Adipocyte OGT governs diet-induced hyperphagia and obesity

Min-Dian Li, Nicholas B. Vera, Yunfan Yang, Bichen Zhang, Weiming Ni, Enida Ziso-Qejvanaj, Sheng Ding, Kaisi Zhang, Ruonan Yin, Simeng Wang, Xu Zhou, Ethan X. Fang, Tian Xu, Derek M. Erion and Xiaoyong Yang ()
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Min-Dian Li: Yale University School of Medicine
Nicholas B. Vera: Pfizer Worldwide Research & Development
Yunfan Yang: Yale University School of Medicine
Bichen Zhang: Yale University School of Medicine
Weiming Ni: Yale University School of Medicine
Enida Ziso-Qejvanaj: Pfizer Worldwide Research & Development
Sheng Ding: Yale University School of Medicine
Kaisi Zhang: Yale University School of Medicine
Ruonan Yin: Yale University School of Medicine
Simeng Wang: Yale University School of Medicine
Xu Zhou: Yale University School of Medicine
Ethan X. Fang: Pennsylvania State University
Tian Xu: Yale University School of Medicine
Derek M. Erion: Pfizer Worldwide Research & Development
Xiaoyong Yang: Yale University School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract Palatable foods (fat and sweet) induce hyperphagia, and facilitate the development of obesity. Whether and how overnutrition increases appetite through the adipose-to-brain axis is unclear. O-linked beta-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) couples nutrient cues to O-GlcNAcylation of intracellular proteins at serine/threonine residues. Chronic dysregulation of O-GlcNAc signaling contributes to metabolic diseases. Here we show that adipocyte OGT is essential for high fat diet-induced hyperphagia, but is dispensable for baseline food intake. Adipocyte OGT stimulates hyperphagia by transcriptional activation of de novo lipid desaturation and accumulation of N-arachidonyl ethanolamine (AEA), an endogenous appetite-inducing cannabinoid (CB). Pharmacological manipulation of peripheral CB1 signaling regulates hyperphagia in an adipocyte OGT-dependent manner. These findings define adipocyte OGT as a fat sensor that regulates peripheral lipid signals, and uncover an unexpected adipose-to-brain axis to induce hyperphagia and obesity.

Date: 2018
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DOI: 10.1038/s41467-018-07461-x

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