2. Academic Validation
  3. Hedgehog associated to microparticles inhibits adipocyte differentiation via a non-canonical pathway

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

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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