Department of Physiology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
Department of Physiology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan; Department of Pathology and Matrix Biology, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
Cell Rep. 2021 Mar 9;34(10):108817. doi: 10.1016/j.celrep.2021.108817.
Primary cilia play a pivotal role in signal transduction and development and are known to serve as signaling hubs. Recent studies have shown that primary cilium dysfunction influences adipogenesis, but the mechanisms are unclear. Here, we show that mesenchymal progenitors C3H10T1/2 depleted of trichoplein, a key regulator of cilium formation, have significantly longer cilia than control cells and fail to differentiate into adipocytes. Mechanistically, the elongated cilia prevent caveolin-1- and/or GM3-positive lipid rafts from being assembled around the ciliary base where insulin receptor proteins accumulate, thereby inhibiting the insulin-Akt signaling. We further generate trichoplein knockout mice, in which adipogenic progenitors display elongated cilia and impair the lipid raft dynamics. The knockout mice on an extended high-fat diet exhibit reduced body fat and smaller adipocytes than wild-type (WT) mice. Overall, our results suggest a role for primary cilia in regulating adipogenic signal transduction via control of the lipid raft dynamics around cilia.
原发性纤毛在信号转导和发育中起着关键作用，已知其作为信号枢纽。最近的研究表明，原发性纤毛功能障碍会影响脂肪生成，但机制尚不清楚。在这里，我们表明，形成纤毛的关键调节因子 trichoplein 缺失的间充质祖细胞 C3H10T1/2 比对照细胞具有明显更长的纤毛，并且无法分化为脂肪细胞。从机制上讲，延长的纤毛阻止了 caveolin-1- 和/或 GM3 阳性脂筏在纤毛基部周围聚集，胰岛素受体蛋白在该处积累，从而抑制了胰岛素-Akt 信号。我们进一步生成了 trichoplein 敲除小鼠，其中脂肪生成祖细胞显示出延长的纤毛并损害了脂筏动力学。在延长的高脂肪饮食下，敲除小鼠比野生型 (WT) 小鼠表现出减少的体脂肪和更小的脂肪细胞。总体而言，我们的结果表明原发性纤毛通过控制纤毛周围的脂筏动力学在调节脂肪生成信号转导中发挥作用。
