Adipocyte MKK3 Increases in Human Obesity protecting against Insulin Resistance by p38-beta activation

Obesity is a major global health concern, and a key predisposing factor for insulin resistance and type 2 diabetes mellitus. Adipocytes play a critical role in the development of obesity-induced insulin resistance, with several signaling pathways influencing insulin sensitivity. Among these, p38 MAP kinases are essential for adipose tissue physiology and the regulation of processes such as differentiation, thermogenesis, and inflammation. p38 activation is mediated by the upstream kinases MKK3 and MKK6 in response to inflammatory signals. While MKK6 inhibition promotes browning and thermogenesis and protects against obesity, the role of MKK3 remains unclear. Here, we investigated the function of MKK3 in adipose tissue. In human adipose tissue samples, MKK3 expression was positively correlated with body mass index (BMI) and negatively correlated with glycated hemoglobin, a marker of hyperglycemia. Using whole-body and adipose-specific Mkk3 and p38{beta} knockout mice, we found that Mkk3 activation in adipose tissue during obesity enhances insulin sensitivity. Mechanistically, adipose tissue from Mkk3- or p38{beta}-deficient mice exhibited elevated basal p70S6K activity compared with wild-type controls. This increased p70S6K activity was linked to higher serine phosphorylation of insulin receptor substrate 1 (IRS1) and impaired insulin-stimulated Akt phosphorylation, contributing to worsened insulin resistance. Collectively, our data suggest that activation of the MKK3/p38{beta} signaling axis in adipocytes may protect against high-fat diet-induced insulin resistance and diabetes.