Abstract

Objective: Heart failure is a major cause of mortality in diabetes and may be causally associated with altered metabolism. Recent reports indicate a role of inflammation in peripheral insulin resistance, but the impact of inflammation on cardiac metabolism is unknown. We investigated the effects of diet-induced obesity on cardiac inflammation and glucose metabolism in mice.

Research Design and Methods: Male C57BL/6 mice were fed high-fat diet (HFD) for 6 wks, and heart samples were taken to measure insulin sensitivity, glucose metabolism, and inflammation. Heart samples were also examined following acute IL-6 or lipid infusion in C57BL/6 mice and in IL-6 KO mice following HFD.

Results: Diet-induced obesity reduced cardiac glucose metabolism, GLUT and AMPK levels, and this was associated with increased levels of macrophages, TLR4, SOCS3, and cytokines in heart. Acute physiological elevation of IL-6 suppressed glucose metabolism and caused insulin resistance by increasing SOCS3 and via SOCS3-mediated inhibition of IRS-1 and possibly AMPK in heart. Diet-induced inflammation and defects in glucose metabolism were attenuated in IL-6 KO mice, implicating the role of IL-6 in obesity-associated cardiac inflammation. Acute lipid infusion caused inflammation and raised local levels of macrophages, CCR2, SOCS3, and cytokines in heart. Lipid-induced cardiac inflammation suppressed AMPK, suggesting the role of lipid as a nutrient stress triggering inflammation.

Conclusions: Our findings that nutrient stress activates cardiac inflammation and that IL-6 suppresses myocardial glucose metabolism via inhibition of AMPK and IRS-1 underscore the important role of inflammation in the pathogenesis of diabetic heart.