Intestinal AMPK modulation of microbiota mediates crosstalk 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, a key nutrient sensor for maintaining cellular energy status, is a known therapeutic target in Type II diabetes. Despite its well-established roles in regulating glucose metabolism in various tissues, the functions of AMPK in the intestine remain largely unexplored. Here we show that AMPKα1 deficiency in the intestine results in weight gain and impaired glucose tolerance under high fat diet feeding, while metformin administration fails to ameliorate these metabolic disorders in intestinal AMPKα1 knockout mice. Further, AMPKα1 in the intestine communicates with brown adipose tissue to promote thermogenesis. Mechanistically, we uncover a link between intestinal AMPKα1 activation and BAT thermogenic regulation through modulating anti-microbial peptide-controlled gut microbiota and the metabolites. Our findings identify AMPKα1-mediated mechanisms of intestine-BAT communication that may partially underlie the therapeutic effects of metformin.

Data-dependent and -independent acquisition lipidomics analysis reveals the tissue-dependent effect of metformin on lipid metabolism

“…3) In line with the prior discovery of metformin effect on gut microbiota 11,21,33 , metformin seems to affect endogenous ethanol production in the small intestine, evidenced by the increase of ethanol and PC product, PEtOH. Even though the exact mechanisms of enhanced ethanol production remain to be elucidated, one plausible explanation is that metformin increases NADH/NAD+ ratio in intestinal epithelial cells, which promotes the conversion of gut bacteria-derived acetaldehyde to ethanol.…”

Cross-Talk Between Gut Microbiota and Adipose Tissues in Obesity and Related Metabolic Diseases

“…AMPK, an essential nutrient sensor for maintaining cellular energy status, plays important role in regulating glucose metabolism in various tissues. Very recently, Huang et al identified that intestinal AMPKa1 stimulates thermogenesis by modulating anti-microbial peptide that manipulates gut mic robiota a nd metabolite s. T hese intestine -BAT communications through AMPKa-related signaling might partially be the underlying mechanism of beneficiary action of metformin on the intestine (52).…”

“…identified that intestinal AMPKα1 stimulates thermogenesis by modulating anti-microbial peptide that manipulates gut microbiota and metabolites. These intestine-BAT communications through AMPKα- related signaling might partially be the underlying mechanism of beneficiary action of metformin on the intestine ( 52 ).…”

The Athlete Gut Microbiome and its Relevance to Health and Performance: A Review

“…Due to their nutrient sensitive natures, both pathways are influenced by intestinal contents, and by extension, the gut microbiota. This has been demonstrated elegantly by showing that a faecal microbiome transplant from AMPK knock-out mice (which have markedly higher lipid deposition than wild-type mice), transfers some of these effects to healthy mice, clear evidence of bidirectional relationship mediated by this pathway [ 54 ]. A similar study showed that mice treated with an mTORC1 inhibitor and fed a high-fat diet had a notably higher abundance of Akkermansia muciniphila, a mucin-degrading gut bacteria generally associated with healthy gut microbiomes, than mice fed only a high-fat diet [ 55 ].…”