Unraveling the neural mechanisms for satiety and weight loss by GLP1-based drugs

PROJECT SUMMARY Over the last several decades, obesity rates have been rising, and research has failed to solve this public health crisis. Now, we are at the precipice of change. Glucagon-like peptide-1 (GLP1)-based obesity drugs have emerged as a promising strategy for weight loss, and their unprecedented success is transforming the treatment of obesity. Despite their popularity, we have little understanding of the brain mechanisms that drive the food intake and body weight reduction from these drugs. In our preliminary studies, we found that hindbrain GLP1 receptor (GLP1R)-expressing neurons are necessary and sufficient for the effects of GLP1-based obesity drugs such as semaglutide (Ozempic®/Wegovy®). Further, our data suggest that the neural circuits that mediate the food intake suppression and the nausea/aversion (the top side effect of these drugs) are anatomically and functionally separable. Specifically, we identified a population of nucleus tractus solitarius (NTS) GLP1R neurons that project to the paraventricular hypothalamus (PVH) that suppresses food intake and body weight without causing aversion. Building on these data, this proposal will behaviorally, physiologically, anatomically, and molecularly characterize NTSGLP1RPVH neurons as a potential target for weight loss drugs with fewer side effects. First, we will test the necessity of NTSGLP1R neurons, their receptors, and their projections to the PVH, in mediating the satiety and weight loss effects of semaglutide. Next, we will determine the endogenous neural activity patterns of NTSGLP1R neurons in response to gut-derived signals and obesity drugs, and how this activity changes in diet-induced obesity. Finally, we will determine the inputs and outputs of NTSGLP1R neurons to map a circuit for non-aversive satiety. This comprehensive analysis of NTSGLP1RPVH neurons will uncover a novel neural circuit for feeding behavior, and determine the suitability of this population as a selective target for future drug development.