TGR5 signalling promotes mitochondrial fission and beige remodelling of white adipose tissue.

Abstract

Remodelling of energy storing white fat into energy expending beige fat could be a promising strategy to reduce adiposity. Here, we show that the bile acid-responsive membrane receptor TGR5 mediates beiging of the subcutaneous white adipose tissue (scWAT) under multiple environmental cues including cold exposure and prolonged high-fat diet feeding. Moreover, administration of TGR5-selective bile acid mimetics to thermoneutral housed mice leads to the appearance of beige adipocyte markers and increases mitochondrial content in the scWAT of Tgr5 ^+/+ mice but not in their Tgr5 ^-/- littermates. This phenotype is recapitulated in vitro in differentiated adipocytes, in which TGR5 activation increases free fatty acid availability through lipolysis, hence fuelling β-oxidation and thermogenic activity. TGR5 signalling also induces mitochondrial fission through the ERK/DRP1 pathway, further improving mitochondrial respiration. Taken together, these data identify TGR5 as a druggable target to promote beiging with potential applications in the management of metabolic disorders.