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Published in final edited form as: Trends Endocrinol Metab. 2009 Oct 7;21(2):68. doi: 10.1016/j.tem.2009.08.004

Insulin, Leptin and Reward

Jon F Davis 1, Derrick L Choi 1, Stephen C Benoit 1
PMCID: PMC2822063  NIHMSID: NIHMS147635  PMID: 19818643

Abstract

Feeding for pleasure, or “non-homeostatic feeding”, potentially contributes to the rapid development of obesity worldwide. Obesity is associated with an imbalance of regulatory hormones which normally act to maintain stable energy balance and body weight. The adiposity hormones insulin and leptin are two such signals elevated in obesity with the capacity to dampen feeding behavior through their action on hypothalamic circuits which regulate appetite and metabolism. Recent evidence suggests that both hormones achieve this degree of regulation by inhibiting the rewarding aspects of feeding behavior, perhaps by signaling within midbrain reward circuits. This review describes the capacity of both insulin and leptin to regulate reward-related behavior.

The prevalence of obesity has reached epidemic proportion, and the development of pharmacological treatments continues to challenge current thinking. Over the past several years, key insights have broadened our understanding of how organisms sense and respond to peripheral and central signals to regulate energy homeostasis. However, this increased understanding has not yet led to successful therapies to reduce body weight. Importantly, feeding for pleasure or “non-homeostatic feeding” is presumed in part to underlie the rapid development of obesity worldwide [1]. Recent evidence suggests that non-homeostatic feeding is controlled by mesolimbic circuitry [2], and it is now clear that consumption of palatable foods elicits neuroadaptive changes within brain reward circuitry which may promote continued overfeeding behavior ([3,4]; for review the reader is directed to [5]). Such an association indicates an overlap in the involvement of brain circuitry that regulates reward and metabolism.

The adipose hormones insulin and leptin signal at distinct brain nuclei to regulate energy expenditure and metabolism by decreasing feeding behavior. However, both insulin and leptin are also capable of signaling within brain reward circuits. Hence, the possibility exists that insulin and leptin regulate food intake by inhibiting the rewarding aspects of feeding. Here, we consider the food and drug reward to be identical phenomena occurring through processes originating in the mesolimbic system. This review details the potential of insulin and leptin to regulate food and drug intake through their action on midbrain reward circuits.

Regulation of homeostatic feeding by insulin and leptin

Insulin produced by pancreatic β-cells and leptin derived from adipocytes increase in proportion to fat mass and consequently relay information about peripheral fat stores to central effectors in the hypothalamus to modify food intake and energy expenditure [6-9]. The actions of insulin and leptin on food intake occur in part by convergence on a specific set of neurons within the Arcuate nucleus (ARC) of the hypothalamus [10, 11] to regulate feeding in response to stored calories or “homeostatic feeding”. The ARC contains two distinct sets of neurons with opposite effects on feeding behavior that each express insulin and leptin receptors. Through coordinated action on hypothalamic neurons that stimulate or inhibit feeding behavior, insulin and leptin function centrally as satiety signals to decrease food intake when energy levels are met and adipose tissue has been restored. Separate from their expression in hypothalamic centers, the receptors for both insulin and leptin are present in brain reward circuitry [12], suggesting their roles in the rewarding aspects of feeding behavior in addition to their effects on metabolism. Moreover, a collection of recent neuroanatomical, behavioral and functional evidence suggests that these effects on food reward are achieved through signaling within these circuits [12-15].

In the context of reward-related behavior, it is interesting to consider how plasma levels of insulin and leptin might be capable of modulating brain reward circuitry. Although insulin and leptin levels increase in response to high energy meals and stored calories, it is known that they also increase in anticipation of a meal [16-17]. The pre-meal rise in insulin can be achieved through learned associations with environmental cues associated with feeding [18, 19]. Leptin normally follows a diurnal pattern of secretion with the largest increases occurring after the onset of the dark period when rodents normally ingest their largest meal [20, 21]. However, similar to insulin, leptin can also be entrained to meal patterns [17], raising the possibility that daily rhythm of leptin secretion is subject to alteration by learned responses associated with altered meal patterns.

