Obesity associates with chronic low-grade inflammation that likely impinges on the metabolic functions of adipocytes and may partially explain the insulin resistance that characterizes type 2 diabetes mellitus (T2DM). We recently demonstrated ectopic expression of the microRNA miR-30a in the subcutaneous fat pad of diabetic mice coupled improved insulin sensitivity and increased energy expenditure with decreased ectopic fat deposition in the liver and reduced WAT inflammation. Further, miR-30a directly inhibited STAT1, a major mediator of inflammatory signals such as interferon gamma (IFNγ). Despite the established dominance of STAT1 in the immune response and the importance of inflammation in the development of T2DM, the role of STAT1 in white adipocytes remains unknown. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. IFNγ treatment of human adipocytes diminished oxidative phosphorylation capacity, along with expression of mitochondrial proteins. STAT1 deletion in white adipocytes (STAT1 fKO) did not change body weight, but improved whole-body insulin sensitivity of diabetic mice. Transcriptome profiling by RNA-Seq suggested STAT1 fKO adipocytes engage GABPa and NFIA target genes that reflect oxidative phosphorylation specifically in the inguinal white adipose tissue (iWAT). Additional metabolomics profiling indicated the metabolic effects of STAT1 deletion in iWAT are associated with accelerated TCA cycle flux and aspartic acid generation, which provides intermediates to support lipid synthesis and histone modifications. These studies reveal important roles of inflammatory signals to suppress metabolism and epigenetic regulation in adipocytes that may underlie insulin resistance and T2DM.
A. Cox: None. P. Masschelin: None. N. Chernis: None. S.M. Hartig: None.
American Diabetes Association (1-18-IBS-105 to S.M.H.); National Institutes of Health (R01DK114356); Baylor College of Medicine (P30DK079638)