INSULIN, LEPTIN, AND FOOD REWARD:
Dianne P. Figlewicz1,2 and Stephen C. Benoit3
1VA Puget Sound Health Care System, Seattle Division, Seattle WA 98108, 2Dept. of Psychiatry
and Behavioral Sciences, University of Washington, Seattle WA 98195, and
3Dept of Psychiatry, University of Cincinnati, Cincinnati OH 45237
Dianne Figlewicz Lattemann, Ph.D.
Research Career Scientist, VA Puget Sound Health Care System
Research Professor, Depts of Psychiatry & Behavioral Sciences,
University of Washington
Address: Metabolism/Endocrinology (151)
VA Puget Sound Health Care System
1660 So. Columbian Way
Seattle WA 98108
This article has not been submitted for publication elsewhere.
Articles in PresS. Am J Physiol Regul Integr Comp Physiol (October 22, 2008). doi:10.1152/ajpregu.90725.2008
Copyright © 2008 by the American Physiological Society.
The hormones insulin and leptin have been demonstrated to act in the central nervous system
(CNS) as regulators of energy homeostasis, acting at medial hypothalamic sites. In a previous
review (2003) we described new research demonstrating that in addition to these direct
homeostatic actions at the hypothalamus, CNS circuitry that subserves reward and motivation is
also a direct and indirect target for insulin and leptin action. Specifically, insulin and leptin can
decrease food reward behaviors and modulate the function of neurotransmitter systems and
neural circuitry that mediate food reward, i.e., midbrain dopamine (DA) and opioidergic
pathways. Here we provide an update, summarizing new behavioral, systems, and cellular
evidence in support of this hypothesis, and in the context of research into the homeostatic roles
of both hormones in the CNS. We discuss some current issues in the field, which should provide
additional insight into this hypothetical model. The understanding of neuroendocrine modulation
of food reward, as well as food reward modulation by diet and obesity, may point to new
directions for therapeutic approaches to overeating or eating disorders.
Key Words: insulin, leptin, motivation, food intake, reward, dopamine
Recent data suggest that the peripheral regulators of energy balance, leptin and insulin, may play
important roles in the occurrence of behaviors typically classified as non-homeostatic. For
example, central insulin and leptin are sufficient to reduce operant responding for palatable foods
and to attenuate food-induced conditioned place preferences independent of their effects to
regulate energy balance. Since findings such as these have generated much interest in the
potential roles of central leptin and insulin signaling in brain reward pathways, we believe it is
instructive to begin with a consideration of such findings in a larger historical context. In fact,
the observation that energy balance or deprivation-state can significantly influence behavioral
responses to obtain food or the reward associated with food is many decades old. In one early
theoretical conceptualization, Clark L. Hull (98,99) proposed that responding or motivation
could be explained by the equation,
sEr = sHr x D x K
where sEr represents the reaction potential or motivation of a behavior; sHr represents the habit
strength or number of experiences; D represents drive or hours of deprivation; and K represents
the value, reward or hedonic quality of the food to be obtained. Hull reasoned that the
expression of a behavior was a direct function not only of learning and experience, but also the
“need” state and the “value” of the food available. As an example, one might train a rat such that
pressing a lever delivers a food pellet. After learning the task, the number of presses on any
given trial would be significantly increased by food depriving the rat and/or increasing the
incentive and hedonic properties of the pellet (such as would be the case with high-fat high-sugar
food pellets). Along these lines, B. F. Skinner observed that response rates on different
schedules of reinforcement in pigeons were significantly increased by restricting their body
weight. In an early series of studies, Skinner and colleagues observed a direct inverse
relationship between the birds’ body weight and their rates of responding for food pellets (64).
Food restriction of experimental animals in these and other similar studies was often imposed to
increase the occurrence of the behaviors which the experimenters sought to study. In many
cases, rats, mice and other experimental animals are regularly food deprived so that the behavior,
neurobiology and genetics of learning and memory can be studied using food reward paradigms.
In this way, the relationship between energy balance and “reward” or “reinforcement” has been
well-characterized (31,34), though for reasons largely unrelated to that which now generates
much interest and enthusiasm: the idea that the modern epidemic of obesity may be in part
related to reward and hedonic mechanisms, and that failure of regulatory systems might be
related to dysregulations of reward-systems. The historical lesson is that food deprivation or
negative energy balance promotes responding for foods and other reinforcements. Coupled with
our current knowledge that negative energy balance leads to low levels of circulating leptin and
insulin, this leads to the hypothesis that low levels of these hormones might be associated with
increased responding to obtain rewards. It also suggests the corollary hypothesis that increased
leptin and insulin might be sufficient to attenuate responding for reward. In fact, recent and
historical data are consistent with both hypotheses and are summarized below. An intriguing
speculation based on Hull’s formulation is that signals that reflect energy balance would be
included in the variable of ‘drive’ (D), and as such would be predicted to act by altering the gain
of other factors determining motivation.
