Hedgehog associated to microparticles inhibits adipocyte differentiation via a non-canonical pathway.
Hedgehog associated to microparticles inhibits adipocyte differentiation via a non-canonical pathway.
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DOI：
10.1038/srep23479
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发表时间：
2016-03-24
影响因子：
4.6
通讯作者：
Le Lay S
中科院分区：
文献类型：
--
作者：
Fleury A;Hoch L;Martinez MC;Faure H;Taddei M;Petricci E;Manetti F;Girard N;Mann A;Jacques C;Larghero J;Ruat M;Andriantsitohaina R;Le Lay S
Hedgehog (Hh) 是脂肪生成的关键调节因子。细胞外囊泡是天然的 Hh 载体，如活化/凋亡淋巴细胞特异性脱落带有形态发生素 (MPHh+) 的微粒 (MP) 所示。我们发现 MPHh+ 抑制脂肪细胞分化并将间充质干细胞定向至促成骨程序。尽管具有 Smoothened (Smo) 依赖性，但与 Smo 激动剂 SAG 或重组 Sonic Hedgehog 所引发的信号通路相反，MPHh+ 抗脂肪形成作用不会激活典型的 Hh 信号通路。 Smo 激动剂 GSA-10 概括了 MPHh+ 抗脂肪形成作用的许多特征。 Smo 拮抗剂 LDE225 消除了 MPHh+ 和 GSA-10 诱导的脂肪生成阻断。我们进一步阐明 Smo/Lkb1/Ampk 轴作为 MPHh+ 和 GSA-10 用于抑制脂肪细胞分化的非典型 Hh 途径。我们的结果首次强调了富含 Hh 的 MP 通过非规范途径发出信号的能力，为调节脂肪发育开辟了新的视角。
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 (MPHh+). We show that MPHh+ inhibit adipocyte differentiation and orientate mesenchymal stem cells towards a pro-osteogenic program. Despite a Smoothened (Smo)-dependency, MPHh+ 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 MPHh+ anti-adipogenic effects. The adipogenesis blockade induced by MPHh+ 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 MPHh+ 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.