Omega-3 Fatty Acids Activate Ciliary FFAR4 to Control Adipogenesis.,Cell

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Omega-3 Fatty Acids Activate Ciliary FFAR4 to Control Adipogenesis.
Cell ( IF 45.5 ) Pub Date : 2019-11-21 , DOI: 10.1016/j.cell.2019.11.005
Keren I Hilgendorf ₁ , Carl T Johnson ₂ , Anja Mezger ₃ , Selena L Rice ₄ , Alessandra M Norris ₅ , Janos Demeter ₁ , William J Greenleaf ₆ , Jeremy F Reiter ₇ , Daniel Kopinke ₄ , Peter K Jackson ₈

Affiliation

Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stem Cell and Regenerative Medicine Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Genetics, Stanford University, Stanford, CA 94305, USA; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden.
Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA.
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL 32610, USA.
Department of Genetics, Stanford University, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA; Department of Applied Physics, Stanford University, Stanford, CA 94305, USA.
Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.

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.

中文翻译：

Omega-3 脂肪酸激活纤毛 FFAR4 以控制脂肪生成。

成人间充质干细胞，包括前脂肪细胞，拥有一种称为初级纤毛的细胞感觉细胞器。纤毛前脂肪细胞大量分布在脂肪中的血管周围，并被高脂肪饮食激活。在这里，我们试图了解前脂肪细胞是否使用它们的纤毛来感知和响应外部线索来重塑白色脂肪组织。消除小鼠的前脂肪细胞纤毛会严重损害白色脂肪组织的扩张。我们发现 omega-3 脂肪酸受体 FFAR4/GPR120 的 TULP3 依赖性纤毛定位促进脂肪生成。FFAR4 激动剂和 ω-3 脂肪酸，但不是饱和脂肪酸，通过快速激活纤毛内 cAMP 的产生来触发有丝分裂和脂肪生成。纤毛 cAMP 激活 EPAC 信号传导、CTCF 依赖性染色质重塑、PPARγ和CEBPα的转录激活以启动脂肪生成。我们建议饮食中的 ω-3 脂肪酸选择性地驱动脂肪细胞数量的增加，以产生新的脂肪细胞并储存饱和脂肪酸，从而实现健康脂肪组织的稳态。

更新日期：2019-11-22

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