I [119,120] have consistently obtained
normal or supernormal feeding response to moderate as well
as high doses (4 or 8 U) of insulin in rats tested during the
static phase of hypothalamic obesity. The same animals dis-
played delayed but otherwise nearly normal feeding re-
sponses to a moderate dose (350 mg/kg) of 2-DG but no
response at all to 750 mg/kg (a dose which consistently
produced optimal effects in control rats). The rats with VMH
lesions ate little or nothing during the first hour after the
injections of 350 mg/kg of 2-DG (when normal rats do most of
their eating) but increased food intake steadily during the
ensuing hours so that the total 6 hour response was com-
parable to that of the controls.
We [120] subsequently repeated the experiment, using a
wide range of doses of 2-DG. Low doses (50-250 mg/kg)
consistently produced delayed feeding responses that were
equal or even larger than those of controls when accumu-
lated over a 6 hour test period. Higher doses (300-400 mg/kg)
305
also produced delayed feeding but the response was smaller
than that of the controls.
These observations are in good agreement with several
other reports in the literature. Houpt and Gold [106], for
instance, found little or no response to 600 mg/kg of 2-DG
but essentially normal although delayed responses to 150 and
300 mg/kg in rats that were obese as a result of parasagittal
knife cuts lateral to the VMH.
It thus seems that VMH lesions delay the feeding re-
sponse to low doses of 2-DG and shift the dose-response
curve such that doses higher than 300--400 mg/kg depress
rather than increase feeding. Rats with VMH lesions are
hyperreactive to noxious stimuli [87] and it is possible that
the reduced response to higher doses of 2-DG may reflect a
non-specific reaction to the stupor and ataxia that are typical
signs of central glucopenia. It is particularly interesting to
compare this with the essentially unchanged or even
facilitated response to insulin which, unlike 2-DG, produces
a potentially life-threatening hypoglycemia.
There is some disagreement in the literature concerning
the effects of VMH lesions on the hyperglycemic response to
ICV 2-DG. Mueller and associates [160] reported that gold
thioglucose induced lesions in the VMH of mice greatly re-
duced but did not abolish the hyperglycemic response to
intraventricular injections of 2-DG. In subsequent publica-
tions from the same laboratory [162,184], large electrolytic
lesions of the VMH were reported to have no effect on the
hyperglycemic response of rats to ICV 2-DG. Indeed, the
2-DG induced blood glucose rise was reported to be larger
than in intact controls in this experiment. It is possible that
the effects of GTG seen in the earlier experiments may be the
result of lesions outside the VMH itself.
Vagotomy also delays and reduces the feeding response
to 2-DG but has little or no effect on (or may in fact facilitate)
insulin-induced feeding [26, 159, 173]. This suggests that
VMH lesions may interfere with vagal connections that
somehow contribute to the initial stage of 2-DG feeding. It is
interesting to note that the inhibitory effects of glucagon on
feeding in the rat and rabbit [141,142] are completely
abolished by subdiaphragmatic vagotomy [142,273]. Selec-
tive hepatic vagotomy, on the other hand, has been reported
to have no effect on feeding responses to 4, 8, or 12 U of
insulin or 125,250, or 500 mg/kg of 2-DG [263].
On balance, the available literature on the effects of VMH
lesions does not support the hypothesis that this region con-
tains glucoreceptor cells that are essential to glucoprivic
feeding. This conclusion is in good agreement with the ob-
servation that intracerebroventricular injections of 2-DG
produce a significant systemic hyperglycemia which is not
affected or facilitated by VMH lesions [162]~
Lateral hypothalamus. The lateral hypothalamus has not
received as much attention from investigators in this field
even though electrophysiological studies have consistently
reported significant EEG, as well as single and multiple unit
changes in response to systemic or central injections of glu-
cose, 2-DG etc. (see above).
Rats with large electrolytic lesions of the LH are aphagic
and adipsic in the immediate postoperative period but regain
voluntary ingestive behavior after some days, weeks, or
sometimes months of intragastric feeding [256,257].
