STAT1 Dissociates Adipose Tissue Inflammation From Insulin Sensitivity in Obesity

Authors

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

Publication Date

12-1-2020

Journal

Diabetes

DOI

10.2337/db20-0384

PMID

32994273

PMCID

PMC7679774

PubMedCentral® Posted Date

9-29-2020

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Adipocytes, Adipose Tissue, Animals, Energy Metabolism, Female, Gene Expression Regulation, Glucose, Homeostasis, Humans, Inflammation, Insulin Resistance, Interferon-gamma, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity, RNA Interference, Receptors, Interferon, STAT1 Transcription Factor, Interferon gamma Receptor

Abstract

Obesity fosters low-grade inflammation in white adipose tissue (WAT) that may contribute to the insulin resistance that characterizes type 2 diabetes. However, the causal relationship of these events remains unclear. The established dominance of STAT1 function in the immune response suggests an obligate link between inflammation and the comorbidities 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 tricarboxylic acid 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-γ activity enhanced insulin sensitivity in diet-induced obesity. Our findings reveal a permissive mechanism that bridges WAT inflammation to whole-body insulin sensitivity.