RNAsequencing of control and STAT3 knocked down transriptomes of EndoC cells

Most obese and insulin resistant individuals do not develop diabetes. This is the result of the capacity of ß-cells to adapt and produce enough insulin to cover the needs of the organism. The underlying mechanism of ß-cell adaptation in obesity, however, remains unclear. Previous studies have suggested a role for STAT3 in mediating ß-cell development and human glucose homeostasis, but little is known about its role in ß-cells in obesity. We observed enhanced cytoplasmatic expression of STAT3 in severe obese and diabetic subjects. To address the functional role of STAT3 in adult ß-cells, we generated mice with tamoxifen-inducible partial or full deletion of STAT3 in ß-cells and fed them a high fat diet before analysis. Interestingly, ß-cell homozygous and heterozygous STAT3 deficient obese mice showed glucose intolerance when compared to controls. Gene expression analysis by RNA-seq showed reduced expression of mitochondrial genes in STAT3 knocked-down human EndoC-ßH1 cells and was confirmed in FACS-purified ß-cells from STAT3 deficient mice. Moreover, knockdown of STAT3 impaired mitochondria activity in EndoC-ßH1 and human islets, suggesting a mechanism for STAT3-regulated ß-cell function. We propose non-canonical STAT3 activity as a marker of ß-cell identity, improving glucose induced insulin secretion in obesity. Overall design: mRNA profiles of control and STAT3 knocked-down ß-cells