Intestinal AMPK modulation of microbiota mediates cross-talk with brown fat to control thermogenesis

Abstract The energy-dissipating capacity of brown adipose tissue through thermogenesis can be targeted to improve energy balance. Mammalian 5′-AMP-activated protein kinase (AMPK), a key nutrient sensor for maintaining cellular energy status, is a known therapeutic target for glucose control in Type II diabetes (T2D). Despite current understandings of its well-established roles in regulating glucose metabolism in various tissues, the functions of AMPK in the intestine, an organ for nutrient processing, remain largely unexplored. Using an intestinal epithelium-specific AMPK-null (AMPK-IKO) mouse model, we demonstrated that AMPK in the intestine communicated with brown adipose tissue (BAT) to promote thermogenesis. Mechanistically, we uncovered a novel link between intestinal AMPK activation and BAT thermogenic regulation through modulating the anti-microbial peptide (AMP)-controlled gut microbiota and the metabolites. Our findings identified a new AMPK-mediated mechanism of intestine-BAT communication that may partially underlie the therapeutic effects of AMPK activator metformin (N, N-dimethylbiguanide).