The Brain-Gut-Islet Connection
Stephen C. Woods, Stephen C. Benoit, and Deborah J. Clegg
Peptide signals from the pancreatic islets and the gastro-
intestinal tract influence the regulation of energy ho-
meostasis by the brain, and the brain in turn influences the
secretions of both the islets and the gut. This article
focuses on how insulin interacts with the brain to influence
food intake, blood glucose, and cognitive behavior. Insulin
is secreted in response to changes of ambient glucose, and
the levels achieved are directly proportional to body adi-
posity. Hence, insulin, like leptin, is an adiposity signal. An
increased insulin signal in the mediobasal hypothalamus
indicates that ample or excess energy is available in the
body and elicits responses that limit food intake and
reduce hepatic glucose secretion. Increased insulin (and
leptin as well) locally within the brain complements other
signals that indicate a surfeit of energy in the body,
including satiety signals generated by the gut during meals,
glucose, and some fatty acids. There is compelling evidence
that overlapping intracellular signaling pathways within
the mediobasal hypothalamus mediate the overall catabolic
response to these diverse metabolic signals. Insulin recep-
tors are also densely expressed in the hippocampus, and
insulin acts there to facilitate learning and memory. The
function of insulin receptors in other brain areas is poorly
understood. Obesity and/or the consumption of diets high
in fat render the brain as well as the body insulin resistant.
In the hypothalamus, this is manifest as a reduced ability of
insulin to reduce food intake and body weight, and in the
hippocampus, it is manifest as a reduced ability of insulin
to improve learning and/or memory. Diabetes 55 (Suppl.
2):S114 –S121, 2006
T
he brain-gut-islet connection refers to the myriad
ways in which signals arising in the three arms of
this important axis interact among themselves,
and at least one overall function of this inte-
grated control system is the regulation of energy ho-
meostasis throughout the body. Many of the interactions
of this triad are well known. The brain regulates activity in
both the gut and the pancreatic islets directly via the
autonomic nervous system and indirectly via changes in
food intake and energy expenditure. Peptide hormones
and other signals secreted from the gut, in addition to
coordinating the digestion and absorption of nutrients,
provide the incretin effect that augments prandial insulin
From the Department of Psychiatry and the Obesity Research Center, Uni-
versity of Cincinnati, Cincinnati, Ohio.
Address correspondence and reprint requests to Stephen C. Woods, Depart-
ment of Psychiatry, University of Cincinnati, 2170 E. Galbraith Rd., Cincinnati,
OH 45237. E-mail: steve.woods@psychiatry.uc.edu.
Received for publication 25 March 2006 and accepted in revised form 27
April 2006.
This article is based on a presentation at a symposium. The symposium and
the publication of this article were made possible by an unrestricted educa-
tional grant from Servier.
ARC, arcuate nucleus; CCK, cholecystokinin.
DOI: 10.2337/db06-S015
© 2006 by the American Diabetes Association.
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked “advertisement” in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
S114
secretion. Many of these peptides also serve as critical
satiety signals to the brain that limit meal size. Islet
hormones influence digestion and control the disposition
of ingested nutrients in addition to providing key signals to
the brain regarding the level of adiposity and circulating
energy. This review focuses on one aspect of this complex
network, i.e., the actions of pancreatic insulin within the
brain and the pathologies that occur when insulin signal-
ing within the brain is compromised. The topic is timely,
with relevant new information appearing almost monthly,
and it is also an area of knowledge where the basic tenets
are being challenged, since insulin was historically
thought not to interact with the brain and subsequently
was thought to mainly influence the control of food intake
and body weight.
CONTROL OF ENERGY INTAKE
The energy equation holds that for body weight to remain
relatively stable over time, food intake must match energy
expenditure, and deviations in either direction will result
in weight gain or loss. Humans and most mammals con-
sume food in discrete episodes or meals. When there are
no restrictions on when or how much individuals are
allowed to eat (i.e., when they are in a free-feeding or ad
lib condition), the impetus to begin a meal is rarely if ever
caused by a biological deficit or need such as insufficient
glucose. Rather, evidence indicates that the timing of
meals is based on psychological factors such as habit, time
of day, the social situation, convenience, and others (1–3).
