Food and Behaviour Research

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Omega-3 Fatty Acids Activate Ciliary FFAR4 to Control Adipogenesis

Hilgendorf KI, Johnson CT, Mezger A, Rice SL, Norris AM, Demeter J, Greenleaf WJ, Reiter JF, Kopinke D, Jackson PK (2019) Cell 2019 Nov;  doi.org/10.1016/j.cell.2019.11.005 

Web URL: Read the abstract on cell.com here

Abstract:

Highlights

  • 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

Summary

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.

FAB RESEARCH COMMENT:

See the associated news article:

Highlights

  • 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

Summary

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.