In 2003 we published a review exploring ‘a new CNS role for adiposity signals’ (65). Since that
review, a number of studies have been carried out, which, first, confirm the actions of insulin and
leptin to decrease food reward and the motivation to feed, and, second, have begun to explore
cellular and CNS circuitry-related mechanisms. Here, we provide an update of the field and
critical discussion of newly developing questions. An early and continued research focus has
been on the actions of these two hormones at the medial hypothalamus which historically has
been identified as playing a major role in the CNS regulation of metabolism, energy balance, and
caloric intake in terms of physiological need. Because the behavioral, cellular, and molecular
actions of insulin and leptin at the medial hypothalamus have been well-studied, this material is
summarized briefly. We refer the reader to recent reviews, including our 2003 review, which
provide more detailed discussion and historical references on this topic (1,11-13,65,96,167,194),
which has provided the groundwork for studies assessing food reward regulation.
INSULIN AND LEPTIN: ADIPOSITY SIGNALING IN THE CNS
In 1979, it was demonstrated in non-human primates that insulin infused into the CNS caused a
significant decline in the animals’ food intake and body weight (193). This observation was
made in the context of a contemporary model, that circulating humoral factors could regulate
both size of individual meals, as well as food intake and body weight over a longer time course
(47,124,141,177). Woods and Porte (193) proposed that insulin served as an ‘adiposity signal’
and completes a negative feedback loop that links the behavior of feeding with size of adipose
stores (153). Many studies over the intervening decades have essentially validated this basic
concept (e.g., (2,3,4,25,38,125). In the mid-90s the candidate adiposity signal and adipose
hormone, leptin, was identified (197), and has been well-characterized as a regulator of energy
As reviewed earlier (65), two critical issues needed to be addressed in order to argue for a role
for adiposity signals in modulating any aspect of CNS function. The first issue is the need for
circulating signals to have access to CNS circuitry. The presence of insulin in the CNS was
reported in 1979 (88), and many studies established that the predominant amount of insulin in the
CNS can be accounted for by receptor-mediated
(46,52,53,79,106,115,164,165). Although intermittent reports have suggested that insulin can be
synthesized locally in the developed CNS, quantities appear to be negligible particularly when
compared to the affinity of the receptor for insulin. The relationship between CNS and plasma
levels of insulin is saturable (non-linear), consistent with a receptor-mediated transport process.
In the 1990s, the adipose hormone leptin was identified and knowledge rapidly acquired, that it
(likewise) could be transported by
(7,10,92,109,121,123,137). Relative levels of both leptin and insulin in the CSF are decreased in
association with obesity (8,9,30,108,162,163,178). The functional implication is that in
circumstances of chronic hyperinsulinemia and hyperleptinemia, such as obesity, relatively less
adiposity signaling would be available to the CNS.
The second basic issue relates to the presence of insulin and leptin receptors in the CNS.
Receptors for both insulin (48,87,113,181,187,195) and leptin (60,119) are widely expressed
throughout the CNS. Extensive research has established that the medial hypothalamus, a key
center for the regulation of energy homeostasis and coordination of metabolic events, is a major
target for both insulin and leptin action (12,127,142,167). Other CNS sites and neural systems
transport into the CNS
multiple mechanisms into the CNS
are targets for insulin and leptin action (73,81,86,126). Studies utilizing antisense
oligonucleotides against the insulin receptor and conditional, localized knockout of the insulin
receptor, have been utilized to elucidate the contribution of the brain insulin receptor to energy
homeostasis and glucose homeostasis (27,116,145,146). The leptin receptor, likewise extensively
expressed, is present as different splice-variant isoforms in the CNS, with the ‘signaling’ form
OBRb having the major role in leptin action. The obese db/db mouse and Zucker fa/fa rat
represent naturally occurring ‘knockouts’ (41) of the leptin receptor, and recent use of receptor
constructs with modifications in signaling capability validate the importance of CNS leptin
action in energy homeostasis.
