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

doi:10.1038/s41598-021-01240-3

Adipose MDM2 regulates systemic insulin sensitivity

Sci Rep. 2021 Nov 8;11(1):21839. doi: 10.1038/s41598-021-01240-3.

Authors

Philip Hallenborg¹, Benjamin Anderschou Holbech Jensen², Even Fjære³, Rasmus Koefoed Petersen², Mohammed-Samir Belmaâti², Sarah Søndergård Rasmussen¹, Jon Petur Gunnarsson¹, Pernille Lauritzen¹, Kenneth King Yip Cheng⁴, Martin Hermansson¹, Si Brask Sonne², Christer S Ejsing^{1

5}, Aimin Xu^{6

7

8}, Irina Kratchmarova¹, Marcus Krüger⁹, Lise Madsen^{2

3}, Karsten Kristiansen^{10

11}, Blagoy Blagoev¹²

Affiliations

¹ Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230, Odense M, Denmark.
² Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, 2100, Copenhagen Ø, Denmark.
³ Institute of Marine Research, 5817, Bergen, Norway.
⁴ Department of Health Technology and Informatics, Hong Kong Polytechnic University, Hong Kong, Hong Kong.
⁵ Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117, Heidelberg, Germany.
⁶ State Key Laboratory of Pharmaceutical Biotechnology, University of Hong Kong, Hong Kong, Hong Kong.
⁷ Department of Medicine, University of Hong Kong, Hong Kong, Hong Kong.
⁸ Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong, Hong Kong.
⁹ Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany.
¹⁰ Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, 2100, Copenhagen Ø, Denmark. [email protected].
¹¹ Institute for Metagenomics, BGI-Shenzhen, Shenzhen, 518083, People's Republic of China. [email protected].
¹² Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230, Odense M, Denmark. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3T3-L1 Cells
Adipocytes / metabolism
Adipose Tissue, White / metabolism*
Animals
Diet, High-Fat / adverse effects
Fatty Acids, Monounsaturated / blood
Fatty Liver / genetics
Fatty Liver / metabolism
Female
Gene Regulatory Networks
Glucose Intolerance / genetics
Glucose Intolerance / metabolism
Haploinsufficiency / genetics
Haploinsufficiency / physiology
Insulin Resistance / genetics
Insulin Resistance / physiology*
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Obesity / genetics
Obesity / metabolism
PPAR gamma / metabolism
Phosphatidate Phosphatase
Proto-Oncogene Proteins c-mdm2 / deficiency
Proto-Oncogene Proteins c-mdm2 / genetics
Proto-Oncogene Proteins c-mdm2 / metabolism*
Transcription Factors / metabolism
Tumor Suppressor Protein p53 / metabolism

Substances

Fatty Acids, Monounsaturated
MORC2 protein, mouse
PPAR gamma
Transcription Factors
Trp53 protein, mouse
Tumor Suppressor Protein p53
palmitoleic acid
Mdm2 protein, mouse
Proto-Oncogene Proteins c-mdm2
Lpin1 protein, mouse
Phosphatidate Phosphatase