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

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ABSTRACT Despite decades of research, effective therapies for obesity are lacking. Given the magnitude of the obesity epidemic, there is a critical need for intervention strategies that effectively reduce body weight and maintain weight loss. Nodose ganglia (NG) neurons of the vagus nerve that innervate the gut are a key component of the nutrient sensing machinery that provides negative feedback to terminate a meal. Postprandial signals are sensed by vagal afferent terminals in the gut and the information is relayed centrally to neurons of the nucleus tractus solitarius (NTS). The neuropeptide cocaine and amphetamine regulated transcript (CART) expressed by NG neurons is a primary molecular signal that controls caloric intake. In obesity, loss of vagal CART is sufficient to increase food intake and body weight. Therefore, we hypothesize that in diet-induced obesity, restoring CART expression in NG neurons will cause voluntary reduction in food intake and sustain body weight after weight loss interventions. To evaluate the therapeutic potential of targeting CART and NG neurons innervating CART (NGCART) we will study 1) how metabolic cues are integrated in NGCART neurons, 2) how this information is relayed centrally, and 3) the impact of overexpressing CART in NG neurons on body weight. We apply powerful genetic and molecular neuroscience tools to the vagus nerve for in vivo imaging, connectivity mapping, and targeted overexpression in NGCART neurons. In aim 1, we propose to determine the metabolic signals that recruit NGCART neurons by using a Cre-dependent viral tracer injected into the NG of CARTCre mice to map the projections and terminals of NGCART neurons in the gut, and record the activation profile of these neurons in live animals by using a genetically targeted calcium indicator. In aim 2, we will combine multisynaptic circuitry tracing with serial two photon tomography to map NGCART neurons synaptic circuitry through the brain. In aim 3, we will use a cre- dependent CART overexpression virus to restore CART expression in NGCART neurons of CARTCre mice and determine the impact on feeding and body weight in diet induced obesity. These studies will elaborate on previous work by identifying a molecular and cellular target that can provide the foundation for developing peripheral treatments for obesity.