After recovery of normal or nearly normal daily intake,
rats with LH lesions display severely impaired or absent
feeding responses to insulin [63] or 2-deoxy-D-glucose [285].
Recent experiments [116] have shown that rats with LH le-
sions do increase their intake of a palatable liquid diet after
insulin as well as 2-DG. It is not yet clear whether this is the
 306
result of partial recovery in animals that may have sustained
only partial destruction of feeding-related components of the
L H or increased acceptance of a highly palatable fluid (it is
well known that recovered laterals are hyperreactive to
taste) rather than a true feeding response to glucoprivation.
Small facilitatory effects on food intake have been re-
ported [249] after a regimen of dally injections of very low
and gradually increasing doses of long-acting protamin zinc
insulin in rats which had recovered voluntary ingestive be-
havior after electrolytic lesions in the LH or intraventricular in-
jections of the neurotoxin 6-hydroxydopamine which produce
effects on ingestive behavior that are similar though typically
less severe than those of large electrolytic lesions in the LH.
This experiment provides evidence of significant responding
to insulin in animals that do not feed in response to a high
dose (750 mg/kg) of 2-DG. Lower doses of 2-DG were, unfor-
tunately, not tested. Five of six 6-OHDA treated animals
increased their food intake in response to gradually increas-
ing doses of insulin much like vehicle-injected controls, the
sixth animal died during the experiment. This provides clear
evidence of insulin feeding after ICV 6-OHDA. The story is,
unfortunately, not as clear when one considers the perform-
ance of animals with lateral hypothalamic lesions. Only four
of 13 rats with electrolytic L H lesions survived 15 days of in-
sulin treatments (the others died after 1,4, 4, 6, 6, 8, 10, 11, and
13 days presumably of hypoglycemic shock). The high mortal-
ity rate appears to be directly related to the animal's inability
to feed during periods of hypoglycemia since the authors
stated that " m o s t of these animals did not show pronounced
initial impairments . . . . " [249].
Electrolytic lesions in the lateral hypothalamus appar-
ently do not reduce the hyperglycemic response to systemic
[300] or intracerebroventricular [162] injections of 2-DG.
Rats that have recovered voluntary feeding after L H le-
sions no longer display inhibitory effects of intraduodenal
infusions of glucose but, instead, increase food intake [175].
Extrahypothalamic Influences
Although the evidence reviewed above indicates that hy-
pothalamic mechanisms may play a significant role in the
regulation of glucostasis, apparently critical input and output
connections can be traced to a variety of other brain struc-
tures.
The nigrostriatal projection system. A number of inves-
tigators [268, 299, 300] have suggested that the effects of
lateral hypothalamic lesions on food intake and glucoprivic
feeding in particular might be due to incidental destruction of
fibers of passage, particularly the dopaminergic nigrostrial
projections.
To address this issue, my colleagues and I have investi-
gated the effects of surgical transections of various compo-
nents of the fiber systems which enter and/or leave the hypo-
thalamus.
In the initial series of studies, we [89,90] demonstrated
that parasagittal cuts along the lateral border of the hypo-
thalamus which interrupted essentially all lateral connec-
tions of the hypothalamus, reproduced the effects of lateral
hypothalamic lesions on food and water intake even though
there was little or no damage to cellular components of the
region. After recovery of voluntary ingestive behavior to
normal or near normal levels, these animals maintained per-
manently lowered but stable body weights apparently by
regulating food intake. They did not, however, eat in re-
sponse to either insulin or 2-DG.
GROSSMAN
Subsequent investigations from this laboratory used
smaller parasagittal cuts lateral to selected portions of the
diencephalon [1, 154, 155]. These cuts produced far less se-
vere and persistent effects on ad lib food and water intake
than the larger ones used earlier (all animals recovered nor-
mal ad lib food intake within 10 days or less). However,
feeding responses to 2-DG as well as insulin were abolished.
In one of these experiments [154], the experimental
animals did not respond to insulin although their food intake
increased reliably after 2-DG, a clear reversal of the pattern
often seen after various extrahypothalamic lesions which
abolish feeding responses to 2-DG but leave insulin eating
intact.
