Role of Lipogenic Pathways in Intestinal Remodeling after Gastric Bypass Surgery

PROJECT SUMMARY The rising incidence of type 2 diabetes (T2D) highlights a growing need to understand mechanisms behind highly-effective therapies such as Roux-en-Y gastric bypass surgery (RYGB) in order to develop better, more widely-applicable treatments. Adaptation in the jejunum (Roux limb) is a hypothesized contributor to diabetes improvement after RYGB, and this is supported by our lab’s work demonstrating a relationship of jejunal adaptation with both glycemic control and T2D remission in humans. Our long-term goal is to understand how changes in GI anatomy effect the powerful, durable shift in energy homeostasis observed after bariatric surgery. The overall objective of this application is to understand how changes in GI anatomy elicit the powerful, durable shift in energy homeostasis observed after bariatric surgery. Our preliminary data demonstrate segment-specific activation of LXR signaling in Roux limb of mice and humans after RYGB which is lost in humans without T2D remission, as well as downregulation of PPARa signaling and enrichment of lipids, especially plasma membrane lipids, in Roux limb. The central hypothesis is that that alteration in intestinal epithelial lipid homeostasis, driven by LXR and PPARa signaling, is necessary for RL adaptation and associated improvements in glucose homeostasis after RYGB. The rationale for this project is that de novo lipogenesis could be a pathway for local intestinal glucose utilization, which is supported by our preliminary data. These experiments will allow us to directly test the role for lipogenic pathways to contribute to intestinal adaptation and metabolic homeostasis more broadly. The central hypothesis will be tested in two specific aims: (1) to test the hypothesis that LXR- and PPARa- mediated lipogenesis drives RL adaptation and glucose regulation in diet-induced obesity; and (2) To test the hypothesis that changes in lipogenesis drive intestinal epithelial adaptation in a disease-relevant in vitro model system. We will use mouse models including our murine model of bariatric surgery in Aim 1; Aim 2 will use a jejunal organoid model derived from human patients with obesity, who are undergoing bariatric surgery. This project will shed light on the key intestinal epithelial cells responsible for Roux limb adaptation and ultimately, potential drug targets that could mimic the beneficial effects of RYGB.