Advanced science (Weinheim, Baden-Wurttemberg, Germany)Oct 29, 2026

A Fat Cell Signaling Pathway Helps Keep Insulin Working in Mice and Changes in Human Obesity

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Nov 2, 2026

Abstract

Adipose MKK3 expression increases early during high-fat feeding and is elevated in human obesity.

MKK3 expression in human visceral adipose tissue is positively associated with body mass index and leptin levels.
MKK3 expression is inversely associated with HbA1c in unadjusted analyses.
Loss of adipocyte MKK3 impairs insulin responsiveness in mice, specifically affecting glucose uptake in subcutaneous white adipose tissue.
Deficiency in MKK3 or p38β leads to increased p70S6K activity and reduced GLUT4 translocation, impairing insulin signaling.
The effects of MKK3 deficiency can be partially rescued by rapamycin or a selective p70S6K inhibitor.

Simplified

Obesity is a major risk factor for insulin resistance and type 2 diabetes. Adipocyte stress responses can either promote metabolic dysfunction or preserve insulin action, but the contribution of the p38 MAPK activator MKK3 to adipose tissue physiology remains poorly understood. Here, we show that adipose MKK3 expression increases early during high-fat feeding and is also elevated in human obesity. In human visceral adipose tissue, MKK3 expression was positively associated with body mass index and leptin and inversely associated with HbA1c in unadjusted analyses. Using germline, Fabp4-Cre, and Adipo-Cre Mkk3-deficient mice, together with p38β-deficient mice and primary adipocytes, we found that loss of adipocyte MKK3 impairs insulin responsiveness. Adipo-Cre;Mkk3^fl/fl (Adipo^Mkk3) mice displayed reduced insulin-stimulated glucose uptake selectively in subcutaneous white adipose tissue despite unchanged body composition and basal brown adipose tissue activity. Mechanistically, MKK3 or p38β deficiency increased p70S6K activity and inhibitory IRS1 Ser307 phosphorylation, reduced GLUT4 translocation and Akt activation, and these defects were partially rescued by rapamycin or the selective p70S6K inhibitor PF-4708671. Together, these findings identify an adipocyte MKK3-p38β-p70S6K axis that helps preserve insulin signaling during nutritional stress.

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A Fat Cell Signaling Pathway Helps Keep Insulin Working in Mice and Changes in Human Obesity

Abstract

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