Leptin and insulin have multiple effects on energy homeostasis which depend on the activation
of key hypothalamic nuclei and peptides to regulate energy balance (103). Among the most
extensively studied mediators are neuropeptide-Y (NPY) (42,43,166,173,188), POMC and its
product α-melanocyte stimulating hormone (α-MSH), and the melanocortin antagonist, AgRP
(for reviews, see 14,135,168,194). POMC and AgRP are selectively expressed in neurons of the
ARC nucleus colocalized with receptors for insulin and leptin, and they are endogenous circuitry
capable of regulating food intake (40, 128,136). Genetic deletion of the critical melanocortin-4
receptor recapitulates the obese phenotype of leptin deficient mice including obesity (100) and
selective ablation of the AgRP neurons in adult mice causes severe starvation and death (82).
Leptin and insulin increase expression of the agonist α-MSH and decrease expression of AgRP
(see (14) for reviews). Collectively, these data suggest that leptin and insulin act on ARC
melanocortin (AgRP and POMC) neurons to regulate food intake and energy balance. (FIGURE
elucidated several other key
players in the regulation of
food intake and body weight
which are likely to mediate
(directly or indirectly) the
effects of leptin and insulin.
Among these, orexin-A and
melanin concentrating hormone
(MCH) are expressed in the
orexigenic, mice lacking either
peptide or its key receptors
have altered metabolic rates
work has also
suggests that orexin-A may be an important factor in the effects of drugs of abuse. Orexin
antagonists blunt the behavioral response to cocaine and other psychostimulants and may be
important for the rewarding effects of food as well (e.g., ; for reviews see [24,91]).
Much has been learned about intracellular signaling by insulin and leptin in the CNS from
studies in the medial hypothalamus. Initial studies validated that signaling for the CNS insulin
receptor is comparable to post-receptor mechanisms in peripheral target tissues. That is, the
receptor is an autophosphorylating tyrosine kinase, and its activation leads not only to tyrosine
phosphorylation of other proteins including the key signaling moiety, IRS, but also to a cascade
of additional phosphorylation events, including activation of the PI3 kinase pathway (83), and
phosphorylation of Akt/PKB (89,90,112,143,171). The leptin receptor, upon leptin binding, can
likewise initiate IRS phosphorylation, and activation of the PI3 kinase pathway (144). However,
the receptor does not have intrinsic tyrosine kinase activity, thus JAK-Stat signaling is a critical
initial event, leading to transcriptional events, and, ultimately, to the generation of SOCS-3
which provides negative feedback on leptin signaling (119,157). Recently, activation of the
mTOR pathway in medial hypothalamic neurons has been reported, and early studies suggest
that activation of this pathway is correlated with anorexigenic and metabolic homeostasis events
(49). Collectively, these studies support the concept that there are both parallel and unique
intracellular pathways by which insulin and leptin can mediate intracellular events related to
ingestive behavior and caloric homeostasis (36,37,152). They provide correlative or direct
evidence of the importance of these signals in mediating in vivo events. A current research
emphasis is upon differential effects of insulin and leptin, both in terms of time course of action,
intracellular mechanisms, and effects on glucose homeostasis vs. energy balance, within the
hypothalamus. This detailed physiological information will contribute to insights into
pathophysiology. For example, in metabolic circumstances in which plasma insulin or leptin
levels are low (starvation and reduced adiposity), signaling would be decreased and drive for
food intake would be increased. Obesity (excessive adiposity) would represent a
pathophysiologic state in which either adiposity signals are decreased in relative or absolute
amount in the CNS; or there is direct CNS resistance to their action (35,45,54,104,138,184). In
summary, thirty years’ of research have confirmed the overall hypothesis that hormones which
reflect the size of adipose and calorie stores can act directly within the CNS to provide negative
feedback on food intake, and modulate energy utilization. As discussed below, this research has
paved the way for studies of insulin and leptin signaling within reward circuitry.
INSULIN, LEPTIN, AND FOOD REWARD
A current extension of this research focuses upon how environmental factors such as diet
composition can interact with the adiposity signal-CNS feedback loop to modulate the
effectiveness of adiposity signals. In 1988, Bray and colleagues made the observation that
putting rats on a high fat diet resulted in an impairment in the action of insulin, given directly
into the CNS, to decrease body weight (6). This finding was subsequently replicated (39), and a
similar observation has been made for leptin (120). The extrapolation of these observations is
that endogenous adiposity signals in the CNS may also become ineffective at providing feedback
signaling. Data collected by the Centers for Disease Control document a pervasive increase of
obesity in adults across the United States in the 1990s and 2000s (93,129,130), and a high
incidence of obesity in the pediatric age group as well (114), interpreted as a significant
environmental influence over the neural circuitry associated with the physiological maintenance
of energy homeostasis. The epidemiologic finding also emphasizes that attention should be
focused on additional CNS circuitry which is either directly or indirectly connected with
hypothalamic circuitry to modulate feeding behavior.
