Obesity rates are on the rise worldwide, resulting in a growing threat to public health. Pharmacotherapies that safely reduce body weight in obesity remain elusive, partially due to our incomplete knowledge of the complex neuronal mechanisms that control food choice (palatable high-calorie versus less palatable low-calorie food). The lateral hypothalamus (LH) is considered a critical node in the maintenance of energy homeostasis and prominently expresses the receptor for leptin, an adipocyte derived anorectic hormone. The development of obesity in rats is associated with deficits in LH sensitivity to rewarding stimuli, a switch in preference towards palatable calorically dense food items yet a seemingly paradoxical deficit in food-related motivation measured by the willingness of obese rats to deploy instrumental responding to receive food rewards. A major output of the LH terminates in the lateral habenula (LHb) which has been described as a “preference center”.We tested the hypothesis that leptin signaling on LHb innervating LH neurons plays an important role in food-related motivation.
Viral induced manipulation of neuronal signaling.Electrophysiology
We foundablation of this pathway decreased levels of instrumental responding, and shifted preference towards palatable calorically dense food, phenotypes conspicuously similar to that seen in rats with diet-induced obesity. Interestingly, inhibition of leptin activity in LHb projecting LH neurons of obese rodents led to similar increases in preference for palatable food and rejection of standard chow. Furthermore, obesity induced disruptions to leptin mediated glutamatergic and GABAergic LH innervation of the LHb suggesting the involvement of leptin in communication between the LH and LHb.
Based on these findings, we hypothesize that deficits in leptin mediated communication between the LH and LHb may emerge during weight gain contributing to obesity-associated behavioral abnormalities.