Abstract: The proper maintenance of body weight and mood are two of the most prevalent health issues present in society today. Obese humans display higher levels of mood-related disorders and the causality of such an association is unknown. A common feature of obesity is the imbalance of regulatory hormones which normally act to maintain stable energy balance and body weight. The adiposity hormone leptin is one such signal elevated in obesity with the capacity to dampen feeding behavior through action on brain circuits which regulate appetite and metabolism. Recent evidence suggests that leptin may regulate motivation through its actions within brain reward circuitry. In addition, leptin signaling within central nervous system regions that regulate cognition and emotion elicits anti-depressant like effects. Together, these data indicate that leptin may regulate the decreased motivation and mood present in obesity and depression. This review describes the capacity of leptin to regulate motivation and depression through actions within brain circuits that modulate effort-based behavior and emotion, respectively.
Obesity and mood disorders are two of the most prevalent health conditions facing humans today. In particular, 34% of U.S. adults are obese, as defined by a body mass index (BMI) of 30 or higher, and 21.4% experience mood disorders, most notably major depression (Flegal et al., 2010; National Institute of Health, 2008). Recent evidence suggests that increases in BMI positively correlate with depression. Obese patients seeking treatment report higher levels of psychopathology, notably binge eating disorders and depression, when compared to non-treatment-seeking obese individuals. In fact, obese individuals have a 25% chance of experiencing some form of mood or anxiety disorder while 35 million adults are likely to experience some form of depression throughout their lifetime (National Institute of Mental Health, 2008). Epidemiological estimations project that obesity and depression are likely to be the major cause of death in humans behind cardiovascular disease by the end of the next decade. Whereas tremendous efforts have yielded a more in-depth understanding of how peripheral hormones interact with the central nervous system (CNS) to regulate energy balance and body weight, much less is known regarding the neural substrates or signals that might mediate depressive illness.
It is now recognized that substantial overlap exists between brain regions that regulate energy homeostasis and emotion. The regulation of body weight is a complex phenomenon involving the processing of homeostatic information pertaining to energy balance as well as cognitive information relating to the hedonic properties of food. In this sense, adiposity signals are unique as they are able to regulate both aspects of feeding behavior. Leptin is one such signal with the capacity to regulate both energy homeostasis and emotion. Because leptin levels fluctuate in response to body weight gain and a variety of cognitive states (stress, depression, schizophrenia), the possibility exists that aberrant CNS leptin signaling may be a factor unifying the etiology of obesity and depression. This review details the potential of leptin to regulate motivation and emotion through its actions within limbic brain centers.
Regulation of Homeostatic Feeding by Leptin
Insulin, produced by pancreatic beta 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 (Frederich et al., 1995; Halass et al., 1995; Panskeep et al., 1972; Woods and Porte, 1974). In this way insulin and leptin act as “adiposity” signals conveying information about peripheral fat stores to the CNS. A substantial effort in the past two decades has increased the understanding regarding how leptin exerts its effects on feeding and energy expenditure (Grill, 2010). Although this is not the focus of the current topic, it is necessary to consider a few points before moving on.
First, the ability of leptin to modulate energy homeostasis seems to occur in large part through its actions within the mediobasal hypothalamus (Abizaid et al., 2008; Elmquist et al., 1998). Second, leptin levels increase in response to high energy meals and stored calories, and it has been known for some time that they also increase in anticipation of an expected meal (Schoeller et al., 1997). Leptin normally follows a diurnal pattern of secretion with the largest increases occurring after the onset of the dark period (Cuesta et al., 2009; Kalsbeek et al., 2001). However, similar to insulin, leptin can also be entrained to meal pattern (Schoeller et al., 1997). This implies that factors which negatively regulate feeding behavior become entrained to feeding behavior itself. Thus, the potential of leptin to affect reward may fluctuate in response to anticipatory responses linked to daily feeding. Although these possibilities remain to be tested directly, many investigators have examined reward behavior using models in which leptin is elevated naturally by obesity or prolonged increases in caloric consumption (Davis et al., 2009).
