The obesity-induced transcriptional regulator TRIP-Br2 mediates visceral fat endoplasmic reticulum stress-induced inflammation.
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.
Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, 835 S. Wolcott Avenue, M/C901, MSB E-202, Chicago, 60612 Illinois, USA.
Guifen
G
Qiang
Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, 835 S. Wolcott Avenue, M/C901, MSB E-202, Chicago, 60612 Illinois, USA.
Hyerim Whang
HW
Kong
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, 10 Center Drive, Bethesda, 20892 Maryland, USA.
Difeng
D
Fang
Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, 835 S. Wolcott Avenue, M/C901, MSB E-202, Chicago, 60612 Illinois, USA.
Maximilian
M
McCann
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, Beijing 100050, China.
Xiuying
X
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, Beijing 100050, China.
Guanhua
G
Du
Department of Medicine, University of Leipzig, Liebigstrasse 18, Leipzig 04103, Germany.
Matthias
M
Blüher
Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, 10 Center Drive, Bethesda, 20892 Maryland, USA.
Jinfang
J
Zhu
Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, 835 S. Wolcott Avenue, M/C901, MSB E-202, Chicago, 60612 Illinois, USA.
Chong Wee
CW
Liew
D017667:Adipocytes / Q000276:immunology; D054392:Adipokines / Q000235:genetics / Q000276:immunology; D000818:Animals; D059865:Endoplasmic Reticulum Stress; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D006801:Humans; D050152:Intra-Abdominal Fat / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D000092468:Bromodomain Containing Proteins
D054392:Adipokines; D050990:GATA3 Transcription Factor; D014157:Transcription Factors; C494748:Gata3 protein, mouse; C486065:Sertad2 protein, mouse; D000092468:Bromodomain Containing Proteins