One obvious target for study is the CNS circuitry which mediates motivation and reward.
Components of this circuitry are activated with, and contribute to, complex behaviors such as
food seeking and food intake ((16,18,19) and see below). This circuitry including portions of the
cerebral cortex, hippocampus, amygdala, and the striatonigral pathway, which is implicated in
transposing motivational aspects of stimuli into motor responses, as well as hedonic evaluation
of the stimulus and associative learning (61,101,105,150,156,158,189,191). As discussed below,
the major neurotransmitter pathways associated with motivation and hedonics are mesolimbic
dopamine (DA) and certain CNS opioid pathways. In terms of neural connectivity, the
hypothalamus is linked to the ‘motivational circuitry’ of the CNS, and numerous mono- and
multi-synaptic pathways between different components of the limbic circuitry and the
hypothalamus have been identified (e.g., 19,20,179). The anatomical and functional relevance of
this circuitry to food intake is discussed in recent reviews (16,110,111). Insulin and leptin
receptors are expressed throughout the limbic forebrain, including the hippocampus; the
amygdala; and the lateral hypothalamic/zona incerta area (69,118,119). This provides one
rationale for exploring the potential that the limbic forebrain may itself be a direct target for
insulin or leptin.
Food intake can be driven by energy demands, i.e., “homeostatic” feeding. However, food
intake can also be driven by the palatability or pleasure associated with eating a preferred food,
“non-homeostatic” feeding (18-20). The palatability of a particular food source is assumed to be
related to the flavor and taste of that food and high-fat diets are generally considered more
palatable than diets that are low in fat, as they are preferentially over-consumed. In humans,
individual differences exist in the reinforcing value of food with obese individuals displaying a
stronger preference for diets high in fat and carbohydrates relative to non-obese individuals (57-
Berridge and colleagues have provided a conceptual framework for the consideration of food
reward, proposing that there is ‘wanting’ of food (or another stimulus) and ‘liking’ of food (16).
The behavior associated with non-homeostatic feeding is in part regulated by the mesolimbic
dopamine system (18), and within this system, the neurotransmitter dopamine plays a substantial
role in the regulation of food reward. They have identified nucleus accumbens (NAc) dopamine
projections as central to ‘wanting’. The NAc represents a functionally specialized subregion of
the striatum which is a critical anatomical component of CNS reward circuitry, with the
extensive projection of DA neurons from the midbrain ventral tegmental area (VTA) and
associated DA cell groups (substantia nigra) (101,102). Activation of these midbrain DA neurons
has been implicated in the motivating, rewarding, reinforcing and incentive salience properties of
natural stimuli such as food and water, as well as drugs of abuse (16,18,155,161,176,192). The
neural mechanisms of food reward are believed to be similar, if not identical, to drug rewards
(29,111). There is also the possibility that dysregulation of those circuits may adversely affect
body weight regulation. For example, studies in humans (183) and animals (21) suggest that
changes in central dopamine may contribute to the development of obesity. Further, some
human studies report that obese individuals have a decreased propensity to engage in the use of
recreational drugs and a decreased frequency of substance abuse disorders (172,185). One
implication of these findings is that obesity is capable of altering processes within the
endogenous reward system of the brain.
Behavioral paradigms evaluating reward and food reward provide evidence for a significant
effect of metabolic status on performance in these paradigms, and support the idea that both
insulin and leptin may play a role in modulating reward function in the CNS (74). Food
restriction or fasting paradigms (in which endogenous insulin and leptin are both decreased)
enhance the addictive or reinforcing properties of drugs of abuse, as found in both drug self-
administration and relapse to drug-taking paradigms; intraventricular leptin can reverse food
deprivation-induced relapse to heroin self-administration (34,169,170). Measurement of DA
levels in nucleus accumbens interstitial fluid has shown that there is a greater DA response to
food reward in rats that are food-deprived vs. ad lib fed rats (190). Data from the experimental
approach of brain self-stimulation have shown that food restriction shifts the dose response curve
for self-stimulation in some perifornical hypothalamus sites to the left, such that weaker
electrical current that normally would not support sustained self-stimulation activity at these sites
becomes efficacious when animals are maintained on a food-restriction paradigm (31,32).
