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

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posted on 28.06.2021, 15:05 by Anaïs Schaschkow, Lokman Pang, Valerie Vandenbempt, Bernat Elvira, Sara A. Litwak, Beata Vekeriotaite, Elisa Maillard, Marjorie Vermeersch, Flavia MM Paula, Michel Pinget, David Perez-Morga, Daniel J. Gough, Esteban N. Gurzov
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 and diabetic subjects. 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 by RNA-Seq showed reduced expression of mitochondrial genes in STAT3 knocked down human EndoC-βH1 cells and was confirmed in FACS-purified β-cells from obese STAT3-deficient mice. Moreover, silencing of STAT3 impaired mitochondria activity in EndoC-βH1 cells and human islets, suggesting a mechanism for STAT3-modulated β-cell function. We propose STAT3 as a regulator of β-cell function, improving glucose-induced insulin secretion in obesity.

Funding

This work was supported by a Fonds National de la Recherche Scientifique (FNRS)-MIS grant (33650793), European Research Council (ERC) Consolidator grant METAPTPs (GA817940) and a JDRF Career Development Award (CDA-2019-758-A-N).

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