Central resistance to insulin and leptin

Importantly, the ability of insulin and leptin to access central circuits is regulated by their active transport across the blood brain barrier (BBB) [22, 23]. As these transport mechanisms are saturatable, they are subject to being rendered insensitive when exposed to elevated plasma levels of each hormone such as that seen in obesity [24, 25]. It is unclear if leptin insensitivity is present in brain reward circuitry; however, given their active transport into the brain, it is quite possible that resistance also occurs in these regions. One implication of this resistance is that the ability of insulin and leptin to diminish reward is most sensitive in lean individuals. It is also possible that prolonged elevations in insulin and leptin during the development of obesity and prior to resistance produce changes that are manifested during obesity. This could be achieved through over activation of insulin and leptin signaling within brain reward circuitry. Nevertheless, this collection of data suggests that insulin and leptin might affect reward processing at distinct temporal intervals or in a more graded fashion as they both increase as a function of stored adipose tissue. Furthermore, the ability of each hormone to reach and act upon central circuits which mediate reward is most likely compromised in obesity and more sensitive in lean individuals. However, both are capable of entering the brain through circumventricular organs without transport across the BBB, leading to the notion that resistance may occur through de-sensitization of receptor signaling rather than decreased central access [26]. Whereas it is clear that sensitivity to each hormone exists at the level of the hypothalamus, there have been no investigations of insulin or leptin flux within brain reward regions or the sensitivity of these systems in relation to their prolonged elevation as seen in obesity. Moreover, there are no studies to date which examine reward behavior during acute temporal intervals linked to feeding when insulin or leptin are elevated endogenously. It therefore remains possible that insulin and leptin affect reward by direct action or through eliciting long term changes within reward circuitry. Although these possibilities remain to be tested directly, many investigators have examined reward behavior using models in which insulin and leptin are elevated naturally by obesity or prolonged increases in caloric consumption [27-35].

Metabolic status and reward related behaviors

In times of caloric restriction or deprivation, both insulin and leptin levels decrease and generally speaking, this augments reward-related behaviors. Laboratory animals trained to self-administer (SA) a variety of psychostimulant drugs increase their SA behavior after food deprivation, an effect dependent on reduced body weight [36, 37]. Caloric restriction represents a less stringent, more prolonged manipulation compared to total food deprivation and restricting the amount of daily consumed calories also enhances the acquisition of drug self-administration and increases the willingness to engage in self-administration behavior [38, 39]. Moreover, caloric restriction increases psychostimulant induced locomotion in DBA/2J mice which are naturally resistant to the behavioral effects of psychomotor drugs [40]. Collectively, these behavioral observations suggest that metabolic perturbations that decrease body weight and hence circulating levels of insulin and leptin, augment the acquisition, expression and locomotor activating properties of psychostimulant drugs. Thus, socioeconomic conditions which limit food availability as well as metabolic interventions such as dieting represent substantial risk factors contributing to disordered eating and addiction [41-43].

Conversely, dietary regimens that increase body weight and hence plasma insulin and leptin, decrease reward-related behaviors. Obesity, defined by a body mass index (BMI) of 30 or greater, is associated with a significantly lower lifetime risk of substance abuse disorders in humans [44]. Indeed, obese individuals abuse nicotine [27] and marijuana [28] significantly less than normal weight subjects, and studies conducted in laboratory animals are consistent with these findings. For example, when exposed to a nutritionally complete high fat diet, obese rats display attenuated acquisition of cocaine self-administration behavior [29]. In addition, both obesity and maintenance on high calorie diets decreased amphetamine induced conditioned place preference and attenuated sucrose responding on schedules that require both low and high work requirements [30]. Similarly, rats rendered obese through exposure to a “supermarket” diet display attenuated operant responding for sucrose [31].

However, obese individuals are sensitive to the rewarding properties of palatable foods. Obese individuals display enhanced neuronal activation of brain reward circuitry when exposed to feeding associated cues [32] and crave energy rich diets to a greater degree than lean individuals [33]. This effect in humans can also be extended to food self-administration, as animals maintained on a variety of energy rich diets display enhanced response for food rewards [34]. Moreover, rats lacking the receptor for the satiety signal cholecytokinin (CCK-1R) self-administer sucrose more than lean controls [35]. Thus, in genetic models predisposed toward becoming obese or during the development of obesity, animals display a high degree of motivation to obtain palatable foods; however, once obese, the motivation to work for palatable foods is decreased below control levels.

In this sense, the process of becoming obese and obesity itself represent dissociable states in relation to motivation, but not reward. This contention is supported by the observation that obese individuals are capable of responding to appetitive stimuli associated with palatable foods, but are unwilling to “work” to obtain either food or drug rewards.