Intraventricular leptin administration shifts the dose-response curve for self-stimulation in food
restriction-sensitive perifornical hypothalamic sites to the right (i.e., reverses the effect of food
restriction); and comparable data demonstrate that administration of insulin into the brain of
either food-restricted or ad libitum feeding rats increases the threshold current needed to sustain
lateral hypothalamic self-stimulation, both reversing the decreased threshold observed with
fasting, and elevating the threshold above its ‘free-feeding’ level (33,76). This evidence,
although limited, suggests that insulin and leptin may play a major role in mediating the effects
of altered metabolic status on reward paradigms in general.
Additionally, several studies implicate insulin and leptin in food reward per se. In addition to
normal feeding, DA activity has been implicated in behavioral paradigms that evaluate different
aspects of reward or motivation: acute licking of palatable solutions (50,160); self-administration
(102); and the conditioning of a place preference (148). Figlewicz and colleagues have
demonstrated suppression of acute sucrose licking (intraventricular insulin) (175); food-
conditioned place preference (intraventricular insulin or leptin) (66); and sucrose self-
administration (intraventricular insulin or leptin) (68) in rats fed ad libitum chow. In these
studies, doses of insulin and leptin were sub-threshold for effects on chronic food intake, or on
body weight, and are observed very acutely (timeframe of minutes). DiLeone and colleagues
(95), and Morton and colleagues (134), have now demonstrated that direct administration of
leptin into the VTA decreases chow intake in ad lib feeding rats. Taken together, the results of
these four different types of behavioral paradigms—self administration, lick rate task, CPP and
free-feeding of the baseline diet, chow—demonstrate that insulin and leptin, across a
concentration range from fasting to free-feeding to elevated (as would occur postprandially)
levels, are able to modify behaviors that reflect acute and learned reward evaluation, independent
of their action(s) to regulate body adiposity. Whether the rapid and chronic effects of both insulin
and leptin are mediated via the same circuitry and the same neural mechanisms remains to be
elucidated. Further, there appear to be different anatomical loci implicated as targets for insulin-
and leptin-induced suppression of food reward, including the lateral hypothalamus (33,76,118).
Studies from Figlewicz and colleagues have focused on insulin and more recently, leptin, effects
on the midbrain DA neurons at both the cellular and the behavioral level. Insulin receptors have
been identified in the VTA and the striatum in previous anatomical studies using receptor
autoradiography and receptor immunocytochemistry approaches (181,187), and insulin and
leptin receptor mRNA is expressed in the substantia nigra (60). We have localized both insulin
receptors and leptin receptors on midbrain DA neurons, including those of the VTA, as well as
medial and lateral substantia nigra (69). The presence of functional receptors has been confirmed
by work of Fulton (75) and Hommel (95). Thus, this critical motivational circuitry has the
potential to serve as a direct target for adiposity signals. Recent studies have identified that
insulin and leptin increase PI3kinase activity when given directly into the VTA (71). Further,
leptin (administered peripherally, intraventricularly, or directly into the VTA) increases Jak-
STAT phosphorylation, and this is critical for the effect of leptin in the VTA to decrease chow
feeding (134). The identification of synaptic or neural mechanisms that underlie insulin and
leptin effects on food reward remain to be elucidated. We have identified one potential cellular
target for insulin action: the dopamine re-uptake transporter (DAT), which inactivates DA
signaling by transporting DA back into the DA nerve terminal from the synapse (107). Both the
synthesis, and the activity or synaptic concentrations, of the DAT can be regulated by
intracellular signaling systems including PI3kinase (77,182). We have observed both in vivo and
in vitro effects of insulin on expression and activity of the DAT (72,149): Insulin can increase
mRNA levels of, and synaptic activity of, the DAT. The functional implication of this would be
that increased DAT activity could result in increased clearance of DA from the synapse, and
hence, decreased DA signaling. This would be consistent with an action of insulin to decrease
the rewarding aspect of food. Comparable cellular studies to identify regulatory proteins in DA
neurons that are targets of leptin have not been done, although there is evidence that leptin
regulates DA release and the electrical activity of DA neurons.
