The obesity-induced transcriptional regulator TRIP-Br2 mediates visceral fat endoplasmic reticulum stress-induced inflammation

Guifen Qiang, Hyerim Whang Kong, Difeng Fang, Maximilian McCann, Xiuying Yang, Guanhua Du, Matthias Blüher, Jinfang Zhu and Chong Wee Liew ()
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Guifen Qiang: College of Medicine, University of Illinois at Chicago
Hyerim Whang Kong: College of Medicine, University of Illinois at Chicago
Difeng Fang: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases
Maximilian McCann: College of Medicine, University of Illinois at Chicago
Xiuying Yang: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
Guanhua Du: State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College
Matthias Blüher: University of Leipzig
Jinfang Zhu: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases
Chong Wee Liew: College of Medicine, University of Illinois at Chicago

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract The intimate link between location of fat accumulation and metabolic disease risk and depot-specific differences is well established, but how these differences between depots are regulated at the molecular level remains largely unclear. Here we show that TRIP-Br2 mediates endoplasmic reticulum (ER) stress-induced inflammatory responses in visceral fat. Using in vitro, ex vivo and in vivo approaches, we demonstrate that obesity-induced circulating factors upregulate TRIP-Br2 specifically in visceral fat via the ER stress pathway. We find that ablation of TRIP-Br2 ameliorates both chemical and physiological ER stress-induced inflammatory and acute phase response in adipocytes, leading to lower circulating levels of inflammatory cytokines. Using promoter assays, as well as molecular and pharmacological experiments, we show that the transcription factor GATA3 is responsible for the ER stress-induced TRIP-Br2 expression in visceral fat. Taken together, our study identifies molecular regulators of inflammatory response in visceral fat that—given that these pathways are conserved in humans—might serve as potential therapeutic targets in obesity.

Date: 2016
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DOI: 10.1038/ncomms11378

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