Obesity markedly increases the odds of developing depression. Depressed mood not only impairs motivation, quality of life and overall functioning but also increases the risks of obesity complications. Abdominal obesity is a better predictor of depression and anxiety risk than overall adipose mass. A growing amount of research suggests that metabolic abnormalities stemming from central obesity that lead to metabolic disease may also be responsible for the increased incidence of depression in obesity. As reviewed here, a higher mass of dysfunctional adipose tissue is associated with several metabolic disturbances that are either directly or indirectly implicated in the control of emotions and mood. To better comprehend the development of depression in obesity, this review pulls together select findings addressing the link between adiposity, diet and negative emotional states and discusses the evidence that alterations in glucocorticoids, adipose-derived hormones, insulin and inflammatory signaling that are characteristic of central obesity may be involved.

ObjectiveThe incidence of depression is significantly compounded by obesity. Obesity arising from excessive intake of high-fat food provokes anxiodepressive behavior and elicits molecular adaptations in the nucleus accumbens (NAc), a region well-implicated in the hedonic deficits associated with depression and in the control of food-motivated behavior. To determine the etiology of diet-induced depression, we studied the impact of different dietary lipids on anxiodepressive behavior and metabolic and immune outcomes and the contribution of NAc immune activity.MethodsAdult C57Bl/6 mice were subjected to isocaloric high-fat/high-sucrose diets (HFD), enriched in either saturated or monounsaturated fat, or a control low-fat diet (LFD). Metabolic responses, anxiodepressive behavior, and plasma and NAc inflammatory markers were assessed after 12 weeks. In separate experiments, an adenoviral construct inhibiting IKKβ, an upstream component of the nuclear factor kappa-b (NFkB) pathway, was a priori injected into the NAc.ResultsBoth HFDs resulted in obesity and hyperleptinemia; however, the saturated HFD uniquely triggered anxiety-like behavior, behavioral despair, hyperinsulinemia, glucose intolerance, peripheral inflammation, and multiple pro-inflammatory signs in the NAc, including reactive gliosis, increased expression of cytokines, antigen-presenting markers and NFкB transcriptional activity. Selective NAc IKKβ inhibition reversed the upregulated expression of inflammatory markers, prevented anxiodepressive behavior and blunted compulsive sucrose-seeking in mice fed the saturated HFD.ConclusionsMetabolic inflammation and NFкB-mediated neuroinflammatory responses in the NAc contribute to the expression of anxiodepressive behavior and heightened food cravings caused by a diet high in saturated fat and sugar.

Overconsumption of dietary fat is increasingly linked with motivational and emotional impairments. Human and animal studies demonstrate associations between obesity and blunted reward function at the behavioral and neural level, but it is unclear to what degree such changes are a consequence of an obese state and whether they are contingent on dietary lipid class. We sought to determine the impact of prolonged ad libitum intake of diets rich in saturated or monounsaturated fat, separate from metabolic signals associated with increased adiposity, on dopamine (DA)-dependent behaviors and to identify pertinent signaling changes in the nucleus accumbens (NAc). Male rats fed a saturated (palm oil), but not an isocaloric monounsaturated (olive oil), high-fat diet exhibited decreased sensitivity to the rewarding (place preference) and locomotor-sensitizing effects of amphetamine as compared with low-fat diet controls. Blunted amphetamine action by saturated high-fat feeding was entirely independent of caloric intake, weight gain, and plasma levels of leptin, insulin, and glucose and was accompanied by biochemical and behavioral evidence of reduced D1R signaling in the NAc. Saturated high-fat feeding was also tied to protein markers of increased AMPA receptor-mediated plasticity and decreased DA transporter expression in the NAc but not to alterations in DA turnover and biosynthesis. Collectively, the results suggest that intake of saturated lipids can suppress DA signaling apart from increases in body weight and adiposity-related signals known to affect mesolimbic DA function, in part by diminishing D1 receptor signaling, and that equivalent intake of monounsaturated dietary fat protects against such changes.

The adipose hormone leptin potently influences physical activity. Leptin can decrease locomotion and running, yet the mechanisms involved and the influence of leptin on the rewarding effects of running ("runner's high") are unknown. Leptin receptor (LepR) signaling involves activation of signal transducer and activator of transcription-3 (STAT3), including in dopamine neurons of the ventral tegmental area (VTA) that are essential for reward-relevant behavior. We found that mice lacking STAT3 in dopamine neurons exhibit greater voluntary running, an effect reversed by viral-mediated STAT3 restoration. STAT3 deletion increased the rewarding effects of running whereas intra-VTA leptin blocked it in a STAT3-dependent manner. Finally, STAT3 loss-of-function reduced mesolimbic dopamine overflow and function. Findings suggest that leptin influences the motivational effects of running via LepR-STAT3 modulation of dopamine tone. Falling leptin is hypothesized to increase stamina and the rewarding effects of running as an adaptive means to enhance the pursuit and procurement of food.

Hormones such as leptin and ghrelin can rapidly rewire hypothalamic feeding circuits when injected into rodent brains. These experimental manipulations suggest that the hypothalamus might reorganize continually in adulthood to integrate the metabolic status of the whole body. In this study, we examined whether hypothalamic plasticity occurs in naive animals according to their nutritional conditions. For this purpose, we fed mice with a short-term high-fat diet (HFD) and assessed brain remodeling through its molecular and functional signature. We found that HFD for 3 d rewired the hypothalamic arcuate nucleus, increasing the anorexigenic tone due to activated pro-opiomelanocortin (POMC) neurons. We identified the polysialic acid molecule (PSA) as a mediator of the diet-induced rewiring of arcuate POMC. Moreover, local pharmacological inhibition and genetic disruption of the PSA signaling limits the behavioral and metabolic adaptation to HFD, as treated mice failed to normalize energy intake and showed increased body weight gain after the HFD challenge. Altogether, these findings reveal the existence of physiological hypothalamic rewiring involved in the homeostatic response to dietary fat. Furthermore, defects in the hypothalamic plasticitydriven adaptive response to HFD are obesogenic and could be involved in the development of metabolic diseases.