Because of this, body weight regulation, the continuous
process that ties energy intake to energy expenditure,
must logically be manifest as a control over how many
calories are consumed once a meal begins, i.e., on meal
size. Consistent with this, during meals, the gut responds
to ingested nutrients by secreting peptide signals propor-
tional to the quantity and quality of calories consumed,
and some of these secretions function as satiety signals to
the brain to limit meal size (4 –7). The prototypical satiety
signal is the duodenal peptide cholecystokinin (CCK).
Humans and animals that are administered CCK just
before eating consume smaller meals, and when adminis-
tered a selective CCK-1 receptor antagonist, they consume
larger meals (5,8). Table 1 lists gut and islet signals
secreted during meals that influence meal size and are
considered to be satiety signals.
Adiposity signals are hormones secreted in direct pro-
portion to body fat. In contrast to satiety signals that are
secreted mainly during meals, adiposity signals are toni-
cally present, providing a relatively continuous message to
the brain concerning fat stored within the body. Pancre-
atic insulin and the adipocyte hormone leptin are the two
best-known adiposity signals, and others such as amylin
and adiponectin also circulate in proportion to body fat
and share many of the same properties. Administering
either insulin or leptin directly into the brain results in
reduced food intake and body weight, and reductions of
either insulin or leptin signaling locally within the brain
DIABETES, VOL. 55, SUPPLEMENT 2, DECEMBER 2006

TABLE 1
Gastrointestinal hormones that affect satiety
Gastrointestinal peptide Effect on food intake
Cholecystokinin Decrease
Glucagon-like peptide 1 Decrease
Enterostatin Decrease
Bombesin/gastrin-releasing peptide Decrease
Oxyntomodulin Decrease
Gastric leptin Decrease
Glucagon Decrease
Amylin Decrease
Peptide YY (3-36) Decrease
Apolipoprotein A-IV Decrease
Ghrelin Increase*
*Ghrelin is the only gastrointestinal hormone that increases food
intake.
results in overeating and weight gain. When an individual’s
weight (i.e., body fat) changes, insulin and leptin secretion
change in parallel, and this is manifest as an altered
adiposity signal to the brain. There are many reviews of
these phenomena (9 –14).
The interaction of adiposity signals with satiety signals
in the control of food intake is a topic of considerable
interest and beyond the scope of this review. The basic
principle is that adiposity signals modulate the sensitivity
of the brain to meal-generated satiety signals (10,12,15). As
an example, the administration of very low doses of either
insulin or leptin directly into the brain enhances the
efficacy of systemic CCK to reduce food intake (16 –22),
and a reduced leptin signal in the brain, which also
reduces brain insulin signaling (23), lowers CCK sensitiv-
ity (24). The implication is that when an individual loses
weight and insulin and leptin secretion are reduced, brain
circuits that control meal size are consequently rendered
less sensitive to meal-generated satiety signals such as
CCK. As a result, more calories than normal must be
consumed before a satiety signal of sufficient magnitude to
terminate a meal is generated. Individuals consequently
eat larger than normal meals until body weight returns to
normal. Conversely, when an individual gains excess
weight, the increased insulin and leptin signal in the brain
causes increased sensitivity to satiety signals, and rela-
tively small meals are consumed until the excess weight is
lost.
INSULIN AS AN ADIPOSITY SIGNAL
Basal plasma insulin is low and increases during meals or
when stimulated by glucose. Basal, prandial, and stimu-
lated insulin levels are all direct functions of stored fat,
with leaner individuals having lower levels and more
obese individuals having higher levels (25–27). Plasma
insulin is therefore positioned to convey an important
signal to the brain indicating the degree of adiposity, and
as discussed below, some insulin enters the brain from the
circulation and provides a key negative feedback signal in
the regulation of body fat as originally proposed by
Kennedy (28) (Fig. 1). When exogenous insulin is admin-
istered near or directly into the mediobasal hypothalamus,
animals behave as if they have excess fat, i.e., they eat less
and lose weight. The response is dose dependent (17,29),
occurs in all species assessed, and is not secondary to
illness or incapacitation (30). When insulin levels in the
brain are clamped by means of slow steady local infusions,
DIABETES, VOL. 55, SUPPLEMENT 2, DECEMBER 2006
S.C. WOODS, S.C. BENOIT, AND D.J. CLEGG
FIG. 1. Insulin is secreted into the blood from the pancreas in direct
proportion to the amount of fat stored in white adipose tissue. As it
circulates through brain capillaries, a small amount of insulin is
transported into the brain, where it acts on insulin receptors on
neurons with either net catabolic or anabolic activity, for example, in
the ARC of the hypothalamus. These neurons in turn influence energy
homeostasis (food intake and energy expenditure) and ultimately the
amount of fat stored in the body by exerting a net catabolic or anabolic
action.