Leptin and Motivation
Motivation, or the amount of effort an organism is willing to exert for a particular reinforcer, is regulated in part by mesolimbic dopamine signaling (Mogenson et al., 1980; Aberman and Salamone, 1999; Caul and Brindle, 2001; Salamone et al., 2009). Dopaminergic fibers emanating from the ventral tegmental area (VTA) in the midbrain which terminate in the nucleus accumbens (NAcc) comprise the primary circuit regulating motivation for both food and abused drugs. Leptin receptors (LepR) are expressed within the VTA (Figlewicz et al., 2003) on both dopaminergic and GABAergic neurons (Fulton et al., 2006) and anatomical studies indicate that LepR containing neurons in the VTA project to the NAcc (Fulton et al., 2006). These data suggest that leptin action in the VTA may modulate mesolimbic dopamine and behavior.
Peripheral leptin administration attenuates firing rates of dopaminergic neurons within the VTA (Hommel et al., 2006). Leptin also decreases the frequency of action potentials within VTA dopaminergic neurons in midbrain slice preparations (Hommel et al., 2006). In contrast, mutant mice which lack endogenous leptin display decreased evoked dopamine release in the NAcc (Fulton et al., 2006). One difference between these two studies is the BMI of the animals used for the dopamine measurements. Mice lacking leptin (ob/ob) are obese whereas the rats used in the Hommel study were of normal body weight. Because obesity alone is capable of reducing mesolimbic dopamine in both rodents (Davis et al., 2008) and humans (Wang et al., 2001), it is possible that the observed effects on dopamine neurochemistry in ob/ob mice may be explained by the animals’ metabolic states. The ob/ob mice lacking functional leptin and predisposed toward becoming obese display increased body-weight within the first two months of life. Interestingly, recent research indicates that disruption of dopamine signaling through the D2 receptor subtype is associated with compulsive seeking of palatable foods (Johnson and Kenny, 2010), suggesting that reductions in dopamine may trigger overfeeding behavior and subsequent increases in body-weight. Therefore, while it is clear that leptin modulates mesolimbic dopamine, the inferences drawn from obesity-prone mutant mice may unveil more in regards to the development of obesity rather than its consequences.
Leptin application within mesolimbic circuitry decreases feeding behavior and intake of palatable foods. When delivered into the VTA, leptin decreases food intake (Hommel et al., 2006; Morton et al., 2009). Reduction of leptin receptor within VTA neurons increases food intake and also increases acute intake of high fat diet. Together, these results indicate that leptin signaling within the VTA is capable of modulating normal and hedonic feeding behavior. In the context of motivated responding, leptin has been shown to regulate the willingness to obtain both food and drug reinforcers. It is necessary to emphasize here that models which require high response costs to obtain a given reinforcer, such as progressive ratio responding operationally, define “motivation” in laboratory animals. For example, intracranial leptin administration reduces progressive ratio responding for sucrose pellets (Figlewicz et al., 2006) as well as the reinstatement of heroin self-administration (Shalev et al., 2001). It is also worth noting that leptin administration reduces the formation of a conditioned place preference to a high fat diet (Figlewicz et al., 2004), suggesting that leptin may also modulate learned associations with palatable foods. Electrical stimulation of the lateral hypothalamus (LHES) is a very well established model for examining motivation in laboratory animals. Using this model, central leptin administration both increases and decreases the rewarding efficacy of lateral hypothalamus (LH) electrical stimulation in rats (Fulton et al., 2000). These unequivocal results seem to stem from the animals’ propensity to respond to food restriction. In these studies, the effects of chronic food restriction on LHES were examined first; animals that responded to food restriction displayed decreased LHES after leptin treatment. In contrast, in animals in which LHES was not altered after food restriction, leptin produced leftward shifts in response curves, indicating that leptin had augmented the rewarding efficacy of LHES (Fulton et al., 2000). Thus, similar to the ability of leptin to modulate dopamine, the prior metabolic status of the animal seems to be a critical predictor of leptin’s ability to modulate LHES.
