GPS2 Deficiency Triggers Maladaptive White Adipose Tissue Expansion in Obesity via HIF1A Activation
Karima Drareni,
Raphaëlle Ballaire,
Serena Barilla,
Mano J. Mathew,
Amine Toubal,
Rongrong Fan,
Ning Liang,
Catherine Chollet,
Zhiqiang Huang,
Maria Kondili,
Fabienne Foufelle,
Antoine Soprani,
Ronan Roussel,
Jean-François Gautier,
Fawaz Alzaid,
Eckardt Treuter,
Nicolas Venteclef
Affiliations
Karima Drareni
INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France
Raphaëlle Ballaire
INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France; Inovarion, 75013 Paris, France
Serena Barilla
Karolinska Institutet, Department of Biosciences and Nutrition, Huddinge, Sweden
Mano J. Mathew
INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France
Amine Toubal
INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France
Rongrong Fan
Karolinska Institutet, Department of Biosciences and Nutrition, Huddinge, Sweden
Ning Liang
Karolinska Institutet, Department of Biosciences and Nutrition, Huddinge, Sweden
Catherine Chollet
INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France
Zhiqiang Huang
Karolinska Institutet, Department of Biosciences and Nutrition, Huddinge, Sweden
Maria Kondili
INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France
Fabienne Foufelle
INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France
Antoine Soprani
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
Ronan Roussel
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
Jean-François Gautier
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
Fawaz Alzaid
INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France
Eckardt Treuter
Karolinska Institutet, Department of Biosciences and Nutrition, Huddinge, Sweden; Corresponding author
Nicolas Venteclef
INSERM, Cordeliers Research Centre, Sorbonne Paris Cité, Université Paris Descartes, Université Paris Diderot, Paris, France; Corresponding author
Summary: 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. : Drareni et al. identify a role for the transcriptional corepressor GPS2 in the regulation of adipocyte hypertrophy. They provide evidence that adipocyte-specific loss of GPS2 predisposes toward maladaptive adipose tissue expansion and pro-diabetic status through activation of HIF1A transcriptional activity. Keywords: corepressor, transcription, adipose tissue, obesity, type 2 diabetes, insulin resistance, GPS2, HIF1A
