An Adipocyte MKK3-p38β Axis Preserves Insulin Responsiveness in Mice and Is Reciprocally Altered in Human Obesity.
11 affiliations
- 1Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
- 2Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain.
- 3Complejo Asistencial de Zamora, Zamora, Spain.
- 4Bariatric Surgery Unit, Department of General Surgery, University Hospital of Salamanca, Department of Surgery, University of Salamanca, Salamanca, Spain.
- 5Department of Physiology, CiMUS, University of Santiago de Compostela, Santiago de Compostela, Spain.
- 6Division of Cell Signalling and Immunology, Faculty of Life Sciences, University of Dundee, Dundee, UK.
- 7Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
- 8Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
- 9Program in Molecular Medicine, University of Massachusetts Chan Medical School, Massachusetts, USA.
- 10Department of Internal Medicine, University Hospital of Salamanca-IBSAL, Salamanca, Spain.
- 11Department of Medicine, University of Salamanca, Salamanca, Spain.
Abstract
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;Mkk3fl/fl (AdipoMkk3) 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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BibTeX
@article{bernardo2026adipocyte,
title = {{An Adipocyte MKK3-p38β Axis Preserves Insulin Responsiveness in Mice and Is Reciprocally Altered in Human Obesity.}},
author = {Edgar Bernardo and Nuria Matesanz and Jorge-Luis Torres and Alba C Arcones and Juan Ignacio Jiménez-Loygorri and Alfonso Mora and Leticia Herrera-Melle and Luis Leiva-Vega and Maria Elena Rodriguez and Lourdes Hernández-Cosido and Marta Leon and Paula Yong González and Teresa Durán and Tamara Parracho and Francisca Mulero and Rubén Nogueiras and J Simon C Arthur and Angel R Nebreda and Roger J Davis and Miguel Marcos and Guadalupe Sabio},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = oct,
doi = {10.1002/advs.202520388},
url = {https://europepmc.org/article/MED/42952173},
note = {CC BY},
}
RIS
TY - JOUR
TI - An Adipocyte MKK3-p38β Axis Preserves Insulin Responsiveness in Mice and Is Reciprocally Altered in Human Obesity.
AU - Edgar Bernardo
AU - Nuria Matesanz
AU - Jorge-Luis Torres
AU - Alba C Arcones
AU - Juan Ignacio Jiménez-Loygorri
AU - Alfonso Mora
AU - Leticia Herrera-Melle
AU - Luis Leiva-Vega
AU - Maria Elena Rodriguez
AU - Lourdes Hernández-Cosido
AU - Marta Leon
AU - Paula Yong González
AU - Teresa Durán
AU - Tamara Parracho
AU - Francisca Mulero
AU - Rubén Nogueiras
AU - J Simon C Arthur
AU - Angel R Nebreda
AU - Roger J Davis
AU - Miguel Marcos
AU - Guadalupe Sabio
PY - 2026
DA - 2026/10/28
JO - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO - 10.1002/advs.202520388
UR - https://europepmc.org/article/MED/42952173
AB - 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;Mkk3fl/fl (AdipoMkk3) 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.
SN - 2198-3844
ER -