Gene

Cell biology

Cilium

White adipose tissue

Biology

Adipogenesis

Endocrinology

Brown adipose tissue

Signal transduction

Genetics

White (mutation)

Internal medicine

Medicine

Hedgehog signaling pathway

Adipose tissue

SSRN Electronic Journal

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 of the ciliary gate. Here, we established Fbf1tm1a/tm1a mice and discovered 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 life time. 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. Collectively, we reveal a central role for ciliary FBF1 pathways in fate specification of preadipocytes and generation of metabolically healthy fat tissue.

FBF1 Deficiency Promotes Beiging and Healthy Expansion of White Adipose Tissue