body weight is maintained and defended at a level deter-
mined by the dose of insulin administered (rev. in 13,31–
33). The response to changes of the insulin signal is
bidirectional in that the administration of insulin antibod-
ies into or near the mediobasal hypothalamus causes
overeating and weight gain (34,35). Likewise, reducing
hypothalamic insulin receptor activity either genetically by
a neuronal-specific knockout of insulin receptors or phar-
macologically via antisense oligonucleotides against the
insulin receptor leads to increased food intake and body
fat (36,37). Although insulin has not been administered
directly into the brains of humans, certain formulations of
insulin have been administered intranasally to humans
with a consequent increase of cerebrospinal fluid but not
plasma insulin. Humans receiving insulin in this way eat
less food and lose body fat (38).
Insulin enters the brain via receptor-facilitated transport
through capillary endothelial cells. The process is satura-
ble, selective for insulin, and regulated (39 – 42). Insulin
transport into the brain is reduced during fasting (43), by
maintenance on a high-fat diet (44), and in genetic and
dietary-induced obesity (45,46). Because brain insulin de-
rives from plasma insulin, it should be the case that
experimentally induced increases of plasma insulin enter
the brain and result in reduced food intake and body
weight. Such procedures are confounded by hypoglycemia
and a consequent increased tendency to eat more food.
However, when insulin is administered systemically at
doses sufficiently low to preclude hypoglycemia, food
intake is reduced (47). Likewise, when sufficient glucose is
administered in conjunction with systemic insulin to cir-
cumvent hypoglycemia, food intake is also reduced (48).
Autoradiographic insulin binding, as well as immunohis-
tochemical analyses, reveal that insulin receptors are
selectively located in several brain regions (49 –52). The
areas of highest concentrations are the olfactory bulb,
hypothalamus, cerebellum, cortex, and hippocampus (53–
55), and most insulin receptor immunoreactivity occurs on
neurons and not on glia.
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 BRAIN-GUT-ISLET AXIS
INSULIN REGULATES ENERGY HOMEOSTASIS IN THE
HYPOTHALAMUS
As discussed above, insulin reduces food intake and body
weight when delivered into the third cerebral ventricle
(i3vt) or directly into the hypothalamus in or near the
arcuate nucleus (ARC). Conversely, reduction of insulin
signaling has the opposite action. Insulin signaling in the
ARC also initiates a signal via the vagus nerve to the liver
to reduce glucose synthesis and secretion into the blood
(56 –58). Hence, insulin’s action in the hypothalamus is
consistent with its better-known systemic actions, i.e., its
net effect is to lower blood glucose (9,11). Reducing the
amount of food consumed and neurally reducing hepatic
glucose output both complement insulin’s ability to facil-
itate glucose uptake by muscle, liver, and other tissues, as
well as complement insulin’s direct action in the liver. It
has recently been reported that administering oleic acid or
glucose into or near the ARC also reduces food intake
(57,59 – 62). Leptin may also act there to influence glucose
homeostasis (63). Hence, ARC neurons respond to diverse
signals indicative of a surfeit of available energy (i.e.,
elevated insulin, fatty acids, or glucose) by reducing the
ingestion of energy and decreasing the secretion of utiliz-
able energy (especially glucose) into the blood. Rossetti’s
group has postulated that manipulating intracellular met-
abolic signaling pathways, especially those involved with
the oxidation of lipids, comprises the actual stimulus that
is important in controlling both food intake and hepatic
glucose production by the hypothalamus (61,64 – 67).
INSULIN AND LEPTIN AS ADIPOSITY SIGNALS
As discussed above, both leptin and insulin function as
adiposity signals, and the two have overlapping actions with
regard to the hypothalamic control of metabolism. While the
existence of two or more adiposity signals might seem
redundant, insulin and leptin in fact reflect different fat
stores, sexes, and risk factors for developing type 2 diabetes,
cardiovascular problems, and the metabolic syndrome.
