SUN-578 HIF-2a signaling in L-cells is crucial for GLP-1 secretion in response to luminal lipids

Abstract Disclosure: R. Mooli: None. K. Balakrishnan: None. N. Gandhi: None. A. Nallanagulagari: None. S. Kling: None. S. Ramakrishnan: None. Glucagon-like peptide-1 (GLP-1), secreted by intestinal L-cells, plays a vital role in enhancing pancreatic insulin secretion, reducing liver fat accumulation, and combating obesity. However, the molecular mechanisms that regulate GLP-1 secretion remain poorly understood. In our previous work, we identified that intestinal hypoxia-inducible factor-2α (HIF-2α) regulates GLP-1 secretion by increasing the expression of the lipid-sensing receptor GPR40. In this study, we show that activating HIF-2α (Hif2LSL:Gcg-Cre) specifically in L-cells significantly boosts circulating GLP-1 levels. These mice exhibit improved glucose tolerance, primarily due to enhanced acute-phase insulin secretion rather than changes in insulin sensitivity. This improvement in glucose tolerance is reversed when the GLP-1 receptor antagonist Exendin 9-39 is administered, confirming that L-cell HIF-2α enhances glucose homeostasis through GLP-1. Furthermore, temporally activating HIF-2α in L-cells (Hif2LSL:Gcg-Cre/ERT2) raises serum GLP-1 levels and improves glucose tolerance. We also investigated whether pharmacological activation of HIF-2α with FG-4592 affects intestinal lipid sensing and GLP-1 secretion. Our results show that FG-4592 increases lipid-induced GLP-1 secretion and improves glucose tolerance in both chow-fed and high-fat-fed mice. Further experiments using L-cell-specific HIF-2α knockout mice (Hif2F/F:Gcg-Cre) demonstrated that FG-4592 promotes metabolic homeostasis via L-cells. Mechanistically, we found that HIF-2α enhances lipid sensing in L-cells through the GPR40 receptor, leading to increased GLP-1 secretion. Thus, our study identifies a target to improve the endogenous production of GLP-1 in response to luminal nutrients, specifically lipids. Presentation: Sunday, July 13, 2025