TonEBP in myeloid cells promotes obesity-induced insulin resistance and inflammation through adipose tissue remodeling

<p>The phenotypic and functional plasticity of adipose tissue macrophages during obesity play 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 pro-inflammatory phenotype of metabolically activated macrophages; decreased expression of inflammatory factors related to insulin resistance; and enhanced insulin sensitivity. TonEBP expression was elevated in the adipose tissue macrophages 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 <em>TonEBP</em> 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. </p>