The biochemical consequences of these smaller parasagit-
tal cuts included significant norepinephrine depletions from
hypothalamus as well as telencephalon and very severe
dopamine depletions in striatum and forebrain [1, 154, 155].
Two further attempts were made to interrupt the nigro-
striatal projections to the striatum without disrupting hypo-
thalamic neurons and their connections. In these experi-
ments [I] two types of knife cuts were made in the horizontal
plane under the striatum. The first of these was intended to
sever fibers that enter or leave the anterior ventral striatum;
the second was intended to selectively transect the posterior
ventral connections of the region. Both cuts produced signif-
icant aphagia and adipsia and a variety of persisting deficits
in food and water intake regulation but had little or no effect
on eating in response to a high dose (750 mg/kg) of 2-DG or 5
U of insulin. It is interesting to note that both of these cuts
severely depleted striatal dopamine but had no effect on hy-
pothalamic NE or 5-HT.
Caudal connections of the diencephalon. Because of the
prominent role of noradrenergic hypothalamic neurons in the
regulation of glucostasis and food intake (above), we also
thought it important to observe the effects of surgical tran-
sections of fiber systems caudal to the substantia nigra.
Knife cuts in the coronal plane in portions of the tegmen-
tum known to contain many ascending noradrenergic fibers
were shown to abolish the feeding response to 2-DG without
reducing the food intake after moderate doses of insulin.
Some but not all of these cuts produced significant hyper-
phagia or hyperdipsia [1,91].
All of these cuts depleted hypothalamic as well as fore-
brain norepinephrine significantly but had no effect on
striatal dopamine. Most of these cuts also depleted hypotha-
lamic and forebrain serotonin [93].
Coronal cuts across lateral components of the medial
forebrain bundle, at the level of the posterior hypothalamus,
have been shown to produce transient aphagia and adipsia
[154,155]. Rats with such cuts displayed essentially normal
responses to insulin after recovery of normal ad lib intake.
When first tested with 2-DG, 1 month after the knife cuts
were made, the animals did not increase their food intake
significantly. When retested 3 months after surgery, animals
with lateral MFB cuts increased their food intakes signifi-
cantly although the response was far smaller than that of
controls. When subsequently tested with a low dose of
2-DG, given in combination with a small dose of caffeine
(designed to overcome the stupor typical of 2-DG treated
animals) the animals with lateral MFB cuts ate as much as
controls.
These cuts did not deplete hypothalamic NE or 5-HT but
reduced telencephalic as well as striatal norepinephrine and
dopamine [154,155].
Similar knife cuts across medial aspects of the medial
GLUCOSE AND FEEDING
forebrain bundle in the posterior hypothalamus resulted in
significant hyperphagia [154,155]. Rats with such cuts did
not increase their food intake in response to 2-DG when
tested 1 month after surgery and actually decreased their
food consumption reliably when retested 3 months after the
cuts were made.
When tested with a low dose of 2-DG, given in conjunc-
tion with caffeine, the rats with cuts across medial compo-
nents of the MFB increased their food intake significantly
although their response remained very much smaller than
that of the controls. When tested with 4 U of insulin, the
experimental animals increased their food intake signifi-
cantly so that their total intake was not significantly different
from that of the controls.
These cuts did not affect hypothalamic N E or 5-HT but
depleted catecholamine as well as 5-HT from striatum as
well as telencephalon.
The observations on the effects of knife cuts across the
MFB are in good agreement with a report by Blass and Kraly
[23] that large lesions in the medial forebrain bundle had no
effect on ad lib feeding but impaired the feeding response to
2-DG. The response to insulin was, unfortunately not tested
in these experiments.
Attempts to demonstrate significant correlations between
the biochemical effects of the various knife cuts made in
these experiments and their influence on 2-DG or insulin
feeding did not result in a meaningful overall pattern [155].
Z o n a incerta. The region immediately dorsal to the area
of the lateral hypothalamus where lesions produce the most
severe and persistent effects on feeding responses to
glucoprivation (and feeding in general) is called z o n a incerta.
This subthalamic area is almost inevitably destroyed, at least
in part, by the L H lesions which produce persistent effects
on ingestive behavior.