Fat stores. Insulin is secreted in proportion to visceral
fat, whereas leptin reflects total fat mass and especially
subcutaneous fat (68,69). This is an important distinction
with regard to the message conveyed to the brain, since
visceral fat carries a greater risk factor for the metabolic
complications associated with obesity than does subcuta-
neous fat. Elevated visceral fat carries an increased risk
for insulin resistance, type 2 diabetes, hypertension, car-
diovascular disease, and certain cancers (68,70,71). Hence,
leptin and insulin each convey specific information to the
brain regarding the distribution of fat, and the combina-
tion of the two additionally conveys information as to the
total fat mass of the body.
Sex. Women have relatively more subcutaneous fat and
higher plasma leptin, whereas men have relatively more
visceral fat and higher plasma insulin (68,70,71). Likewise,
male rats have relatively more visceral fat and higher
plasma insulin, whereas female rats have more subcuta-
neous fat and higher plasma leptin (72). We have found
that the brain of females is more sensitive to the catabolic
action of leptin, whereas the brain of males is more
sensitive to the catabolic action of insulin (73), and that
estrogen mediates this difference (72). These data are
consistent with a growing literature documenting sex
differences in the actions of many compounds that influ-
ence energy homeostasis, including CCK (74), insulin
(38,73), leptin (73), and ghrelin (D.J.C., L.M. Brown, C.J.
S116
Kemp, A.D. Strader, S.C.B., S.C.W., M. Mangiarachina, N.
Geary, unpublished data), and this may be manifest in the
selection of foods (75,76) as well as the preferred strategy
used by males and females to defend their body weight
(77). The physiological basis of these sex differences is an
important clinical issue, since males are far more likely to
develop symptoms of the metabolic syndrome (70),
whereas females are far more likely to develop eating
disorders (78).
Risk factors for developing type 2 diabetes. Although
insulin and leptin each signal the degree of adiposity to the
brain, and whereas each lowers food intake as well as
hepatic glucose secretion, they do so by stimulating dif-
ferent ARC neurons and circuits (79) as well as by altering
different hepatic enzyme systems (80). Further, each has
important other functions. Insulin is a major controller of
the levels and utilization of glucose throughout most of the
body, including the brain (9,11). Leptin also influences
glucose parameters via the brain, although via different
neural circuits than stimulated by insulin (80). Low circu-
lating leptin and the resultant decrease of leptin signaling
have been hypothesized to regulate many vital systems
when animals are severely hypocaloric and have low body
fat (81– 83). The secretion of insulin is adjusted in re-
sponse to every acute change of metabolism (9,84), with
levels increasing during meals or when glucose is elevated
for some other reason and decreasing during stress and
exercise. The half-life of insulin in the blood (2–3 min) is
consistent with its role as a minute-to-minute indicator of
ongoing metabolism, and all of its fluctuations are directly
proportional to total body fat (26). Leptin is secreted from
adipocytes in direct proportion to the amount of stored fat
(85) (although the actual stimulus is related more to the
metabolic activity of the fat cell than to actual fat storage
[86] such that dissociations can occur between stored fat
and leptin release, particularly during a fast [86 – 88]).
Nonetheless, under normal conditions and with a half-life
of 45 min, plasma leptin levels are a reliable and relatively
stable indicator of body fat. Hence, insulin levels reflect
the interaction of ongoing metabolic processes and body
adiposity, whereas leptin levels reflect the activity of
adipose cells more directly.
As described above, both insulin and leptin act in the
ARC (and probably other brain areas) to reduce food
intake and body weight, and both also act in the ARC to
reduce hepatic output of glucose. In some instances, the
overlap of function may result from common intracellular
signaling pathways of insulin and leptin, since both acti-
vate a pathway using insulin receptor substrate 1 and 2,
and both cause increased intracellular cAMP degradation
(89 –91). Insulin upregulates the expression of mRNA of the
long form of the leptin receptor (OB-Rb) in neuronal but not
other cell types (92), and insulin facilitates leptin’s ability to
activate the JAK-STAT pathway in the hypothalamus (90,93).
