Omega-3 Fatty Acids Activate Ciliary FFAR4 to Control Adipogenesis

• Published in: Cell 2019-11, Vol.179 (6), p.1289-1305.e21
• Main Authors: Hilgendorf, Keren I., Johnson, Carl T., Mezger, Anja, Rice, Selena L., Norris, Alessandra M., Demeter, Janos, Greenleaf, William J., Reiter, Jeremy F., Kopinke, Daniel, Jackson, Peter K.
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Adipocytes - drug effects; Adipocytes - metabolism; adipogenesis; Adipogenesis - drug effects; Adipose Tissue, White - metabolism; Animals; CCAAT-Enhancer-Binding Proteins - metabolism; CCCTC-Binding Factor - metabolism; Chromatin - metabolism; Cilia - drug effects; Cilia - metabolism; ciliary signaling; Cyclic AMP - metabolism; diabetes; Docosahexaenoic Acids - pharmacology; Fatty Acids, Omega-3 - pharmacology; FFAR4; GPR120; Intracellular Signaling Peptides and Proteins - metabolism; Macrophages - drug effects; Macrophages - metabolism; mesenchymal stem cells; Mice; Mice, Inbred C57BL; obesity; omega-3 fatty acid; PPAR gamma - metabolism; preadipocyte; primary cilia; Receptors, G-Protein-Coupled - metabolism
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2019.11.005

Adult mesenchymal stem cells, including preadipocytes, possess a cellular sensory organelle called the primary cilium. Ciliated preadipocytes abundantly populate perivascular compartments in fat and are activated by a high-fat diet. Here, we sought to understand whether preadipocytes use their cilia to sense and respond to external cues to remodel white adipose tissue. Abolishing preadipocyte cilia in mice severely impairs white adipose tissue expansion. We discover that TULP3-dependent ciliary localization of the omega-3 fatty acid receptor FFAR4/GPR120 promotes adipogenesis. FFAR4 agonists and ω-3 fatty acids, but not saturated fatty acids, trigger mitosis and adipogenesis by rapidly activating cAMP production inside cilia. Ciliary cAMP activates EPAC signaling, CTCF-dependent chromatin remodeling, and transcriptional activation of PPARγ and CEBPα to initiate adipogenesis. We propose that dietary ω-3 fatty acids selectively drive expansion of adipocyte numbers to produce new fat cells and store saturated fatty acids, enabling homeostasis of healthy fat tissue. [Display omitted] •Preadipocytes, located along blood vessels, are ciliated in vitro and in vivo•Loss of preadipocyte ciliation strongly impairs white adipose tissue expansion•Ciliary GPCRs are critical for adipogenesis, and FFAR4/GPR120 localizes to cilia•ω-3 fatty acids activate ciliary FFAR4 and trigger adipogenesis via ciliary cAMP An omega-3 fatty acid drives adipogenesis through ciliary signaling.