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

Most obese and insulin-resistant individuals do not develop diabetes. This is the result of the capacity of beta -cells to adapt and produce enough insulin to cover the needs of the organism. The underlying mechanism of beta -cell adaptation in obesity, however, remains unclear. Previous studies have suggested a role for STAT3 in mediating beta -cell development and human glucose homeostasis, but little is known about STAT3 in beta -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 beta -cells, we generated mice with tamoxifen-inducible partial or full deletion of STAT3 in beta -cells and fed them a high-fat diet before analysis. Interestingly, beta -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-beta H-1 cells, confirmed in FACS-purified beta -cells from obese STAT3-deficient mice. Moreover, silencing of STAT3 impaired mitochondria activity in EndoC-beta H-1 cells and human islets, suggesting a mechanism for STAT3-modulated beta -cell function. Our study postulates STAT3 as a novel regulator of beta -cell function in obesity.