Pharmacological regulation of reward by insulin and leptin

Brain Stimulation Reward

Electrical stimulation of the lateral hypothalamus (LH) is a potent way to assay reward behavior in laboratory animals. In this model, rats actively seek out stimulation of the LH [36], an effect known as “brain stimulation reward” (BSR). Early studies investigating the effects of metabolic factors on BSR indicated that anorectic doses of insulin caused rats to self-stimulate less [45]. Over twenty years following this discovery, it was demonstrated that intraventricular (ICV) administration of both insulin and leptin elevated BSR thresholds [46, 47], thus decreasing the rewarding properties associated with LH stimulation. These demonstrations were particularly impressive in that 1) both insulin and leptin were administered into the third ventricle of the brain and 2) both decreased BSR for a prolonged period after administration. Thus, insulin and leptin are capable of affecting reward through direct action within the brain.

Intravenous Self-Administration

Studies investigating the effects of insulin and leptin on drug SA are limited; however, a few important studies indicate that both are capable of modulating drug intake. Rats trained to self-administer cocaine display decreased rates of responding when insulin levels are artificially lowered through streptozotocin treatment [48], suggesting that circulating insulin modulates drug taking behavior. In addition, central administration of leptin decreases food deprivation-induced reinstatement of heroin SA [49] indicating that leptin negates the facilitating effects of caloric deprivation on drug SA behavior. Combined with the observation that obese individuals SA abuse drugs less often, these studies underscore the potential for insulin and leptin to modulate drug intake.

Self-Administration of Palatable foods

Similar to drug SA behavior, laboratory animals can be trained to self-administer palatable foods such as sucrose or diets high in fat. Using this mode of reinforcement, ICV delivery of both insulin and leptin decreased responding for sucrose [13] suggesting that similar to their effects on BSR, insulin and leptin act centrally to modulate food reward. A series of behavioral pharmacological manipulations performed by Figlewicz and colleagues determined that the ARC nucleus of the hypothalamus is the sole site responsible for insulin’s negative effects on food SA behavior [50], suggesting that insulin signaling within the ARC may synaptically mediate reward through its connections with brain reward circuitry outside the hypothalamus [51]. Although leptin receptors are expressed in brain reward circuits, at this point, it remains unclear where leptin might act to reduce reward behavior; this aspect of leptin signaling will be discussed in greater detail in the following section.

Perhaps more important is the observation that central insulin and leptin signaling can be rendered ineffective through increased caloric consumption prior to increases in body weight [13]. This finding is in agreement with the demonstration that exposure to high fat diets in rodents attenuates food SA and the acquisition of psychostimulant place preferences [30], suggesting that insulin and leptin negatively impact food reward prior to the development of obesity. Thus, due to the modulation of insulin and leptin sensitivity by diet, it is possible that the process contributing to decreased reward behavior in obese individuals occurs during the development of obesity when both are naturally elevated in the blood. Therefore, the changes observed once body weight has increased may be due to plastic changes within reward circuitry brought about by prolonged elevations in insulin and leptin. However, this hypothesis requires further investigation.

Modulation of feeding by insulin and leptin within mesolimbic circuits

Separate from their expression in hypothalamic regions that regulate energy balance, both insulin and leptin receptors are expressed within the mesolimbic system, namely the ventral tegmental area (VTA) (12) (Figure 1). The VTA contains dopaminergic neurons which innervate the nucleus accumbens (NAcc) to comprise the mesolimbic dopamine system (Box 1). Mesolimbic signaling has been hypothesized to play an integral role in mediating the rewarding properties of abused drugs and food [63], thus raising the possibility that insulin and leptin may provide feedback on mesolimbic circuitry to regulate reward-related behavior. Dopamine signaling within mesolimbic neurons mediates the willingness to engage in rewarding behaviors or “wanting”, while the pleasure associated with a particular reward or “liking” is attributed to mesolimbic opioid action [64]. Although no direct evidence exists in relation to which aspect of motivation is affected by insulin or leptin respectively, or if this process is similar for food and drug reward, anatomically speaking, both are in position to modulate processes regulated by mesolimbic dopamine. It is unclear if insulin signaling within VTA neurons affects drug-related reward, although insulin delivered directly into the VTA does not affect food SA [50]. However, insulin signaling within the VTA is capable of affecting feeding behavior in models known to stimulate consumption of palatable foods. Specifically, direct application of insulin into the VTA also decreases opioid induced sucrose intake in rats [50], suggesting that insulin signaling within VTA neurons negatively regulates the “liking” of palatable foods.

Figure 1.

