Mesenteric Fat Lipolysis Mediates Obesity-associated Hepatic Steatosis and Insulin Resistance

Abstract

Hepatic steatosis and insulin resistance are among the most prevalent metabolic disorders and tightly associated with obesity and type 2 diabetes. However, underlying mechanism linking obesity to hepatic lipid accumulation and insulin resistance are incompletely understood. Glycoprotein 130 (gp130) is the common signal transducer of all interleukin 6 (IL-6) cytokines. Herein, we provide evidence that gp130-mediated adipose tissue lipolysis promotes hepatic steatosis and insulin resistance. In obese mice, adipocyte-specific gp130 deletion reduced basal lipolysis and enhanced insulin's ability to suppress lipolysis from mesenteric but not epididymal adipocytes. Consistently, free fatty acid levels were reduced in portal but not in systemic circulation of obese knockout mice. Importantly, adipocyte-specific gp130 knockout mice were protected from high fat diet (HFD)-induced hepatic steatosis as well as insulin resistance. In humans, omental but not subcutaneous IL-6 mRNA expression correlated positively with liver lipid accumulation (r=0.31; p<0.05) and negatively with euglycemic clamp glucose infusion rate (r=-0.28; p<0.05). Our results demonstrate that IL-6 cytokine-induced lipolysis may be restricted to mesenteric WAT and that it contributes to hepatic insulin resistance and steatosis. Therefore, blocking IL-6 cytokine signaling in (mesenteric) adipocytes may be a novel approach to blunt detrimental fat-liver crosstalk in obesity.