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

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 cor...

Full description

Saved in:

Bibliographic Details
Published in:	Cell reports (Cambridge) 2018-09, Vol.24 (11), p.2957-2971.e6
Main Authors:	Drareni, Karima, Ballaire, Raphaëlle, Barilla, Serena, Mathew, Mano J., Toubal, Amine, Fan, Rongrong, Liang, Ning, Chollet, Catherine, Huang, Zhiqiang, Kondili, Maria, Foufelle, Fabienne, Soprani, Antoine, Roussel, Ronan, Gautier, Jean-François, Alzaid, Fawaz, Treuter, Eckardt, Venteclef, Nicolas
Format:	Article
Language:	eng
Subjects:	adipose tissue Biochemistry, Molecular Biology corepressor Genomics GPS2 HIF1A insulin resistance Life Sciences Medicin och hälsovetenskap obesity transcription type 2 diabetes
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
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. [Display omitted] •Adipose-specific GPS2 deficiency predisposes for adipocyte hypertrophy•Loss of GPS2 triggers transcriptional activation of HIF1A pathways•Deregulation of GPS2-HIF1A interplay provokes disrupted mitochondrial activity•GPS2 and HIF1A levels are negatively correlated in human adipose tissue 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.
ISSN:	2211-1247 2211-1247