The rising incidence of pediatric type 2 diabetes (T2D) highlights a growing need to understand mechanisms behind highly-effective therapies such as bariatric surgery, in order to develop better, more widely-applicable treatments. Our work suggests that metabolic changes at the level of the small intestine may contribute to these beneficial health effects of bariatric surgery, including T2D remission. Our long-term goal is to understand mechanisms for these changes in order to design better treatments for pediatric patients. The goal of this application is to understand how 2 specific pathways, driven by PXR and CAR, to respond to nutrients in the intestine and in turn influence local metabolism. Our preliminary data demonstrate metabolic changes in nutrient-facing sections of small intestine after bariatric surgery, including reduced fatty acid oxidation and suppression of both PXR and CAR signaling, but this pattern is reversed in parts of the intestine that after surgery do process see luminal nutrients. The central hypothesis is that that alteration in intestinal epithelial lipid homeostasis, driven by CAR and/or PXR signaling, may drive local glucose utilization, which has been linked to improvement in glucose homeostasis. The rationale for this project is that fatty acid synthesis could glucose utilization (via carbon utilization to build fatty acids), which is supported by our preliminary data. These experiments will allow us to directly test the role for selected pathways to contribute to intestinal adaptation and metabolic homeostasis more broadly. The central hypothesis will be tested in two specific aims using our human organoid model of obesity, derived from human adolescent patients undergoing bariatric surgery: (1) determine the role of PXR to influence intestinal epithelial glucose and lipid metabolism; and (2) determine the role of CAR to influence glucose and lipid metabolism in intestinal epithelium. This project will shed light on key candidate pathways influencing intestinal epithelial metabolism and, ultimately, potential drug targets for pediatric T2D, that could mimic the beneficial effects of bariatric surgery without the problematic invasiveness of surgery.