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Cell Rep. 2018 Sep 11;24(11):2957-2971.e6. doi: 10.1016/j.celrep.2018.08.032.

GPS2 Deficiency Triggers Maladaptive White Adipose Tissue Expansion in Obesity via HIF1A Activation.

Author information

1
INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France.
2
INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France; Inovarion, 75013 Paris, France.
3
Karolinska Institutet, Department of Biosciences and Nutrition, Huddinge, Sweden.
4
INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France; Clinique Geoffroy Saint-Hilaire, Ramsey General de Santé, Paris, France.
5
INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France; Diabetology, Endocrinology and Nutrition Department, DHU FIRE, Bichat Hospital, AP-HP, Paris, France; Faculty of Medicine, University Paris-Diderot, Paris, France.
6
INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France; Assistance Publique-Hôpitaux de Paris, Lariboisière Hospital, Department of Diabetes, Clinical Investigation Centre (CIC-9504), University Paris-Diderot, Paris, France; Faculty of Medicine, University Paris-Diderot, Paris, France.
7
Karolinska Institutet, Department of Biosciences and Nutrition, Huddinge, Sweden. Electronic address: eckardt.treuter@ki.se.
8
INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France. Electronic address: nicolas.venteclef@inserm.fr.

Abstract

Hypertrophic white adipose tissue (WAT) represents a maladaptive mechanism linked to the risk for developing type 2 diabetes in humans. However, the molecular events that predispose WAT to hypertrophy are poorly defined. Here, we demonstrate that adipocyte hypertrophy is triggered by loss of the corepressor GPS2 during obesity. Adipocyte-specific GPS2 deficiency in mice (GPS2 AKO) causes adipocyte hypertrophy, inflammation, and mitochondrial dysfunction during surplus energy. This phenotype is driven by HIF1A activation that orchestrates inadequate WAT remodeling and disrupts mitochondrial activity, which can be reversed by pharmacological or genetic HIF1A inhibition. Correlation analysis of gene expression in human adipose tissue reveals a negative relationship between GPS2 and HIF1A, adipocyte hypertrophy, and insulin resistance. We propose therefore that the obesity-associated loss of GPS2 in adipocytes predisposes for a maladaptive WAT expansion and a pro-diabetic status in mice and humans.

KEYWORDS:

GPS2; HIF1A; adipose tissue; corepressor; insulin resistance; obesity; transcription; type 2 diabetes

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