Adipose MDM2 regulates systemic insulin sensitivity through nuclear import of MORC2 and the PPARγ cofactor LIPIN1

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, insulin resistance, 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. Mechanistically, lowered MDM2 levels led to nuclear exclusion of the transcriptional cofactors, MORC2 and LIPIN1, thus hampering adipocyte function by antagonizing LIPIN1-mediated PPARγ coactivation. Collectively, these data argue for a p53-independent role of MDM2 in controlling adipocyte function through LIPIN1.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Epididymal White Adipose Tissue, Cell Culture

SUBMITTER: Michele Puglia  

LAB HEAD: Blagoy Blagoev

PROVIDER: PXD020812 | Pride | 2022-02-15

REPOSITORIES: Pride