3031-LB: An Intestinal mTOR-Gut Microbiota–White Adipose Tissue Axis in Metabolic Regulation

Introduction and Objective: Type 2 diabetes (T2D) and obesity are major metabolic diseases driven by an imbalance between nutrient intake and energy expenditure. The mammalian target of rapamycin (mTOR) integrates nutrient and hormonal signals to regulate cell growth and metabolism, and its dysregulation contributes to metabolic diseases. However, the role of intestinal mTOR in regulating systemic metabolism remains poorly understood. Methods: We generated intestinal epithelium-specific mTOR knockout (mTOR-IKO) mice and observed significantly enhanced white adipose tissue (WAT) browning and improved glucose homeostasis relative to wild-type (WT) controls. Furthermore, fecal microbiota transplantation from mTOR-IKO mice to WT mice reproduced these metabolic benefits, indicating that intestinal mTOR regulates WAT browning through modulation of the gut microbiota profile. Results: In plasma samples of mTOR-IKO mice, we identified significant alterations in several metabolites, linked with tryptophan metabolism. Moreover, the gut microbiota profile of mTOR-IKO mice was markedly shifted compared to that of WT control mice, showing several bacterial species which could be associated with tryptophan metabolism. Conclusion: We conclude that intestinal mTOR remotely controls WAT browning through a mTOR-gut microbiota metabolite-WAT axis. Determining the role of intestinal mTOR mediated pathways in energy and metabolism will help fill the gap in our current understanding of how the intestine serves as a key site of nutrient sensors (AMPK/mTOR) action in metabolic regulation.