Intestinal AMPK modulation of gut microbiota mediates cross‐talk with brown fat to control metabolism

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. In this study, we generated the intestinal AMPKα1 specific knock out mice (IKO) and observed that the AMPKα1 IKO mice displayed impaired thermogenesis function of brown adipose tissue both in chow diet and high fat diet condition. Moreover, HFD‐fed AMPKα1 IKO mice showed more severe impaired glucose tolerance and insulin resistance. Mechanistically, we revealed that intestinal AMPK can regulate the anti‐microbial peptides (AMPs) Reg3 and result in a shift in the gut microbiota composition, which leading to the elevation of the fermentation products methylglyoxal, and methylglyoxal can significantly suppress the UCP1 expression in the brown adipose tissue. While transplantation of the microbiota from AMPKα1 IKO mice to antibiotic‐induced microbiome depletion (AIMD) mice, the mice also showed impaired thermogenesis function of brown adipose tissue and elevated serum methylglyoxal level. In addition, we found that the metabolic effect and the AMP regulation of metformin is dependent on the intestinal AMPK.These results demonstrated that the intestinal nutrient sensor AMPKα1 can regulate the thermogenesis function of brown adipose tissue through modulating AMKP expression and reshaping the gut microbiome. These findings provide a new gut‐brown adipose tissue axis mechanism for activating energy expenditure and treating metabolic diseases.