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]).
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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