Leptin/Orexin Modulation of Mesolimbic Circuitry
Recent evidence indicates that the orexin system, the brain’s endogenous arousal system, is capable of activating the mesolimbic system and modulating motivation. The evidence for this contention is multifold. First, orexin receptors are expressed in brain reward circuitry, most notably the VTA and NAcc (Trivedi et al., 1998; Marcus et al., 2001). Second, orexin neurons in the lateral hypothalamus send direct projections to dopamine neurons in the VTA which in turn stimulate dopamine release in the NAcc (Narita et al., 2006). Thus, anatomically speaking, the orexin system is situated in such a way that it may act as an integrator and/or initiator of mesolimbic circuitry. Behavioral data suggest that orexin signaling promotes progressive ratio responding for palatable foods while blockade of orexin signaling attenuates reward-based feeding of a high fat diet (Choi and Davis et al., 2010). In addition, genetic deletion of orexin peptide within lateral hypothalamic neurons attenuates progressive ratio responding for food (Sharf et al., 2010). Initial anatomical studies reported that leptin receptors are present on orexin neurons within the LH (Hakansson et al., 1999; Horvath et al., 1999) while more recent reports refute this contention (Leinninger et al., 2009). In either case, leptin administration within LH activates signaling cascades downstream of the leptin receptor, which suggests that these receptors are functional. In the LH, leptin application increases NAcc dopamine levels and decreases food intake (Leinninger et al., 2009); it is unclear if leptin signaling within the LH modulates motivation to obtain food or drug rewards. However, humans experiencing enhanced nicotine craving display decreased plasma orexin and increased plasma leptin levels (von der Goltz et al., 2010), perhaps indicating an inverse relationship regarding the modulation of motivation by these two peptides. Interestingly, both central leptin administration and elevation of endogenous leptin as seen in obesity decrease hypothalamic orexin expression (Lopez et al., 2000). Collectively these studies highlight the ability of leptin to synaptically modulate mesolimbic dopamine through interfacing with the LH orexin system and raise the possibility that leptin may target orexin to manifest its actions on motivation.
Leptin, Dopamine, and Depression
Apart from regulating motivation, the mesolimbic dopamine system is beginning to receive considerable attention for its role in mediating depression. Disturbances in mesolimbic dopamine signaling have been hypothesized to underlie the anhedonia or lack of pleasure observed in depressed individuals (Wise, 1982). In sum, clinical and experimental data continue to emerge which support the idea that decreased basal dopamine contributes to anhedonia and decreased motivation (Nestler and Carlezon, 2005). Importantly, recent evidence indicates an association between obesity and increased risk of depression and other mood disorders (Bjerkeset et al., 2007; Zhao et al., 2009; Simon et al., 2006; Strine et al., 2008), suggesting that metabolic disturbances may precipitate or participate in depressive illness.
