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

Maximilian McCann,Hyerim Whang Kong,Xiuying Yang,Guanhua Du,Jinfang Zhu,Matthias Blüher,Guifen Qiang,Chong Wee Liew,Difeng Fang

doi:10.1038/ncomms11378

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.

Highlights

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
We discovered that, unlike in humans, there are three TRIP-Br2 isoforms
Our results showed that endoplasmic reticulum (ER) stress regulates Trip-br[2] in 3T3-L1 adipocytes in a time-dependent manner in line with the upregulation of ER stress markers (Fig. 2b)

Summary

Introduction

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. Considering the metabolic risks associated with visceral fat, identification of key visceral fat-specific regulators are likely to have high therapeutic potential to combat obesity-induced metabolic diseases. Owing to the striking conservation of visceral fat-specific regulation of TRIP-Br2 expression in human and mouse white adipose tissues as well as the metabolic protective phenotype of the knockout (KO) mouse, we hypothesized that TRIP-Br2 plays a role in the regulation of differential metabolic risks between different white fat depots during obesity, especially in visceral adipocytes. We found that expression of TRIP-Br2 in visceral fat is regulated by obesity-induced inflammatory cytokines and fatty acids via the endoplasmic reticulum (ER) stress pathway. We observed that transcription factor GATA3 is regulated in visceral fat upon physiological or pharmacological ER stress induction and inhibition of GATA3 abolished visceral adipocyte ER stress-induced TRIP-Br2 expression

Methods

Results

Conclusion