2042-LB: The Gut–Fat Cross Talk in Metabolic Regulation through Microbiome

Current treatments are still limited in their ability to mitigate obesity and its complications. Obesity develops due to an imbalance between nutrient intake and energy expenditure; therefore, there is an urgent need to better understand the mechanisms governing nutrition and energy balance, with the long-term goal of developing novel strategies to treat obesity and associated metabolic diseases. Our previous study uncovered a novel link between intestinal AMPK activation and brown adipose tissue (BAT) thermogenic regulation through modulating the anti-microbial peptides (AMPs)-controlled gut microbiota and their metabolites. We also identified the new AMPK-mediated mechanism of intestine-BAT communication that may partially underlie the effects of metformin in metabolic diseases. Our current study discovered that another nutrient sensor mTOR crosstalk with white adipose tissue (WAT) browning regulates glucose homeostasis and energy metabolism. We observed significantly enhanced WAT browning and glucose homeostasis in intestinal epithelium-specific mTOR knockout (mTOR-IKO) mice compared to mTOR^fl/fl mice. Moreover, the gut microbiota profile of mTOR-IKO mice was markedly shifted compared to that of mTOR^fl/fl mice. Similarly, we identified significant differences in the serum and fecal levels of some bacterial metabolites in mTOR-IKO mice. Furthermore, we observed enhanced WAT browning and glucose homeostasis in WT mice after fecal microbiota transplantation from mTOR-IKO mice. Mechanistically, we found that the expression of various AMPs, including REG3 and RELMb were significantly lower in the intestines of mTOR-IKO mice compared to controls. These results indicate that intestinal mTOR remotely controls WAT browning through a mTOR-AMPs-microbiome-WAT axis. Determining the role of intestinal AMPK/mTOR-AMPs pathways in energy and metabolism will help fill the gap in our current understanding of how the intestine serves as an important site of AMPK/mTOR action in metabolic regulation.