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

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posted on 01.06.2016, 00:00 by G Qiang, HW Kong, D Fang, M McCann, X Yang, G Du, M Blüher, J hu, CW Liew
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.

Funding

This publication is partly supported by the Research Open Access Publishing (ROAAP) Fund of the University of Illinois at Chicago. This work was supported by K99 DK090210, R00 DK090210, Novo Nordisk Great Lakes Science Forum Award, RayBiotech Innovative Research Grant Award, Center for Society for Clinical and Translational Research Early Career Development Award and UIC Startup fund (C.W.L.). The human studies were supported by a grant of the Deutsche Forschungsgemeinschaft, Obesity Mechanisms (SFB 1052, B01 to M.B.). D. Fang and J. Zhu are supported by the intramural research program of NIAID, NIH

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Publisher Statement

This is a copy of an article published in Nature Communications © 2016 Nature Publishing Group. © The Authors.

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Nature Publishing Group

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25/04/2016

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