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Summary: 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.

Primary cilia play pivotal roles in signal transduction and development, and are known to serve as signaling hubs. Recent studies have shown that primary cilia dysfunction influences adipogenesis, but the mechanisms are unclear. Here, we show that mesenchymal progenitors C3H10T1/2 depleted of trichoplein, a key regulator of cilia formation, have significantly longer cilia than control cells, and fail to differentiate into adipocytes. Mechanistically, the elongated cilia prevent lipid rafts/caveolae from being assembled around the ciliary base where insulin receptor proteins accumulate, thereby inhibiting propagation of insulin signaling to Akt. We further generated trichoplein knockout mice, in which adipogenic progenitors display elongated cilia and impaired dynamics of lipid rafts/caveolae. The knockout mice on an extended high-fat diet exhibit reduced body fat, and smaller adipocyte than WT mice. Overall, our results suggest a novel role for primary cilia in regulating adipogenic signal transduction via control of lipid rafts/caveolae dynamics around cilia.