Figure 1

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The ability of insulin and leptin to reduce reward related behaviors could occur through action at two distinct regions that modulate mesolimbic activity. Tyrosine hydroxylase (TH) neurons in the (VTA) promote feeding and drug taking behavior; these neurons receive a direct connection from orexin neurons located in the lateral hypothalamus (LH) which activates VTA neurons through signaling at the orexin-1 receptor, as indicated by the vertical black lines. This circuit mediates non-homeostatic food consumption and drug relapse behavior. Leptin receptors are present on LH neurons and leptin negatively regulates orexin and orexin-1-receptor gene expression within LH neurons. Moreover, insulin and leptin act upon VTA neurons to negatively regulate dopamine tone and over-consumption of palatable foods as indicated by the green arrows. It is unclear if leptin acting within LH neurons affects arousal, feeding or anticipation of rewards; likewise it is unclear if leptin signaling within VTA neurons affects reward related behaviors. Thus, insulin and leptin may act at two distinct brain regions to modulate mesolimbic signaling and reward related behaviors. VTA: ventral tegmental area, LH: Lateral Hypothalamus.

Box 1. Neuroanatomical regulation of mesolimbic signaling by Insulin and Leptin.

A large body of evidence supports a role for mesolimbic dopamine signaling in both food and drug reward paradigms. Research in this area has benefited from the use of a variety of manipulations to study this concept including genetic, functional, and pharmacological approaches. For instance, mice unable to synthesize dopamine display drastically reduced food intake and body weight, and require exogenous dopamine to prevent starvation [52]. Ablation of dopamine neurons using 6-OHDA leads to decreased food hoarding behavior [53], as well as decreased feeding efficiency [54]. A prominent theory of midbrain dopaminergic signaling ascribes that DA neurons report errors in predicted expectancies of reward [55, 56]. In this way, dopamine initially associated with reward consummation is over time, converted and used as a signal that predicts the emergence or availability of a rewarding stimulus. In support of this hypothetical framework, studies utilizing in vivo microdialysis and voltammetric techniques to monitor sub-second fluctuations of dopamine during operant conditioning experiments have confirmed this idea. In these studies, animals trained to lever press for sucrose reliably displayed an increase in dopamine release immediately prior to pressing the lever to receive a sucrose reward. However, this dopamine surge returned to baseline levels upon consummation of the reward itself [56, 57]. Recent evidence indicates that the orexin system, the brain’s endogenous arousal system, is capable of activating the mesolimbic system and modifying dopamine dependent behaviors [58, 59]. Pharmacological blockade of orexin receptors within ventral tegmental area (VTA) neurons attenuates both food and drug reward [60, 61]. Interestingly, leptin receptors are expressed in the brain region that produces orexin, the lateral hypothalamus (LH). Centrally administered leptin is capable of downregulating orexin expression in the LH [62], and insulin and leptin are capable of modulating feeding behavior through their direct action on VTA neurons. Thus, it is possible that leptin and insulin act at two distinct regions within this circuitry to mediate reward related to food and drug intake.

It is unclear if manipulation of leptin signaling within the VTA alter reward-related behaviors. However, systemic doses of leptin are sufficient to decrease the firing threshold of dopaminergic neurons within the VTA [15] and, like insulin, direct administration of leptin into the VTA decreases food intake [15, 65]. Furthermore, reducing leptin receptor via central genetic manipulations within VTA neurons augments food intake and acute feeding responses in animals exposed to a palatable high fat diet [15]. This suggests that leptin signaling within this region modulates food intake and potentially the hedonics associated with palatable food consumption.

VTA neurons are activated in part by the hypothalamic orexin system [59, 60]. Importantly, orexin neurons are activated in response to both food and drug related cues, and orexin signaling within VTA neurons regulates non-homeostatic feeding behavior [58, 61]. Interestingly, central leptin administration is capable of downregulating prepro-orexin and orexin-1 receptor mRNA in the hypothalamus [62], suggesting that in addition to modulating VTA neuronal function directly, leptin can also mediate activation of this circuitry (Figure 1). When considering these findings collectively, it is intriguing to speculate that leptin regulates feeding through its actions on hypothalamic orexin neurons and reward-related behaviors through VTA signaling mechanisms that ultimately affect dopamine tone; however these hypotheses remain to be tested.