As mentioned above with respect to energy homeostasis, some effects of insulin and leptin are
medited through secondary hypothalamic peptide effector systems, including melanocortins and
orexin-A. For example, melanocortin receptors (MC3R and MC4R) are also expressed in brain
regions implicated in addictive behavior (e.g., ) and pharmacological studies have outlined
functional roles for these receptors in the modulation of drug-taking behavior. Antagonism of
these receptors in nucleus accumbens inhibits operant responding for cocaine, while central
agonism of this system augments amphetamine-induced behaviors (e.g., ). As discussed
elsewhere, orexin neurons exhibit diverse projections in the CNS to sites including the VTA
(e.g., ). Orexin-expressing neurons of the LH have mu-opioid receptors; and the molecular
physiology of these neurons is altered with morphine administration or withdrawal, emphasizing
their role in CNS reward circuitry (78). Orexinergic projections signal specifically on a majority
of dopamine neurons to activate the mesolimbic pathway (198), and VTA neuron populations
express both orexin receptor subtypes (122). Exogenous orexin can increase VTA dopaminergic
neuron firing rates. A specific role for endogenous orexin action in the VTA on reward-seeking
behavior is implied in the findings that an orexin antagonist could block the reinstatement of an
extinguished place preference for morphine, and that intra-VTA orexin-A was sufficient to
reinstate the place preference, in rats (84). Additional evidence comes from studies of genetic
models demonstrating the inability of orexin-deficient mice to form morphine-CPPs (140).
Orexin action in the LH also appears necessary for the acquisition and expression of morphine-
induced CPP (85). Finally, Borgland (23) reported that intra-VTA administration of an orexin
antagonist effectively prevents behavioral sensitization and neurophysiological changes that
typify chronic cocaine use. The important point is that to the degree that peripheral adiposity
signals may affect reward function, they are likely to do so in part through these critical effector
peptides. One important consequence of this could be that neither insulin nor leptin would have
CNS SITES OF
CNS SITES OF
OPIOID- -STIMULATED STIMULATED
to act directly on VTA or NAc cells to exert regulatory control. Rather, as an additional
mechanism, they could activate (or inactivate) effector systems in hypothalamic neurons that in
turn project to the reward circuitry. This is supported by a recent study evaluating the specific
CNS targets of intraventricular insulin to suppress food reward: The effect of insulin to decrease
sucrose self-administration was found to be due to action at the arcuate nucleus (67).
INSULIN, LEPTIN, AND PALATABILITY
Palatability influences both the amount and type of food that is ingested (15-17). For example, it
is well known that even non-caloric solutions will elicit drinking behavior in sated rats if they are
made to taste sweet (28). Several hypothalamic peptides project to CNS areas important for taste
processing (nucleus of the solitary tract), and hedonics and reward, including the VTA, nucleus
accumbens, and substantia nigra. As discussed above, this system is a direct target of both
insulin and leptin, and suggests one mechanism whereby adiposity signals might modulate
palatability. Berridge and colleagues have suggested that ‘liking’ of foods is mediated in the
CNS by endogenous opioids. Leptin and insulin, which simulate a state of satiation, have been
found to regulate the hedonic qualities of brain self-stimulation (76), for which CNS opioidergic
signaling has been implicated (32). Work from Levine and colleagues, and other labs, has
documented the role for opioid peptides to preferentially enhance intake of palatable food over
less palatable food (rat chow) (80), although this is somewhat dependent upon the opioid
receptor populations being targeted. Thus, some opioid receptive sites appear linked
predominantly to palatability, some to caloric homeostasis (22,147,196). The question of
whether adiposity signals
can blunt palatability-
induced feeding has been
evaluated to a limited
extent. Figlewicz and
colleagues reported that
could both blunt the
ability of the exogenous
sucrose pellet intake, and
also synergize with a
subthreshold dose of the
decrease baseline intake
of sucrose pellets (174).
(FIGURE 2 HERE.) This would be consistent with an action at the medial hypothalamus, where
dynorphin receptors have been localized. Additionally, they have reported a direct action of
insulin and leptin at the VTA to reverse mu opioid-stimulated sucrose feeding (71). Although
this study did not evaluate palatability per se, rats were tested immediately after feeding and thus
sucrose intake would not reflect caloric need, but presumptively correlated with liking of the
sucrose. Given the identification in human eating disorders of a role for mu opioids (57) such
studies have potential clinical relevance. This is underscored by the recent report that leptin
treatment in two obese leptin-deficient patients was sufficient to reduce food intake, reduce self-
report ratings of preference for images of food, and reduce neural activity in the striatum (63).
