PROJECT SUMMARY/ABSTRACT The average American adult consumes over 40 pounds of sugar per year. While sugar intake is necessary for energy metabolism and survival, this overconsumption has led to rampant obesity and diabetes. Therefore, it is critical to determine the gut-brain circuit that drives sugar overconsumption. Recently, specialized sensory cells in the intestinal epithelium, known as neuropod cells, were found to sense intestinal sugars and drive sugar appetite. Neuropod cells sense sugars using sodium-glucose transporters (SGLTs). Most studies on intestinal sugar sensing have focused on glucose transport ability itself, but little is known about sensing in the absence of transport. Here, we will use an anti-diabetic molecule specific to human SGLTs to probe whether it is glucose transport or sensing that is necessary to activate the neuropod cell sugar sensing circuit. My hypothesis is that sugar sensing, in the absence of transport, will activate neuropod cells, causing glutamate release and vagus nerve activity. Therefore, I am pursuing the following aims: 1) to determine whether specific SGLT activation leads to neuropod cell glutamate release and 2) to determine whether an anti-diabetic molecule leads to rapid, neuropod cell dependent vagal activity. My approach includes neurogenetic manipulations of intestinal organoids and in vitro and in vivo electrophysiology. These studies may uncover a pharmacological target for modulating rapid gut-brain control of food choice without perturbing life-sustaining sugar absorption. My co-sponsors, Drs. Diego Bohórquez, Ph.D. and David D’Alessio, M.D., are experts in neuropod cell nutrient sensing and hormone signaling in obesity, respectively. Consistent with their long- established track record of mentorship, the proposed studies and training plan will provide me with the rigorous scientific training and leadership skills necessary for a career as a physician-scientist based on gut-brain circuit manipulation as a bariatric intervention.

PROJECT NARRATIVE The consequences of sugar overconsumption in America are clear: two-thirds of Americans suffer from diet- related chronic illnesses including obesity and diabetes. Specialized sensory cells in the intestine, called neuropod cells, drive sugar appetite. The proposed studies will define the receptor required for neuropod cell sugar sensing, revealing a novel pharmaceutical target for downregulating sugar appetite.