Both leptin (94,95) and insulin (94,95) exert their catabolic
action through phosphatidylinositol 3-kinase.
INSULIN AND LEPTINⴕS INTERACTION WITH CENTRAL
NEUROPEPTIDES
Insulin and leptin interact with two populations of ARC
neurons. Activity of those that synthesize proopiomelano-
cortin, the precursor molecule of the melanocortins, is
stimulated by insulin and leptin, whereas activity of those
that synthesize neuropeptide Y plus Agouti-related protein
is inhibited by insulin and leptin. ␣-Melanocyte–stimulat-
DIABETES, VOL. 55, SUPPLEMENT 2, DECEMBER 2006

ing hormone is a melanocortin that is derived from ARC
proopiomelanocortin and is an agonist at melanocortin
receptors (MC3R and MC4R) in several hypothalamic
nuclei; Agouti-related protein is an endogenous antagonist
of these same melanocortin receptors. Central administra-
tion of insulin or leptin, or the administration of ␣-mela-
nocyte–stimulating hormone or synthetic agonists for
melanocortin receptors, or the application of treatments
that reduce ARC neuropeptide Y (e.g., antisense oligonu-
cleotides administered directly into the ARC [96]), all
result in reduced food intake and body weight. Conversely,
the administration of neuropeptide Y, Agouti-related pro-
tein, or synthetic melanocortin antagonists, or the absence
of endogenous insulin or leptin signaling, all result in a net
increase of food intake and body weight (rev. in 11,83,97–
101).
OTHER ACTIONS OF INSULIN WITHIN THE BRAIN
It is important to consider what a change in the insulin
signal at its receptor in diverse brain areas actually signi-
fies. The obvious answer is that acute changes of insulin
reflect an increase (or decrease) in energy in the form of
glucose interacting with the pancreas, whereas sustained
changes additionally reflect the amount of fat stored in the
visceral or abdominal region. Based on this, it is easy to
generate an explanation for why neurons in the medio-
basal hypothalamus express insulin receptors, since these
neurons are intimately involved in the regulation of energy
homeostasis. An intriguing related question, however, con-
cerns the rationale for more remote areas of the brain to
express insulin receptors, such as the hippocampus or the
olfactory bulb.
In the hippocampus, immunoreactivity for insulin recep-
tors is found in the molecular layer of the dentate gyrus
and on dendrites of CA1 pyramidal cells (51,102). Insulin
binding in the hippocampus is colocalized with immuno-
labeled phosphotyrosine (54) and insulin receptor sub-
strate 1 (103), and as is discussed above, these compounds
are important for the insulin receptor’s intracellular sig-
naling pathways (104). Thus, the binding of insulin in the
hippocampus, as it is in the hypothalamus, appears to be
closely associated with functional effects of insulin. Glu-
cose metabolism in hippocampal cells is sensitive to
application of exogenous insulin (105), and this sensitivity
depends on the insulin receptor (106,107). Further, insulin
receptors in the hippocampus are localized in dendritic
fields, suggesting a neuromodulatory role (51,54,55). Fur-
thermore, there is a relationship between certain meta-
bolic disorders and cognitive decline (108). In diabetes, for
example, patients must rely on exogenous insulin admin-
istration to keep blood glucose levels within a life-sustain-
ing range. These patients also often exhibit increased
cognitive impairment correlated with the progression of
their diabetes (109). Other disease states are also accom-
panied by changes in metabolic status. The progression of
diverse central nervous system disorders such as Hunting-
ton’s disease (110), Parkinson’s disease (111), and schizo-
phrenia is correlated with changes in glucose levels,
insulin, and metabolic activity. Likewise, the progression
of Alzheimer’s disease is correlated with disturbances in
basal insulin levels as well as glucose metabolism (112).
More striking is the finding that when Alzheimer’s
patients are made hyperinsulinemic, their performance on
several assessments of memorial tasks is improved (113).