My associates and I have consistently found that even
very small electrolytic lesions in the rostromedial zona in-
certa abolish or sharply reduce 2-DG eating without affect-
ing the feeding response to insulin [92, 150, 151, 175, 236].
Rats with zona incerta lesions are not aphagic or adipsic
after surgery although a slight and transient hypophagia and
persisting hypodipsia are often seen. After a few days of
postoperative recovery, animals with rostromedial zona in-
certa lesions eat normal quantities of food under ad lib as
well as deprivation conditions, adjust their intake to caloric
dilution or enrichment of their diet [159], and display essen-
tially normal responses to various gustatory stimuli [42].
However, they do not eat in response to a wide range of
IP doses of 2-DG (including 50, 150, 300, 600, 750 and 900
mg/kg) [92, 150, 151, 153]; respond poorly or not at all to
intragastric injections of 750, 1000, or 1250 mg/kg; a route of
administration that was found to elicit optimal feeding and
few side effects (such as ataxia and stupor) in control
animals; and eat little or nothing after 200 or 300 mg/kg of
2-DG administered SC (a treatment paradigm found to be as
effective in controls as much larger doses given IP [236]).
When tested in the dark, rats with ZI lesions did not in-
crease their intake after 250 or 450 mg/kg of 2-DG and actu-
ally ate significantly less than on saline control tests when
given a dose of 650 mg/kg [152]. When 2-DG was adminis-
tered in conjunction with CNS stimulants such as caffeine
and amphetamine, rats with ZI lesions responded signifi-
cantly to low doses of 2-DG but their best response was still
far smaller than that consistently shown by controls which
also increased their feeding response to 2-DG when caffeine
or amphetamine was added to the treatment. It is interesting
307
to note that apomorphine had no significant effects either in
the experimental or the control animals [152].
In all of these experiments, we administered a range of
doses of insulin IP. In most tests, including an extensive
dose-response analysis which examined feeding responses to
0.5, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0 and 7.0 units we found no
indication of an impairment in the same animals that refused
to eat after 2-DG [151,283]. However, in some tests, con-
ducted in the same laboratory, often by the same personnel
[ 153,236], a small but statistically significant impairment was
noted. It is possible that sensory-motor dysfunctions which
are seen after some but not all ZI lesions may be responsible
for the inconsistency of this effect.
Attempts to establish a correlation between the biochem-
ical and behavioral effects of ZI lesions have not been suc-
cessful. The ZI lesions made in these experiments consis-
tently depleted forebrain norepinephrine by 40-50% but this
effect did not correlate with the severity of the behavioral
consequences of the lesion. Forebrain DA and 5-HT, striatal
DA and 5-HT, and hypothalamic NE and 5-HT were not
significantly affected by the ZI lesions [284].
Severe inhibitory effects on 2-DG eating have also been
observed after iontophoretic injections of the neurotoxin
kainic acid into the zona incerta, suggesting that the often
complete disappearance of 2-DG eating after ZI lesions may
be due to the destruction of nerve cell bodies in the region
rather than to the interruption of fibers of passage [31].
Rats with zona incerta lesions do increase their intake of a
palatable liquid diet following 2-DG much like rats with lat-
eral hypothalamic lesions do [258]. The rat with ZI lesions
overreacts to the palatability of its diet [42] and it is possible
that a severely impaired response to glucoprivation could
initiate feeding if sufficient incentive were provided in the
form of a palatable diet. Other interpretations are, of course,
possible.
O t h e r brain regions. We [43], as well as other [15,19],
have observed significant impairments in 2-DG eating in rats
with dorsomedial hypothalamic lesions that responded well
to insulin. Neill and Kaufman [164] have reported impaired
2-DG feeding after ventrobasal thalamic lesions that did not
appear to infringe on the adjacent tissue of the zona incerta.
Tordoff et al. [262] have observed impaired feeding re-
sponses to several doses of 2-DG in rats with amygdaloid
lesions that fed normally to a large dose of insulin.
