Primary cilia-dependent lipid raft/caveolin dynamics regulate adipogenesis

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. [Display omitted] •Lipid rafts of adipogenic progenitors accumulate around ciliary base upon stimuli•Lipid raft accumulation propagates adipogenic IR/IGF1R-Akt signaling upon stimuli•Ciliary elongation in APs suppresses lipid raft accumulation upon stimuli•Tchp−/− mice are resistant to obesity by high-fat diet and increased thermogenesis Primary cilium dysfunction influences adipogenesis, but the mechanisms are unclear. Yamakawa et al. show that loss of trichoplein leads to ciliary elongation, a decrease in caveolin-1/GM3 accumulation around the cilium, thereby inhibiting adipogenic IR/IGF1R-Akt signaling and protection from high-fat-diet-induced obesity and metabolic syndrome.