Evaluating the therapeutic potential of vagal CART circuitry for treating metabolic disease

Abstract Obesity is a global crisis with severe health and economic repercussions. One of the root causes of obesity is overeating diets rich in fats and sugars. The vagus nerve is a critical conduit for gut-brain communication that senses nutrients and in turn controls feeding behavior. During the previous grant, we established novel technical advances to manipulate vagal sensory neurons in freely behaving animals and leveraged them to identify gut-brain circuits that separately control satiety and reward. The current proposal builds on that previous work to address how these circuits are changed in diet-induced obesity. We hypothesize that impaired vagal signaling develops early in response to high-fat/high-sugar diet, but that downstream central nervous system (CNS) circuits, for satiety and reward, remain functional and could therefore be targeted to treat obesity. We will test this with three specific aims: (1) determine the timing and extent of impaired vagal sensing, using in vivo calcium imaging of vagal sensory neurons, and identify mechanisms for disruption using state-of-the-art transcriptomic profiling; (2) assess whether CNS satiety and reward circuits that are downstream of vagal signaling remain functional in obesity; and (3) address the poorly understood role nigrostriatal dopamine in the CNS control of food intake and obesity, particularly its impact on food preference and motivation. The proposed research will advance our understanding of gut-brain signaling in obesity and, if successful, promises to unveil new targets for obesity treatment.