Importantly, this occurs even at doses of insulin that do
DIABETES, VOL. 55, SUPPLEMENT 2, DECEMBER 2006
S.C. WOODS, S.C. BENOIT, AND D.J. CLEGG
not affect peripheral glucose levels. Further, hyperinsu-
linemic states do not appear to increase Alzheimer’s
patients’ performance on visual-spatial or physical-coordi-
nation tasks. This finding adds support to the hypothesis
that insulin levels are specific to cognitive process (e.g.,
memory) in Alzheimer’s patients. Finally, patients with
type 2 diabetes who are insensitive to the effects of insulin
(i.e., who are insulin resistant) are also impaired on some
measures of cognitive ability (114 –117). These and other
findings encourage the hypothesis that insulin plays an
important role in normal cognitive functions and memorial
processes. Moreover, it encourages the hypothesis that
alterations in insulin signaling may play an important role
in neurodegenerative disease.
In addition to the epidemiological and clinical studies, a
growing body of evidence from animal experiments also
implicates insulin as an important factor in learning and
memory (118). Experimental removal of insulin leads to
disrupted learning and performance. For example, admin-
istration of streptozotocin leads to impaired learning on a
number of learning tasks in mice (119). In rats, streptozo-
tocin-induced diabetes leads to disrupted performance on
avoidance tasks and in Morris water mazes (109,120 –123).
Central streptozotocin also produces impairment in work-
ing and reference memory in rats (124), and it alters
intracellular signaling by N-methyl-D-aspartate (125) and
␣-amino-3-hydroxy-5-methyl-4-isoxaziole-propionate (126)
receptors that are implicated in the development of long-
term potentiation (127). Thus, disruption of systemic
insulin signaling is associated with impairments of memo-
rial processes in rodents.
Importantly, administration of exogenous insulin im-
proves performance on some learning tasks and corrects
the learning and memory deficits produced by streptozo-
tocin or diabetes. For example, administration of exoge-
nous insulin improves rats’ performance in the one-trial
learning of a passive avoidance task (128,129). It also
ameliorates the diabetic impairments observed on radial-
arm maze tasks and water mazes (122,123). A key point is
that administration of insulin directly into the brain, where
it does not improve peripheral glucose metabolism, also
improves learning (128,130), although some studies have
reported contradictory findings, i.e., that administration of
insulin impairs learning and memory performance (131–
134).
Therefore, data from both humans and animals support
the hypothesis that insulin is an important factor in
memorial processes. However, the exact nature of that
role remains elusive. This is due, in part, to the fact that
much of the previous work suffers from one or both of two
serious confounds. First, it is often difficult to disentangle
the effects of altered insulin from the effects of altered
metabolism. Large changes in basal insulin levels can
produce profound disruptions in metabolic status that
might account for some of the observed disruptions in
learning in and of themselves. Second, because most
manipulations of insulin occur systemically, it is difficult to
identify the effects of insulin uniquely in regions of the
brain known to be important for learning and memory.
Finally, the ability of insulin to improve cognitive behavior
might be task or reinforcement specific. It might be, for
example, that increased insulin in the hippocampus, which
reflects an increase of available energy in the body,
facilitates learning tasks that help procure food. That is,
elevated insulin might well enable remembering where
food is located, or the best time to access it, or related
S117
 BRAIN-GUT-ISLET AXIS
factors. Likewise, increased insulin activity in the olfac-
tory bulb could help form associations between specific
odors and food. The point is that any general hypothesis of
insulin action in the brain must account for what changes
of insulin actually reflect.
DIETARY FAT, OBESITY, AND INSULIN RESISTANCE
As previously mentioned, when leptin is administered into
the brains of experimental animals, there is a selective
reduction of body fat, with lean body mass being spared
(135). Likewise, when insulin is administered into the
brain, there is a reduction of the respiratory quotient,
suggesting that the body is oxidizing relatively more fat
(136). These observations suggest that one action of these
adipose signals within the brain is to reduce body fat, and
a corollary of this is that fat ingestion would be expected
to be reduced as well. Consistent with this, we have
observed that when insulin is administered into the third
cerebral ventricle of rats, fat intake is selectively reduced
(137). Hence, it is reasonable to hypothesize that leptin
and insulin, acting in the brain, reduce body fat by
increasing lipid mobilization and oxidation and simulta-
neously by reducing the consumption of dietary fat.
