Insulin resistance (IR) means the failure of cells to respond normally to insulin, commonly associated with obesity and causing various metabolic dysregulations in type 2 diabetes. As a mediator of innate immunity, stimulator of interferon genes (STING) in human subjects is positively correlated with excessive fat deposition and liver inflammation, which both trigger hepatic and systemic IR. Also, STING expression is increased in insulin-responsive tissues in mice fed a high-fat diet (HFD) for 3 months, coupled with the decreased sensitivity of systemic insulin signaling. However, it is unknown about the effect of STING on IR in mice upon prolonged HFD feeding, which reflects the long-term course of human obesity. In this study, wild-type (WT) and STING-disrupted (STgt) male mice were fed an HFD for 3 months and examined for obesity and IR. Some HFD-fed mice were examined for hepatic insulin signaling upon a bolus injection of insulin into the portal vein. Additional STgt and WT mice were fed an HFD for 7 months and examined for obesity and systemic insulin sensitivity. Compared to male 3-m-HFD-WT mice, male 3-m-HFD-STgt mice gained smaller body weights and decreased levels of hepatic steatosis and inflammation, along with increased response to insulin. Consistently, insulin-stimulated Akt phosphorylation in the liver, adipose tissue, and skeletal muscle from male 3-m-HFD-STgt mice were much greater than those in the respective tissues from male 3-m-HFD-WT mice. However, upon prolonged HFD feeding, STgt mice displayed notably increased severity of obesity, hepatic steatosis and inflammation, all of which cause hepatic and systemic IR, relative to WT or STgt mice upon 3-month HFD feeding. These results indicate HFD feeding for 7 months abolishes the protective effect of STING deletion on obesity-associated hepatic steatosis/inflammation, and IR. As such, diets approach is key in managing obesity-induced metabolic diseases.
X. Guo: None. H. Li: None. C. Wu: None.
National Institutes of Health (DK124854)
