1948-P: STING in Hematopoietic Cells Promotes Obesity-Associated Adipose Tissue Inflammation and Systemic Insulin Resistance in Mice

Abstract

Stimulator of interferon genes (STING) is a mediator of innate immunity. Previous research has validated that STING promotes macrophage-stimulated nonalcoholic fatty liver disease. However, it remains to be elucidated how STING regulates the pathogenesis of white adipose tissue (WAT) inflammation, which is a causal factor of obesity-associated systemic insulin resistance and metabolic dysregulation. We examined the expression of STING in adipose tissue of mice with high fat diet (HFD)-induced obesity. We also determined the effect of STING disruption or presence only in hematopoietic cells on diet-induced WAT inflammation and systemic insulin resistance in chimeric mice. Upon HFD feeding for 12 weeks, C57BL/6J mice revealed overt WAT inflammation and systemic insulin resistance compared with mice fed a low-fat diet. These changes were accompanied with increased STING expression in WAT whereas STING-positive cells were located predominantly within the crown structures. In mice whose STING was disrupted in all cells, the severity of HFD-induced WAT inflammation and systemic insulin resistance was significantly smaller than that in wild type mice. When the role of STING in hematopoietic cells was examined, the severity of HFD-induced WAT inflammation and systemic insulin resistance in chimeric mice whose STING was disrupted only in hematopoietic cells was also smaller than that in control chimeric mice whose STING was intact in all cells. In contrast, the severity of HFD-induced phenotype in mice whose STING was intact only in hematopoietic cells was greater than that in mice whose STING was disrupted in all cells. In cultured cells, STING-driven macrophage factors increased adipocyte proinflammatory responses and decreased adipocyte insulin signaling. Together, these results suggest that increased STING in hematopoietic cells plays a critical role in promoting WAT inflammation and systemic insulin resistance. Disclosure B. Zhu: None. H. Li: None. C. Wu: None. Funding American Diabetes Association (1-17-IBS-145 to C.W.)