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Adipocyte Reprogramming by the Transcriptional Coregulator GPS2 Impacts Beta Cell Insulin Secretion

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2020

Cell Rep. 2020 Sep 15;32(11):108141. doi: 10.1016/j.celrep.2020.108141.

Adipocyte Reprogramming by the Transcriptional Coregulator GPS2 Impacts Beta Cell Insulin Secretion

Drareni K;Ballaire R;Alzaid F;Goncalves A;Chollet C;Barilla S;Nguewa JL;Dias K;Lemoine S;Riveline JP;Roussel R;Dalmas E;Velho G;Treuter E;Gautier JF;Venteclef N

Cordeliers Research Centre, INSERM, Immunity and Metabolism in Diabetes Laboratory, Sorbonne Université, Université de Paris, 75006 Paris, France. Inovarion, Paris, France. Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge 14157, Sweden. Department of Diabetes, Clinical Investigation Centre (CIC-9504), Lariboisière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France. École Normale Supérieure, PSL Research University, Centre National de la Recherche Scientifique (CNRS), INSERM, Institut de Biologie de l'École Normale Supérieure (IBENS), Plateforme Génomique, Paris, France.

Service type: Knockout mice

Abstract

Glucose homeostasis is maintained through organ crosstalk that regulates secretion of insulin to keep blood glucose levels within a physiological range. In type 2 diabetes, this coordinated response is altered, leading to a deregulation of beta cell function and inadequate insulin secretion. Reprogramming of white adipose tissue has a central role in this deregulation, but the critical regulatory components remain unclear. Here, we demonstrate that expression of the transcriptional coregulator GPS2 in white adipose tissue is correlated with insulin secretion rate in humans. The causality of this relationship is confirmed using adipocyte-specific GPS2 knockout mice, in which inappropriate secretion of insulin promotes glucose intolerance. This phenotype is driven by adipose-tissue-secreted factors, which cause increased pancreatic islet inflammation and impaired beta cell function. Thus, our study suggests that, in mice and in humans, GPS2 controls the reprogramming of white adipocytes to influence pancreatic islet function and insulin secretion. Keywords: G protein pathway suppressor 2; GPS2; adipose tissue; beta cells; insulin; organ crosstalk; pancreas; transcriptional coregulator; type 2 diabetes.

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