Ω3 Fatty Acids Activate Ciliary FFAR4 to Trigger Adipogenesis in Perivascular Preadipocytes

Recent studies find that mesenchymal progenitor cells including preadipocytes are ciliated and primary cilia are required for adipogenesis. The signaling function and location of ciliated cells in fat are unknown. We discover that ciliated preadipocytes abundantly populate a perivascular compartment in fat and are activated by high fat diet. We show Tulp3-dependent ciliary receptor trafficking is required for adipogenesis and identify the ω3 fatty acid receptor Ffar4/Gpr120 as the Tulp3-dependent ciliary GPCR. Ffar4 agonists and ω3 fatty acid DHA trigger mitogenesis and adipogenesis. DHA or FFAR4 agonists, but not saturated fatty acids, rapidly activate cAMP production inside cilia to activate EPAC signaling, induce CTCF-dependent chromatin remodeling, promote transcriptional activation of Pparγ/Cebpα, and initiate adipogenesis. DHA can replace cAMP activators to trigger adipogenesis. We propose dietary ω3 fatty acids selectively drive expansion of adipocyte numbers ensuring production of new fat cells to balance storage of saturated fatty acids, allowing homeostasis of heathy fat tissue.