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Published on: May 19, 2023
Hedgehog associated to microparticles inhibits adipocyte differentiation via a non-canonical pathway
Audrey Fleury1, Lucile Hoch2, M Carmen Martinez1
1INSERM U1063, Université d'Angers, IBS-IRIS Rue des Capucins, F-49100 Angers, France.
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.
Insights
Extracellular vesicles carrying Hedgehog (Hh) inhibit fat cell differentiation via a non-canonical pathway. This discovery offers new strategies for modulating fat development and understanding stem cell fate.
Area of Science:
- Cell Biology
- Biochemistry
- Stem Cell Biology
Background:
- Hedgehog (Hh) signaling is crucial for regulating adipogenesis (fat cell formation).
- Extracellular vesicles, such as microparticles (MP) from lymphocytes, can carry Hh.
- These Hh-enriched microparticles (MP(Hh+)) influence stem cell differentiation.
Purpose of the Study:
- To investigate the mechanism by which MP(Hh+) affect adipogenesis and stem cell fate.
- To determine if MP(Hh+) utilize the canonical Hh signaling pathway.
- To identify the non-canonical pathway involved in MP(Hh+) mediated effects.
Main Methods:
- Treatment of mesenchymal stem cells with MP(Hh+), Smoothened (Smo) agonists (SAG, GSA-10), and antagonists (LDE225).
- Analysis of adipocyte differentiation and stem cell osteogenic programming.
- Elucidation of signaling pathways, including the Smo/Lkb1/Ampk axis.
Main Results:
- MP(Hh+) inhibit adipocyte differentiation and promote osteogenic differentiation of mesenchymal stem cells.
- MP(Hh+) effects are Smo-dependent but do not activate the canonical Hh pathway.
- The Smo agonist GSA-10 mimics MP(Hh+) effects, and both are blocked by LDE225.
- A non-canonical Smo/Lkb1/Ampk pathway mediates the anti-adipogenic effects.
Conclusions:
- Hedgehog-enriched microparticles signal through a non-canonical pathway to inhibit adipogenesis.
- This non-canonical Smo/Lkb1/Ampk axis provides a novel mechanism for regulating fat development.
- These findings open new therapeutic perspectives for modulating adipogenesis and related disorders.
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