TonEBP in Myeloid Cells Promotes Obesity-Induced Insulin Resistance and Inflammation Through Adipose Tissue Remodeling

Author:

Lee Hwan Hee1,Jeong Gyu Won1,Ye Byeong Jin1,Yoo Eun Jin1,Son Keoung Sun1,Kim Dong Ki2,Park Hye-Kyung1,Kang Byoung Heon1,Lee-Kwon Whaseon1,Kwon Hyug Moo1,Choi Soo Youn13ORCID

Affiliation:

1. 1School of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea

2. 2Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea

3. 3Department of Biology, Jeju National University, Jeju, Republic of Korea

Abstract

The phenotypic and functional plasticity of adipose tissue macrophages (ATMs) during obesity plays a crucial role in orchestration of adipose and systemic inflammation. Tonicity-responsive enhancer binding protein (TonEBP) (also called NFAT5) is a stress protein that mediates cellular responses to a range of metabolic insults. Here, we show that myeloid cell–specific TonEBP depletion reduced inflammation and insulin resistance in mice with high-fat diet–induced obesity but did not affect adiposity. This phenotype was associated with a reduced accumulation and a reduced proinflammatory phenotype of metabolically activated macrophages, decreased expression of inflammatory factors related to insulin resistance, and enhanced insulin sensitivity. TonEBP expression was elevated in the ATMs of obese mice, and Sp1 was identified as a central regulator of TonEBP induction. TonEBP depletion in macrophages decreased induction of insulin resistance–related genes and promoted induction of insulin sensitivity–related genes under obesity-mimicking conditions and thereby improved insulin signaling and glucose uptake in adipocytes. mRNA expression of TonEBP in peripheral blood mononuclear cells was positively correlated with blood glucose levels in mice and humans. These findings suggest that TonEBP in macrophages promotes obesity-associated systemic insulin resistance and inflammation, and downregulation of TonEBP may induce a healthy metabolic state during obesity.

Funder

National Research Foundation of Korea

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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