The table below summarizes the effects of insulin and leptin on reward behaviors. Studies that
have focused specifically on reward behavior linked with food, or feeding stimulated within
reward circuitry, have not evaluated the possible generalization of insulin or leptin effects on
other types of reward (e.g., drugs of abuse). However, the generalized effect of food restriction
on drug-seeking (34), and the study of Shalev et al. demonstrating leptin reversal of food
restriction-induced heroin relapse (170), suggest that insulin, leptin, and other signals of
metabolic status (e.g., ghrelin) may act by modulation of dopaminergic or opioidergic function.
EFFECTS OF INSULIN OR LEPTIN ON REWARD BEHAVIORS
Behavior Insulin (Route)
Brain self-stimulation decrease (ICV)
Relapse to heroin seeking
Acute sucrose licking decrease (ICV)
Food-conditioned place preference decrease (ICV)
Sucrose self-administration decrease (ICV,ARC) decrease (ICV)
Acute chow intake (4-24 hr) decrease (ICV)
Opioid-stimulated sucrose intake decrease (ICV,VTA) decrease (VTA)
A final point to emphasize about these effects is that there are both extremely acute effects
(timeframe of minutes) and longer-acting effects, i.e., the effect of intra-VTA leptin on 24-h
chow intake (not yet examined for insulin). This is consistent with observations of both acute
and chronic leptin action on energy regulatory circuitry and its function, as well. The very acute
effects of insulin, whether observed in fasted/food-restricted or free-feeding rats, support the
possibility that within the context of a meal or eating bout of (e.g.) 30 min’ duration (a timeframe
that would correspond to increased insulin access to the CNS) prandial insulin elevation may
curtail meal size by impacting on the rewarding aspects of food. Currently, there are no data
evaluating interaction or synergy of insulin and leptin on food reward, and such studies now
INSULIN, LEPTIN, AND FOOD REWARD IN MODELS OF RESISTANCE OR
While the findings described above have been obtained in non-obese rats and, for the most part,
in rats eating a conventional (low fat) chow diet ad libitum, recent studies evaluating reward
function and circuitry in animals that are significantly food restricted, chronically maintained on
a high fat diet, or obese, suggests that disordered energy homeostasis has a significant impact on
the regulation of food reward, and CNS DA activity. For example, duration and severity of food
restriction have opposite effects on DA release and DA turnover, within the nucleus accumbens
(154,190). Likewise, the genetically obese ob/ob mouse, which lacks functional leptin, has
decreased DA turnover in the nucleus accumbens (75); and releasable DA stores are decreased
(159). This contrasts with studies demonstrating that intraventricular leptin in non-obese rats
decreases basal and food-stimulated DA release in the nucleus accumbens (117), and directly
decrease (ICV, SC)
decrease (ICV, VTA) 2,3,75,95,134
decreases DA neuronal activation (95). In terms of behavior, a 5-week exposure to moderately
high fat diet, that did not induce frank obesity, has been shown to increase sucrose self-
administration and to block the ability of intraventricular insulin or leptin to suppress it (68). In
contrast, rats put on a high fat diet for an extended period of time display decreased sucrose self-
administration (51). In that series of studies, rats were maintained on high fat diet for
approximately 3 months before undergoing training for sucrose self-administration, with one
group fed high fat diet ad libitum, and a separate control group pair-fed the high fat diet, to
matched the kcal consumed by a low-fat control-fed group. The pair-fed group did not exhibit
significant increased body mass or adiposity, but both groups of rats consuming the high fat diet
had elevated plasma (and presumptively, CNS) levels of leptin, and both groups exhibited
attenuated sucrose self-administration, relative to controls. One obvious interpretation of this
finding is that the rats compared high fat diets and sucrose and, in effect, access to the high fat
diet in the homecage decreased the perceived reward value of sucrose. To assess whether this
difference in responding was due solely to such a ‘contrast effect’ for food, conditioned
responding for amphetamine was also assessed. AMPH injection conditioned a place preference
only in rats maintained on low-fat diet. Consistent with this, DA turnover in the nucleus
accumbens was found to be substantially decreased in rats maintained on high fat, relative to low
fat, diet. Thus it appears that additional mechanism(s) for an interaction between chronic access
to high fat diet and brain reward circuitry must be invoked. It seems reasonable to propose that
impaired DA release underlies the altered reward behaviors in rats fed the high fat diet, a
hypothesis which can be readily evaluated experimentally.