In spite of the ubiquity of forebrain structures which ap-
pear to be essential for intact 2-DG feeding, there is some
evidence that at least some aspects of the physiological re-
sponse to glucoprivation are not dependent upon forebrain
glucoreceptors. DiRocco and Grill [55], for instance, have
reported that the hyperglycemic response to 2-DG is intact in
chronically decerebrate rats. Ritter et al. [197] have impli-
cated the lower brainstem in glucoprivic feeding with the
observation that microinjections of the glucose analogue
5-thioglucose into the lateral or fourth cerebral ventricle
elicited feeding in rats. When the aqueduct was obstructed,
the animals continued to respond to 4th ventricle injections
but not to infusions into the lateral ventricle.
CONCLUSIONS
Is the role of glucose and related hormones in the regula-
tion of hunger and/or satiety elucidated? I think not. As we
have seen there has been a good deal of interest and active
research on this question but the outcome has as often raised
more questions as it has provided answers.
308
The recent literature suggests that blood glucose levels
may show a sudden decrease just prior to a meal. That may
provide a clue to the elusive signal which is responsible for
the initiation of meals but the data are strictly correlative, the
magnitude of the effects is disappointingly small, and it is not
entirely clear why a sudden fall to blood glucose, which
presumably reflects increased utilization, should occur just
before a meal.
Experimental treatments which induce glucopenia, sys-
temically or centrally, initiate food intake in a wide variety of
species but there are many unanswered questions.
Feeding responses to insulin are reliable but large "phar-
macological" doses are required and the time course of the
resulting hypoglycemia does not parallel that of the in-
creased food intake (which can be delayed by as much as
60-90 minutes). These issues have become more trou-
blesome with the publication of reports that very low single
doses or slow infusions of insulin do, in fact, produce inhibi-
tory rather than facilitatory effects on food intake.
Similar questions must be raised about the feeding re-
sponse to 2-DG and other nonmetabolizable glucose
analogues. The effect can be quite large but seems capri-
cious. Although 2-DG produces significant hyperglycemia
and symptoms of central glucopenia within a few minutes
after systemic or ICV injections, feeding responses are de-
layed by as much as several hours and are not a reliable
phenomenon in many individuals. Moreover, when access to
food is delayed, feeding may occur 6-8 hours after the 2-DG
treatment, at a time when blood glucose and cellular glucose
utilization have returned to normal levels.
The functional significance of glucoprivic feeding has
been questioned by the fact that numerous brain lesions
which increase, decrease, or have no effect on ad lib food
intake abolish or severely impair feeding responses to 2-DG.
The feeding response to insulin is not impaired by most of
the lesions that abolish 2-DG feeding, suggesting that funda-
mentally different mechanisms may be involved.
Systemic injections of glucagon produce hyperglycemia
and reduce food intake in free-feeding animals, possibly be-
cause the glucose output of the liver is stimulated. However,
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GROSSMAN
1CV injections of extremely small doses of glucagon produce
similar effects, suggesting a direct action of the hormone on
brain mechanisms related to the control of food intake. A
recent report of increased feeding after very low systemic
doses of glucagon further complicates the picture.
The question whether hormones such as insulin and
glucagon or glucose analogues such as 2-DG may affect food
intake entirely or in part because of a direct action on brain
mechanisms rather than their systemic effects on glucose
availability or utilization has generated much debate. Vagot-
omy abolishes the satiety effects ofglucagon, but merely delays
the ingestive response to 2-DG and has no effect on
the response to insulin. The results of experiments that have
investigated the effects of nutrients other than glucose are
difficult to interpret because fuels such as ketone bodies that
can potentially nourish brain, may be able to do so only after
considerable delays. It is also possible that nutrients which
are excluded from brain may nonetheless affect metabolism
by making glucose reserves more readily available to it.
There is a good deal of evidence for a direct central action
of insulin. Insulin as well as insulin-bindingsites indicative of
insulin receptors have been demonstrated in several species.
Insulin has been shown to affect hypothalamic glucose utili-
zation and iontophoretic injections of insulin have been
shown to modulate the electrical activity of cells in the ven-
tromedial and lateral hypothalamus. ICV infusions of very
low doses of insulin reduce food intake and body weight and
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