Online_Appendix_rev_081920_final_R1.pdf (1.94 MB)

STAT1 dissociates adipose tissue inflammation from insulin sensitivity in obesity

Download (1.94 MB)
posted on 29.09.2020 by Ada Admin, Aaron R. Cox, Natasha Chernis, David A. Bader, Pradip K Saha, Peter M. Masschelin, Jessica B. Felix, Robert Sharp, Zeqin Lian, Vasanta Putluri, Kimal Rajapakshe, Kang Ho Kim, Dennis T. Villareal, Reina Armamento-Villareal, Huaizhu Wu, Cristian Coarfa, Nagireddy Putluri, Sean M. Hartig
Obesity fosters low-grade inflammation in white adipose tissue (WAT) that may contribute to the insulin resistance that characterizes type 2 diabetes mellitus (T2DM). However, the causal relationship of these events remains unclear. The established dominance of signal transducer and activator of transcription 1 (STAT1) function in the immune response suggests an obligate link between inflammation and the co-morbidities of obesity. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes (STAT1a-KO­­­) enhanced mitochondrial function and accelerated TCA cycle flux coupled with reduced fat cell size in subcutaneous WAT depots. STAT1a-KO reduced WAT inflammation, but insulin resistance persisted in obese mice. Rather, elimination of type I cytokine interferon gamma (IFNg) activity enhanced insulin sensitivity in diet-induced obesity. Our findings reveal a permissive mechanism that bridges WAT inflammation to whole-body insulin sensitivity.


This work was funded by American Diabetes Association #1-18-IBS-105 (S.M.H.) and NIH grants R01DK114356 (S.M.H.) and R01DK121348 (H.W.). This study was also funded (in part) by an award from the Baylor College of Medicine Nutrition and Obesity Pilot and Feasibility Fund. The Cellular and Molecular Morphology Core receives support from the Texas Digestive Diseases Center (P30DK056338). The Metabolomics Core was supported by the CPRIT Core Facility Support Award RP170005 “Proteomic and Metabolomic Core Facility,” NCI Cancer Center Support Grant P30CA125123, and intramural funds from the Dan L. Duncan Cancer Center (DLDCC). This study was also supported, in part, by the Assistant Secretary of Defense for Health Affairs endorsed by the DOD PRMRP Discovery Award (No. W81XWH‐18‐1‐0126 to K.H.K.) and VA Merit Review I01 CX00042403 (to R.A.V.) from the United States Department of Veterans Affairs Clinical Sciences Research and Development and R01 HD093047 (to R.A.V.).



Logo branding