Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
Mayo Clinic Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA; Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA.
Cell Rep. 2021 Aug 3;36(5):109481. doi: 10.1016/j.celrep.2021.109481.
Preadipocytes dynamically produce sensory cilia. However, the role of primary cilia in preadipocyte differentiation and adipose homeostasis remains poorly understood. We previously identified transition fiber component FBF1 as an essential player in controlling selective cilia import. Here, we establish Fbf1 mice and discover that Fbf1 mice develop severe obesity, but surprisingly, are not predisposed to adverse metabolic complications. Obese Fbf1 mice possess unexpectedly healthy white fat tissue characterized by spontaneous upregulated beiging, hyperplasia but not hypertrophy, and low inflammation along the lifetime. Mechanistically, FBF1 governs preadipocyte differentiation by constraining the beiging program through an AKAP9-dependent, cilia-regulated PKA signaling, while recruiting the BBS chaperonin to transition fibers to suppress the hedgehog signaling-dependent adipogenic program. Remarkably, obese Fbf1 mice further fed a high-fat diet are protected from diabetes and premature death. We reveal a central role for primary cilia in the fate determination of preadipocytes and the generation of metabolically healthy fat tissue.
前脂肪细胞动态地产生感觉纤毛。然而，初级纤毛在脂肪细胞分化和脂肪组织稳态中的作用仍知之甚少。我们之前确定过渡纤维成分 FBF1 是控制选择性纤毛内流的必需因子。在这里，我们构建了 Fbf1 敲除小鼠，并发现 Fbf1 敲除小鼠会发展为严重肥胖，但令人惊讶的是，它们不易发生不良代谢并发症。肥胖的 Fbf1 敲除小鼠拥有出乎意料的健康白色脂肪组织，其特征为自发性米色化增强、增生而非肥大、以及终生炎症水平低。在机制上，FBF1 通过 AKAP9 依赖性、纤毛调节的 PKA 信号限制米色化程序来控制脂肪细胞分化，同时募集 BBS 伴侣蛋白到过渡纤维来抑制 hedgehog 信号依赖性脂肪生成程序。值得注意的是，进一步用高脂肪饮食喂养肥胖的 Fbf1 敲除小鼠可预防糖尿病和过早死亡。我们揭示了初级纤毛在脂肪细胞命运决定和代谢健康脂肪组织生成中的核心作用。