A common factor among these models--chronic food restriction, diet-induced obesity, and
genetic obesity—is an absence of normal leptin and insulin action. Even short term access to
high fat diet is able to inhibit central leptin or insulin signaling in the CNS. For example,
previous research has suggested that as little as 3-days’ access to high fat diet is sufficient to
attenuate the central effects of insulin and leptin on food intake and glucose homeostasis
(104,132,137,139,152,184). These findings suggest that dietary dysregulation of leptin and
insulin effects on reward would not be solely due to hedonic contrast in general, or with respect
to food reward specifically. Intriguingly, studies from other model systems suggest that both
insulin (133,180) and leptin (186) may provide trophic effects on DA neurons, hence models of
extreme starvation, insulin and leptin resistance, or obesity may result in impaired DA neuronal
function and signaling. Studies in the dopamine-deficient mouse model suggest that other CNS
circuitry may be recruited to mediate reward function, in the absence of functional DA circuitry,
for example, Hnasko and colleagues (94) have demonstrated that serotonergic pathways mediate
cocaine reward in this model. While the limitations and specific parameters of the models cited
here need to be taken into account, it nonetheless should be considered that states of very low
insulin and leptin action would result in low or an-hedonic, mood and affect, and motivation.
We suggest that insulin and leptin effects on reward circuitry and function would be bimodal,
such that low “permissive” concentrations of insulin and leptin sustain dopaminergic neuronal
viability, intermediate physiological levels suppress reward function, but elevated levels, linked
to resistance and metabolic pathophysiology, lead to impaired dopaminergic function. Whether
other CNS systems could take over reward function in the context of this pathophysiology is
purely conjecture at this point. Careful evaluation of this theory might provide links between
obesity, and common psychiatric disorders such as eating disorders, depression, and drug
addiction. It also has implications for the possible efficacy—or lack thereof—of CNS-targeted
therapeutics for obesity. Thus, returning to Hull’s equation, if the variable ‘D’ has a
dopaminergic component which is blunted in obese conditions, then evaluation of the regulation
of the variable ‘habit strength’ and its neuropharmacologic underpinnings may prove a more
fruitful line of research for therapeutic approaches.
In conclusion, studies over the past decade confirm and extend the historic finding that food
deprivation or restriction sensitizes brain reward circuitry and function. This review has focused
upon studies of insulin and leptin function. Newer studies, not reviewed here, suggest that the
‘hormone of need’, ghrelin, has predictably opposing effects. Studies in models of
pathophysiology are also revealing new dimensions to the modulation of reward function.
Understanding of new findings should shed considerable light on the contribution of non-
homeostatic feeding to obesity in contemporary societies that offer abundant, affordable, highly
palatable foods (55,56). Regardless of the specific outcomes of future studies, it seems
reasonably clear at present that the neurobiological controls of eating (especially non-
homeostatic food intake) are tightly linked to the well-established circuits underlying other kinds
of reward. Additionally, elucidation of the roles that leptin and insulin play in the regulation of
these systems may offer key insights into the evolution and function of these circuits and their
control of behavior. Finally, a clearer understanding of the function of these circuits may in fact
help us to answer a difficult theoretical issue: What exactly is reward? And, what makes
something rewarding? Identification of the precise neural mechanisms would (and will) allow
us to abandon the hypothetical constructs to nostalgia, and instead formulate predictive
descriptions of behavior based on specific physiological variables, essentially re-defining Hull’s
equation. This understanding may have broad impact on the development of pharmacotherapies
for obesity, as well as treatments of psychiatric disorders and drug abuse.
This work is supported by a Career Scientist Award from the Dept. of Veterans Affairs and NIH
Grant DK40963 (DPF), and by NIH Grant DK066223 (SCB).
Figure 1. Energy regulatory (grey) and reward circuitry (rose) and major synaptic connections.
Green labels highlight targets of both insulin and leptin. Blue labels highlight targets of insulin
(not determined for leptin).
Figure 2. Food intake, energy regulatory, and reward circuitry. Magenta labels highlight CNS
sites in which opioid administration stimulates food intake.
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CNS SITES OF
CNS SITES OF
OPIOID- -STIMULATED STIMULATED
EFFECTS OF INSULIN OR LEPTIN ON REWARD BEHAVIORS
Behavior Insulin (Route)
Brain self-stimulation decrease (ICV)
Relapse to heroin seeking not determined
Acute sucrose licking decrease (ICV)
Food-conditioned place preference decrease (ICV)
Sucrose self-administration decrease (ICV,ARC) decrease (ICV)
Acute chow intake (4-24 hr) decrease (ICV)
Opioid-stimulated sucrose intake decrease (ICV,VTA) decrease (VTA)
decrease (ICV, SC)
decrease (ICV, VTA) 2,3,74,95,134