FBF1 deficiency promotes beiging and healthy expansion of white adipose tissue

• Published in: Cell reports (Cambridge) 2021-08, Vol.36 (5), p.109481-109481, Article 109481
• Main Authors: Zhang, Yingyi, Hao, Jielu, Tarrago, Mariana G., Warner, Gina M., Giorgadze, Nino, Wei, Qing, Huang, Yan, He, Kai, Chen, Chuan, Peclat, Thais R., White, Thomas A., Ling, Kun, Tchkonia, Tamar, Kirkland, James L., Chini, Eduardo N., Hu, Jinghua
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Adaptor Proteins, Signal Transducing - deficiency; Adaptor Proteins, Signal Transducing - metabolism; Adipocytes - metabolism; Adipogenesis; Adipose Tissue, Beige - metabolism; Adipose Tissue, White - metabolism; Animals; BBS; beiging; Cell Respiration; Cilia - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; diabetes; FBF1; Female; Fibroblasts - metabolism; healthy obesity; Hedgehog; Hedgehog Proteins - metabolism; Homozygote; Humans; Hyperphagia - complications; Hyperphagia - pathology; Hyperplasia; Inflammation - pathology; Male; Metabolic Syndrome - complications; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microtubule-Associated Proteins - metabolism; Obesity - complications; PKA; preadipocyte; primary cilia; Signal Transduction; Transcription Factors - metabolism
• ISSN: 2211-1247; 2211-1247
• 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 Fbf1tm1a/tm1a mice and discover that Fbf1tm1a/tm1a mice develop severe obesity, but surprisingly, are not predisposed to adverse metabolic complications. Obese Fbf1tm1a/tm1a 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 Fbf1tm1a/tm1a 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. [Display omitted] •Fbf1tm1a/tm1a mice exhibit “healthy obesity” with healthy and beiging white fat tissue•FBF1 controls the beiging program via a cilia-specific, AKAP9-dependent, PKA signaling•FBF1 governs the adipogenic program via Hh signaling•Fbf1tm1a/tm1a mice are protected from diabetes and show reduced risk of dying prematurely Zhang et al. demonstrate that Fbf1tm1a/tm1a mice exhibit “healthy obesity” with healthy and beiging white fat tissue. Mechanistically, FBF1 governs preadipocyte differentiation by constraining the beiging program through cilia-regulated PKA signaling, while suppressing the Hh-dependent adipogenic program. Fbf1tm1a/tm1a mice fed a high-fat diet are protected from diabetes and premature death.