title: Hedgehog associated to microparticles inhibits adipocyte differentiation via a non-canonical pathway.
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.
authors.affiliation: INSERM U1063, Université d'Angers, IBS-IRIS Rue des Capucins, F-49100 Angers, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Fleury
authors.affiliation: CNRS, UMR-9197, Neuroscience Paris-Saclay Institute, Molecules Circuits Department, 1 Avenue de la Terrasse, F-91198, Gif sur Yvette, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Hoch
authors.affiliation: INSERM U1063, Université d'Angers, IBS-IRIS Rue des Capucins, F-49100 Angers, France.
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Martinez
authors.affiliation: CNRS, UMR-9197, Neuroscience Paris-Saclay Institute, Molecules Circuits Department, 1 Avenue de la Terrasse, F-91198, Gif sur Yvette, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Faure
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, I-53100, Siena, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taddei
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, I-53100, Siena, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Petricci
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, I-53100, Siena, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.affiliation: CNRS, UMR-7200, Laboratoire d'Innovation Thérapeutique, Université de Strasbourg, 74 Route du Rhin, BP 60024, F-67401 Illkirch, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Girard
authors.affiliation: CNRS, UMR-7200, Laboratoire d'Innovation Thérapeutique, Université de Strasbourg, 74 Route du Rhin, BP 60024, F-67401 Illkirch, France.
authors.forename: André
authors.initials: A
authors.lastname: Mann
authors.affiliation: INSERM U1063, Université d'Angers, IBS-IRIS Rue des Capucins, F-49100 Angers, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Jacques
authors.affiliation: 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.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Larghero
authors.affiliation: CNRS, UMR-9197, Neuroscience Paris-Saclay Institute, Molecules Circuits Department, 1 Avenue de la Terrasse, F-91198, Gif sur Yvette, France.
authors.forename: Martial
authors.initials: M
authors.lastname: Ruat
authors.affiliation: INSERM U1063, Université d'Angers, IBS-IRIS Rue des Capucins, F-49100 Angers, France.
authors.forename: Ramaroson
authors.initials: R
authors.lastname: Andriantsitohaina
authors.affiliation: INSERM U1063, Université d'Angers, IBS-IRIS Rue des Capucins, F-49100 Angers, France.
authors.forename: Soazig
authors.initials: S
authors.lastname: Le Lay
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D053823:Hedgehog Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D053823:Hedgehog Proteins; D014157:Transcription Factors