Adipose MDM2 regulates systemic insulin sensitivity

Philip Hallenborg,Rasmus Koefoed Petersen,Si Brask Sonne,Even Fjære,Sarah Søndergård Rasmussen,Aimin Xu,Martin Hermansson,Marcus Krüger,Christer S Ejsing,Mohammed-Samir Belmaâti,Pernille Lauritzen,Benjamin Anderschou Holbech Jensen,Jon Petur Gunnarsson,Kenneth King Yip Cheng,Blagoy Blagoev,Karsten Kristiansen,Irina Kratchmarova,Lise Madsen

doi:10.1038/s41598-021-01240-3

Abstract

The intimate association between obesity and type II diabetes urges for a deeper understanding of adipocyte function. We and others have previously delineated a role for the tumor suppressor p53 in adipocyte biology. Here, we show that mice haploinsufficient for MDM2, a key regulator of p53, in their adipose stores suffer from overt obesity, glucose intolerance, and hepatic steatosis. These mice had decreased levels of circulating palmitoleic acid [non-esterified fatty acid (NEFA) 16:1] concomitant with impaired visceral adipose tissue expression of Scd1 and Ffar4. A similar decrease in Scd and Ffar4 expression was found in in vitro differentiated adipocytes with perturbed MDM2 expression. Lowered MDM2 levels led to nuclear exclusion of the transcriptional cofactors, MORC2 and LIPIN1, and thereby possibly hampered adipocyte function by antagonizing LIPIN1-mediated PPARγ coactivation. Collectively, these data argue for a hitherto unknown interplay between MDM2 and MORC2/LIPIN1 involved in balancing adipocyte function.

Highlights

The intimate association between obesity and type II diabetes urges for a deeper understanding of adipocyte function
Because p53 plays a pivotal role in the regulation of metabolism and adipose function, we explored the importance of its key regulator, Murine Double Minute 2 (MDM2), in adipocyte biology
Since several genes known to affect adipogenesis are essential for adipocyte function, we set out to explore the role of MDM2 in mature adipocytes

Summary

Introduction

The intimate association between obesity and type II diabetes urges for a deeper understanding of adipocyte function. We show that mice haploinsufficient for MDM2, a key regulator of p53, in their adipose stores suffer from overt obesity, glucose intolerance, and hepatic steatosis These mice had decreased levels of circulating palmitoleic acid [non-esterified fatty acid (NEFA) 16:1] concomitant with impaired visceral adipose tissue expression of Scd[1] and Ffar[4]. Lowered MDM2 levels led to nuclear exclusion of the transcriptional cofactors, MORC2 and LIPIN1, and thereby possibly hampered adipocyte function by antagonizing LIPIN1-mediated PPARγ coactivation. Peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/Enhancer-binding protein α (C/EBPα) are the two main regulators of adipocyte development and function Anomalies in their expression, recruitment of other transcriptional regulators as well as post translational modification status all impact on adipocyte function[3,4]. MDM2 targets p53 for nuclear export and proteasomal degradation

Methods

Results

Conclusion