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

  • Sci Rep. 2016 Mar 24:6:23479. doi: 10.1038/srep23479.
Audrey Fleury  1 ,  Lucile Hoch  2 ,  M Carmen Martinez  1 ,  Hélène Faure  2 ,  Maurizio Taddei  3 ,  Elena Petricci  3 ,  Fabrizio Manetti  3 ,  Nicolas Girard  4 ,  André Mann  4 ,  Caroline Jacques  1 ,  Jérôme Larghero  5 ,  Martial Ruat  2 ,  Ramaroson Andriantsitohaina  1 ,  Soazig Le Lay  1
Affiliations
  • 1. INSERM U1063, Université d'Angers, IBS-IRIS Rue des Capucins, F-49100 Angers, France.
  • 2. CNRS, UMR-9197, Neuroscience Paris-Saclay Institute, Molecules Circuits Department, 1 Avenue de la Terrasse, F-91198, Gif sur Yvette, France.
  • 3. Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, I-53100, Siena, Italy.
  • 4. CNRS, UMR-7200, Laboratoire d'Innovation Thérapeutique, Université de Strasbourg, 74 Route du Rhin, BP 60024, F-67401 Illkirch, France.
  • 5. Assistance Publique - Hôpitaux de Paris, Hôpital Saint-Louis, Unité de Thérapie Cellulaire; Inserm UMR1160 et CIC de Biothérapies; Univ Paris Diderot, Sorbonne Paris Cité, F-75475, Paris, France.
PMID: 27010359 DOI: 10.1038/srep23479
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.

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