As mentioned previously, leptin is capable of modulating dopamine through its actions within the mesolimbic pathway and the lateral hypothalamic orexin system; thus it is possible that leptin signaling may also participate in the regulation of depression. Leptin receptors are present on dopaminergic projection neurons present in the VTA and substantia nigra (Figlewicz et al., 2003); together these two loci modulate dopamine release into mesolimbic and ventral striatal circuitry, respectively. In most cases the effects of stress on mesolimbic dopamine signaling have been investigated in animal models of depression. In fact, both chronic unpredictable stress and social stress reduce circulating leptin levels, an effect independent of body mass (Lu et al., 2007). Perhaps more importantly, this drop in plasma leptin cross-sensitizes across stressors thereby raising the possibility that repeated stress exposure may yield further decreases in CNS leptin availability. Conversely, leptin is also capable of inhibiting the initiation of the stress response by attenuating hypothalamic-pituitary-adrenal (HPA) axis activity. For example, leptin deficient ob/ob mice display increased plasma corticosterone levels which can be decreased by leptin replacement (Heiman et al., 1997). Additionally, leptin pre-treatment attenuates stress-induced rises in plasma corticosterone, an effect mediated through leptin’s action on corticotrophin releasing hormone (CRH) (Heiman et al., 1997). These data support the contention that leptin may “feedback” to CRH neurons which attenuate HPA axis activity thereby reducing stress responsivity. Thus low leptin levels secondary to stress may exacerbate the initiation of the stress response. The nature of stress-induced leptin decline is still unclear; however, the low leptin levels present in stressed laboratory rodents and human schizophrenic patients have led to the “leptin insufficiency” hypothesis of depression. In terms of obesity, leptin insensitivity through reduced CNS leptin has been championed as rationale regarding the inability of obese individuals with elevated leptin to counter-regulate food intake and body weight gain. When combined, the observation of decreased leptin in stressed and obese individuals represents a unique mechanism whereby obesity may modulate mood and depression.
It has been suggested that etiology of depression is most likely distributed throughout several brain regions where the VTA-NAcc pathway may act as a “gate” mediating the cognitive emotional aspects of stress on limbic function (Nestler and Carlezon, 2005). In addition to its expression in the midbrain, leptin receptors are also present in the hippocampus, amygdala, and frontal cortex (Mercer et al., 1996), areas that have been extensively investigated for their roles in mediating depression and mood. Thus, leptin is capable of signaling in a variety of brain regions responsible for mediating the processing of cognitive-emotional information.
Behavioral data from animal models of depression indicate that leptin acts as an anti-depressant. Systemic leptin administration increases consumption of a dilute sucrose solution in stressed rats (Lu et al., 2006), a common measure of anhedonia in rodents. A standard for measuring depression-like behaviors in rodents is the forced swim test (FST). In this test the rodents are placed in a cylinder filled with water and the latency to become immobile is used as a measure of behavioral despair; classical anti-depressants reverse immobility in this model thus validating their potential as therapies for depression. Systemic leptin administration dose-dependently decreases immobility in the FST without affecting locomotor activity. Taken together, these two behavioral findings suggest that leptin may have anti-depressant like effects. Functional anatomical evidence suggests that leptin may exert its anti-depressant like effects through signaling in the hippocampus. Rats with decreased immobility latencies in the FST after leptin treatment display increased neuronal activation within hippocampal neurons. Behavioral pharmacological studies indicate that application of leptin directly into the hippocampus decreases immobility times in the FST (Lu et al., 2006), suggesting that disturbances in leptin signaling within the hippocampus may underlie depressive illness.
Summary and Perspectives
In this review, evidence is provided supporting the contention that the adiposity hormone leptin negatively impacts motivation. In contrast, leptin action within limbic circuitry appears to convey anti-depressant like effects. A critical aspect in the regulation of motivation is the temporal component of leptin resistance which suggests that caloric overconsumption may be due to decreased mesolimbic dopamine levels secondary to increased leptin signaling. Importantly, leptin is capable of signaling within brain reward circuitry and perturbations of leptin action within these regions negatively impact feeding behavior and consumption of palatable foods. Plasma leptin levels decrease after stress, a known inducer of depression, and leptin application within limbic structures attenuates the negative motivational state associated with several forms of depressive illness. It is hypothesized here that leptin action in mesolimbic neurons negatively regulates motivation and that during times of leptin resistance, such as obesity, the lack of leptin signaling in limbic circuitry contributes to negative motivational state. Both dopamine and orexin are associated with motivation and depression, and leptin is capable of modulating each system indicating that aberrant leptin signaling may be a unifying factor for both conditions. The emergence of novel tools which selectively alter leptin receptor expression/signaling within discrete limbic nuclei makes it possible to test these hypotheses directly. Through the utilization of these techniques and others, the exact nature of leptin’s ability to suppress motivation and boost emotion will certainly be defined more clearly.
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