Adipose MDM2 regulates systemic insulin sensitivity

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


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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.

TidsskriftScientific Reports
Udgave nummer1
Antal sider17
StatusUdgivet - dec. 2021

Bibliografisk note

Funding Information:
The plasmid pcDNA3-Myc-Mdm2 was a generous gift by Dr. Jean-Christophe Marine. The GFP-LIPIN1, GFP-LIPIN2 and GFP-LIPIN3 constructs kindly donated by Dr. Moritz Mall. We thank Dr. Michele Puglia for the help with data deposition. This work was in part funded by the Lundbeck Foundation, the Novo Nordisk Foundation (NNF18OC0052768), the Carlsberg Foundation, the Danish National Research Foundation (DNRF grant no. 141 to ATLAS), the Danish Medical Research Council and the Danish Natural Science Research Council (DFF—1323-00191, DFF—1026-00013). The work was also supported in part by the Villum Foundation through the Villum Center for Bioanalytical Sciences. We would like to thank the PRO-MS Danish National Mass Spectrometry Platform for Functional Proteomics for instrument support.

Publisher Copyright:
© 2021, The Author(s).


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