Unraveling the homeostatic and hedonic circuits underlying feeding behavior and obesity

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PROJECT SUMMARY The striking prevalence of obesity and its associated personal and public health consequences highlights the importance of understanding why individuals overeat and gain weight. It is widely recognized that overeating results from a combination of homeostatic (i.e., nutrient need, hunger) and hedonic (i.e., pleasure, reward) drives. While these homeostatic (e.g., hypothalamic) and hedonic [e.g., midbrain dopamine (DA)] systems have been characterized as discrete drivers of food intake, there is considerable evidence that these systems overlap. For example, DA signaling in response to food is potentiated by hunger, increasing the reward value of food during times of homeostatic need. Our recent findings in rodent models revealed a neural correlate for the interaction between homeostatic and hedonic systems. Activity in hunger-sensitive, hypothalamic agouti-related protein (AgRP)-expressing neurons potentiates the DA response to food. Conversely, DA signaling enhances the homeostatic AgRP neuron response to food. What are the circuits through which AgRP and DA neurons interact in response to food? Do they help explain why some individuals are more likely to overeat and gain weight? This proposal will test the overarching hypotheses that distinct AgRP and DA neuron subpopulations mediate the interaction between homeostatic and reward signaling and that individual differences in AgRP and DA responses to food predict future weight gain. Aim I experiments will determine the AgRP neuron projection subpopulations that potentiate DA responses to food. We will leverage the anatomical organization of AgRP neurons, as well as optogenetic and chemogenetic technologies, to individually test how each AgRP projection subpopulation influences food-evoked DA signaling. Aim II experiments will determine sites of action for DA modulation of AgRP neuron activity. We will use genetic and pharmacological approaches to examine how DA projections and neurotransmitter signaling influence AgRP neuron activity. Aim III will determine how AgRP and DA activity predicts future overeating and weight gain. Taking advantage of the variability in weight gain in response to a high-fat, high-sugar diet, we will determine if individual differences in neural activity in lean mice predict future overeating and the development of obesity. Overall, these experiments take a unique approach to understanding weight gain by (1) determining the neural intersection of homeostatic and hedonic circuits that have classically been considered discrete drivers of intake and (2) identifying neural activity biomarkers to predict overeating and obesity predisposition. Ultimately, results from the proposed studies will reveal cellular and molecular targets that can be leveraged to develop obesity prevention and more effective weight loss strategies.