When animals become obese after exposure to high-fat
diets, they become resistant to leptin and insulin’s ability
to regulate food intake and body weight. The epidemiolog-
ical data that increasing dietary fat accelerates the devel-
opment of obesity are quite compelling and have been
summarized in several reviews (138 –140). Animal studies
provide strong corroborative evidence, i.e., across numer-
ous experiments, diets, and species, and the conclusion
that increased consumption of high-fat diets leads to
increased body fat is inescapable (141–148). Importantly,
there are strong genetic influences that dictate whether or
not a given individual will be prone or resistant to becom-
ing obese when exposed to a high-fat diet (141,146,149 –
153). As Bray and Popkin (138) point out, a high-fat diet
can be viewed as the environmental agent that acts on a
susceptible host animal to produce the noninfectious
disease obesity. Importantly, the consequences of obesity,
including dietary-induced obesity, are well documented
and include type 2 diabetes and insulin insensitivity.
Further, some detrimental effects of dietary fat are not
limited to obese individuals. For example, we have re-
cently demonstrated that while high-fat diet–induced obe-
sity decreases central sensitivity to the anorexic effects of
central insulin administration, increased dietary fat, in the
absence of frank obesity, also attenuates the potency of
central insulin to reduce food intake and body weight (148;
K. Gotoh, M.D. Wortman, S.C.B., D.J.C., D. D’Alessio, P.
Tso, R.J. Seeley, S.C.W., unpublished data).
HIPPOCAMPAL INSULIN RESISTANCE
Consistent with the concept that insulin acts in multiple
regions of the brain to influence multiple processes, di-
etary-induced insulin resistance has recently been linked
to impaired cognitive function in both humans and ani-
mals. Specifically, high levels of dietary saturated fats and
simple carbohydrates (which promote insulin resistance
and obesity) have been demonstrated to reduce hippocam-
pal-dependent memory processes. For example, Gomez-
Pinilla and colleagues (154) have shown that long-term
access to obesigenic diets impairs rats’ performance in the
Morris water maze task, a classic measure of spatial
memory. These deficits are associated with reductions in
S118
FIG. 2. Insulin has many actions in the brain. A: Insulin circulates in the
blood in direct proportion to stored calories. Within the hypothalamus,
it regulates food intake and energy expenditure, thus contributing to
the maintenance of a relatively stable body weight. B: Insulin levels are
also a function of blood glucose. Elevated glucose increases insulin
secretion, and the increased insulin signal in the hypothalamus reduces
hepatic glucose secretion, thus contributing to the regulation of blood
glucose. C: Insulin stimulates receptors in the hippocampus, facilitat-
ing certain kinds of learning and memory. This action, as well as an
action in the olfactory bulb, is hypothesized to facilitate foraging
behavior.
hippocampal expression of brain-derived neurotrophic
factor mRNA (155). We and others have found that in-
creased body weight and peripheral metabolic disruptions
are also associated with reduced insulin receptor gene
expression in the hippocampus. Several important ques-
tions remain unanswered, however, including the specific
molecular mechanisms by which central insulin resistance
might lead to decreased expression of such factors as
brain-derived neurotrophic factor.
SUMMARY
To summarize, increased insulin in the mediobasal hypo-
thalamus provides a signal that ample or excess energy is
available in the body, and one consequence is a reduction
of food intake. It has recently been reported that the
increased hypothalamic insulin signal also elicits a vagal
reflex to the liver that reduces glucose secretion. In-
creased insulin (and probably leptin) locally within the
hypothalamus therefore can be considered to be analo-
gous to other signals that indicate a surfeit of energy in the
body. In addition to satiety and adiposity signals, this
includes certain lipids and glucose, and there is compel-
ling evidence that overlapping intracellular signaling path-
ways within the mediobasal hypothalamus mediate the
overall catabolic response to these diverse metabolic
signals. Insulin receptors are also densely expressed in the
hippocampus, and there is evidence that insulin acts there
to facilitate certain cognitive functions. The function of
insulin receptors in other brain areas is poorly understood.
Obesity and/or the consumption of diets high in fat render
the brain as well as the body insulin resistant. In the
hypothalamus, this is manifest as a reduced ability of
insulin to reduce food intake and body weight, and in the
hippocampus, it is manifest as a reduced ability of insulin
to improve learning and/or memory. Figure 2 is a model
depicting some of the feedback loops involving insulin in
the brain.
DIABETES, VOL. 55, SUPPLEMENT 2, DECEMBER 2006

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