Hedgehog associated to microparticles inhibits adipocyte differentiation via a non-canonical pathway.

Audrey Fleury, Lucile Hoch, M Carmen Martinez, Hélène Faure, Maurizio Taddei, Elena Petricci, Fabrizio Manetti, Nicolas Girard, André Mann, Caroline Jacques, Jérôme Larghero, Martial Ruat, Ramaroson Andriantsitohaina, Soazig Le Lay

Index: Sci. Rep. 6 , 23479, (2016)

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Abstract

Hedgehog (Hh) is a critical regulator of adipogenesis. Extracellular vesicles are natural Hh carriers, as illustrated by activated/apoptotic lymphocytes specifically shedding microparticles (MP) bearing the morphogen (MP(Hh+)). We show that MP(Hh+) inhibit adipocyte differentiation and orientate mesenchymal stem cells towards a pro-osteogenic program. Despite a Smoothened (Smo)-dependency, MP(Hh+) anti-adipogenic effects do not activate a canonical Hh signalling pathway in contrast to those elicited either by the Smo agonist SAG or recombinant Sonic Hedgehog. The Smo agonist GSA-10 recapitulates many of the hallmarks of MP(Hh+) anti-adipogenic effects. The adipogenesis blockade induced by MP(Hh+) and GSA-10 was abolished by the Smo antagonist LDE225. We further elucidate a Smo/Lkb1/Ampk axis as the non-canonical Hh pathway used by MP(Hh+) and GSA-10 to inhibit adipocyte differentiation. Our results highlight for the first time the ability of Hh-enriched MP to signal via a non-canonical pathway opening new perspectives to modulate fat development.