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

Laura A. Velazquez-Villegas, Alessia Perino, Vera Lemos, Marika Zietak, Mitsunori Nomura, Thijs Willem Hendrik Pols and Kristina Schoonjans ()
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Laura A. Velazquez-Villegas: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne
Alessia Perino: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne
Vera Lemos: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne
Marika Zietak: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne
Mitsunori Nomura: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne
Thijs Willem Hendrik Pols: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne
Kristina Schoonjans: Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02068-0

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