Molecular regulation of reward by insulin and leptin

Both insulin and leptin signal through the tyrosine kinase family of receptors [66-68]. Typically, tyrosine kinase mediated signaling occurs through autophosphorylation of adjacent receptors or through recruitment of signaling molecules to phosphorylated tyrosine residues in the receptor tail [69]. A critical difference in insulin and leptin mediated signaling lies in the method of activation upon ligand binding -- the insulin receptor has intrinsic activity in that insulin binding stimulates auto-phosphorylation and activation of downstream signaling targets, whereas leptin receptor requires Jak-STAT binding for full activation [67, 68]. Once activated, both insulin and leptin activate insulin receptor substrate (IRS) [68, 69] and its downstream targets (Figure 2). Interestingly, IRS signaling within mesolimbic neurons regulates several aspects of psychostimulant exposure. Apart from being a downstream mediator of insulin and leptin signaling, IRS is a neurotrophic factor which mediates the effects of morphine on mesolimbic cellular morphology [70], an effect implicated in the addictive process. In addition, IRS overexpression in the VTA augments the rewarding and psychomotor activating effects of cocaine, while blocking IRS signaling attenuates these behaviors [71]. Although IRS is capable of binding many intracellular signaling proteins, the majority of its binding sites activate the phosphatidylinositol triphosphate (PI3-K) pathway [26]. Consistent with the effects of IRS on cocaine reward, modulation of PI3-K regulates the expression of behavioral sensitization to cocaine [72], suggesting that IRS-PI3-K signaling within mesolimbic circuits modulates drug reward behaviors. A recent study by Morton and colleagues report that the ability of leptin to reduce food intake when administered into the VTA is dependent on Jak-STAT signaling but not IRS activation [65] which may represent a level of molecular specificity in relation to the regulation of food intake and food reward. When viewed collectively, these results suggest that manipulation of effector proteins linked to insulin and leptin receptor activation are capable of altering drug reward as well as food intake. However, at this point there is no functional evidence available suggesting that insulin or leptin signal through these effectors to modulate reward.

Figure 2.

Figure 2

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The ability of insulin and leptin to mediate reward behavior at the molecular level might occur through the activation of insulin receptor substrate (IRS-2) in ventral tegmental area (VTA) neurons. Both insulin and leptin receptors are present on VTA neurons and upon activation, both activate intracellular signaling cascades that ultimately affect gene transcription. Intracellular signaling from both the insulin and leptin receptor converges at IRS-2. IRS-2 signaling regulates the psychostimulant mediated plasticity and reward. Thus, it is possible for insulin and leptin to regulate reward behaviors through their action on IRS-2 in the VTA. It is unclear if insulin and leptin signaling within VTA neurons elicits IRS-2 activation; however, the ability of leptin to negatively regulate food intake behavior is mediated by Jak-2 (Jak-STAT) signaling within VTA neurons. IRS-2: Insulin receptor substrate, VTA: ventral tegmental area, Jak-2: Janus kinase, Jak-STAT: Janus kinase signal transducers and activators of transcription, TH: Tyrosine hydroxylase.

Summary and perspectives

In this review, we discuss evidence that the adiposity hormones insulin and leptin negatively impact reward behavior. A critical aspect of this regulation is the temporal component of insulin and leptin resistance which suggests that increased caloric consumption alone is capable of negatively influencing reward, an effect independent of body weight gain. Importantly, both hormones are capable of signaling within brain reward circuitry, and perturbations of their signaling mechanisms in these regions decrease feeding behavior and consumption of palatable foods. Insulin signaling in mesolimbic regions has been associated with decreases in opioid driven behaviors while leptin action in mesolimbic neurons negatively regulates dopamine tone. Due to the dissociation of overall reward into “liking” an opioid driven phenomenon and “wanting” a dopaminergic dependent process, it is possible to hypothesize that the ability of each hormone to affect reward is also dissociated. In this way, insulin action in mesolimbic neurons might affect the pleasure associated with palatable food consumption while leptin signaling in this region negatively regulates the motivation necessary to obtain a food reward. It is also possible that the effects of insulin and leptin on reward occur independent of opioid signaling. Both insulin and leptin inhibit food self-administration in laboratory rodents, a process dependent on intact dopamine function.

In either case, it is important to note that at this point these hypotheses are highly speculative and require further testing to be validated. Nevertheless, the emergence of genetic tools which selectively alter insulin and leptin receptor expression/signaling within discrete mesolimbic nuclei make it possible to now test these hypotheses directly. Through the utilization of these techniques and others, the exact nature of the ability of insulin and leptin to negate reward behavior will undoubtedly be further refined.

Footnotes

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