STAT3 Regulates Mitochondrial Gene Expression in Pancreatic β-Cells and Its Deficiency Induces Glucose Intolerance in Obesity.
Anaïs SchaschkowLokman PangValerie VandenbemptBernat ElviraSara A LitwakBeata VekeriotaiteElisa MaillardMarjorie VermeerschFlavia M M PaulaMichel PingetDavid Perez-MorgaDaniel J GoughEsteban Nicolas GurzovPublished in: Diabetes (2021)
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.
Keyphrases
- induced apoptosis
- type diabetes
- high fat diet
- insulin resistance
- cell proliferation
- cell cycle arrest
- metabolic syndrome
- gene expression
- weight loss
- adipose tissue
- endothelial cells
- single cell
- endoplasmic reticulum stress
- cardiovascular disease
- cell death
- high fat diet induced
- oxidative stress
- dna methylation
- blood pressure
- body mass index
- skeletal muscle
- glycemic control
- weight gain
- cell therapy
- breast cancer cells
- pi k akt
- obese patients
- wild type