STAT3 Regulates Mitochondrial Gene Expression in Pancreatic β-Cells and Its Deficiency Induces Glucose Intolerance in Obesity

Anaïs Schaschkow, Lokman Pang, Valerie Vandenbempt, Bernat Elvira, Sara A. Litwak, Beata Vekeriotaite, Elisa Maillard, Marjorie Vermeersch, Flavia M.M. Paula, Michel Pinget, David Perez-Morga, Daniel J. Gough, Esteban N. Gurzov

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Abstract

Most obese and insulin-resistant individuals do not develop diabetes. This is the result of the capacity of β-cells to adapt and produce enough insulin to cover the needs of the organism. The underlying mechanism of β-cell adaptation in obesity, however, remains unclear. Previous studies have suggested a role for STAT3 in mediating β-cell development and human glucose homeostasis, but little is known about STAT3 in β-cells in obesity. We observed enhanced cytoplasmic expression of STAT3 in severely obese subjects with diabetes. To address the functional role of STAT3 in adult β-cells, we generated mice with tamoxifen-inducible partial or full deletion of STAT3 in β-cells and fed them a high-fat diet before analysis. Interestingly, β-cell heterozygous and homozygous STAT3-deficient mice showed glucose intolerance when fed a high-fat diet. Gene expression analysis with RNA sequencing showed that reduced expression of mitochondrial genes in STAT3 knocked down human EndoC-β1H cells, confirmed in FACS-purified β-cells from obese STAT3-deficient mice. Moreover, silencing of STAT3 impaired mitochondria activity in EndoC-β1H cells and human islets, suggesting a mechanism for STAT3-modulated β-cell function. Our study postulates STAT3 as a novel regulator of β-cell function in obesity.

Original languageEnglish
Pages (from-to)2026-2041
Number of pages16
JournalDiabetes
Volume70
Issue number9
DOIs
Publication statusPublished - 1 Sep 2021

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