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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

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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.

Original language	English
Article number	21839
Journal	Scientific Reports
Volume	11
Number of pages	17
ISSN	2045-2322
DOIs	https://doi.org/10.1038/s41598-021-01240-3
Publication status	Published - 2021

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

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Hallenborg, P., Jensen, B. A. H., Fjære, E., Petersen, R. K., Belmaâti, M. S., Rasmussen, S. S., Gunnarsson, J. P., Lauritzen, P., Cheng, K. K. Y., Hermansson, M., Sonne, S. B., Ejsing, C. S., Xu, A., Kratchmarova, I., Krüger, M., Madsen, L., Kristiansen, K., & Blagoev, B. (2021). Adipose MDM2 regulates systemic insulin sensitivity. Scientific Reports, 11, [21839]. https://doi.org/10.1038/s41598-021-01240-3

Adipose MDM2 regulates systemic insulin sensitivity. / Hallenborg, Philip; Jensen, Benjamin Anderschou Holbech; Fjære, Even; Petersen, Rasmus Koefoed; Belmaâti, Mohammed Samir; Rasmussen, Sarah Søndergård; Gunnarsson, Jon Petur; Lauritzen, Pernille; Cheng, Kenneth King Yip; Hermansson, Martin; Sonne, Si Brask; Ejsing, Christer S.; Xu, Aimin; Kratchmarova, Irina; Krüger, Marcus; Madsen, Lise; Kristiansen, Karsten; Blagoev, Blagoy.

In: Scientific Reports, Vol. 11, 21839, 2021.

Research output: Contribution to journal › Journal article › Research › peer-review

Hallenborg, P, Jensen, BAH, Fjære, E, Petersen, RK, Belmaâti, MS, Rasmussen, SS, Gunnarsson, JP, Lauritzen, P, Cheng, KKY, Hermansson, M, Sonne, SB, Ejsing, CS, Xu, A, Kratchmarova, I, Krüger, M, Madsen, L, Kristiansen, K & Blagoev, B 2021, 'Adipose MDM2 regulates systemic insulin sensitivity', Scientific Reports, vol. 11, 21839. https://doi.org/10.1038/s41598-021-01240-3

Hallenborg, Philip ; Jensen, Benjamin Anderschou Holbech ; Fjære, Even ; Petersen, Rasmus Koefoed ; Belmaâti, Mohammed Samir ; Rasmussen, Sarah Søndergård ; Gunnarsson, Jon Petur ; Lauritzen, Pernille ; Cheng, Kenneth King Yip ; Hermansson, Martin ; Sonne, Si Brask ; Ejsing, Christer S. ; Xu, Aimin ; Kratchmarova, Irina ; Krüger, Marcus ; Madsen, Lise ; Kristiansen, Karsten ; Blagoev, Blagoy. / Adipose MDM2 regulates systemic insulin sensitivity. In: Scientific Reports. 2021 ; Vol. 11.

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title = "Adipose MDM2 regulates systemic insulin sensitivity",

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.",

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AU - Jensen, Benjamin Anderschou Holbech

AU - Fjære, Even

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AU - Belmaâti, Mohammed Samir

AU - Rasmussen, Sarah Søndergård

AU - Gunnarsson, Jon Petur

AU - Lauritzen, Pernille

AU - Cheng, Kenneth King Yip

AU - Hermansson, Martin

AU - Sonne, Si Brask

AU - Ejsing, Christer S.

AU - Xu, Aimin

AU - Kratchmarova, Irina

AU - Krüger, Marcus

AU - Madsen, Lise

AU - Kristiansen, Karsten

AU - Blagoev, Blagoy

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N2 - 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.

AB - 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.

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