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.
Highlights
Remodelling of energy storing white fat into energy expending beige fat could be a promising strategy to reduce adiposity
DRP1 phosphorylation was significantly increased in adipocytes stimulated with INT-777 at days 5 and 7 of differentiation, as was the mitochondrial content marker voltage-dependent anion channel 1 (VDAC1) (Supplementary Fig. 7E–H). These results suggest that the regulation of mitochondrial fission after activation of the TGR5-extracellular signal-regulated kinase (ERK) signalling pathway goes in parallel with an induction in mitochondrial biogenesis, most likely orchestrated by cAMP, which is an established inducer of genes involved in mitochondrial biogenesis[45,46]
Our data support a model in which TGR5 activation triggers lipolysis, mitochondrial biogenesis and DRP1-mediated fission, three processes critically required to promote beiging and thermogenesis of white fat depots
Summary
Remodelling of energy storing white fat into energy expending beige fat could be a promising strategy to reduce adiposity. Brown-like cells, referred to as beige or brite cells, have been described within the white adipose tissue (WAT)[1,2] Such beige cells display functional characteristics similar to brown adipocytes, including the ability to convert chemical energy into heat via the expression of uncoupling protein 1 (UCP1), known to dissipate the mitochondrial electrochemical gradient through proton leak and to induce uncoupled respiration[3,4]. Through this process, beiging of WAT increases the utilisation of nutrients and may contribute to whole-body energy homeostasis[1,5,6,7]. Cold exposure induces changes in bile acid (BA) composition, including an increase in secondary BAs17,18
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