Nutrient stress activates inflammation and reduces glucose metabolism by suppressing AMP-activated protein kinase in the heart
Program in Molecular Medicine
AMP-Activated Protein Kinases; Animals; Diabetic Angiopathies; Dietary Fats; Fatty Acids, Nonesterified; Glucose; Heart; Heart Failure; Humans; Inflammation; Infusions, Intravenous; Interleukin-6; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium
Life Sciences | Medicine and Health Sciences
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 a high-fat diet (HFD) for 6 weeks, and heart samples were taken to measure insulin sensitivity, glucose metabolism, and inflammation. Heart samples were also examined following acute interleukin (IL)-6 or lipid infusion in C57BL/6 mice and in IL-6 knockout mice following an HFD.
RESULTS: Diet-induced obesity reduced cardiac glucose metabolism, GLUT, and AMP-activated protein kinase (AMPK) levels, and this was associated with increased levels of macrophages, toll-like receptor 4, suppressor of cytokine signaling 3 (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 insulin receptor substrate (IRS)-1 and possibly AMPK in heart. Diet-induced inflammation and defects in glucose metabolism were attenuated in IL-6 knockout mice, implicating the role of IL-6 in obesity-associated cardiac inflammation. Acute lipid infusion caused inflammation and raised local levels of macrophages, C-C motif chemokine receptor 2, 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.
DOI of Published Version
Diabetes. 2009 Nov;58(11):2536-46. Epub 2009 Aug 18. Link to article on publisher's site
Ko, Hwi Jin; Zhang, Zhiyou; Jung, Dae Young; Jun, John Y.; Ma, Zhexi; Jones, Kelly E.; Chan, Sook Y.; and Kim, Jason K., "Nutrient stress activates inflammation and reduces glucose metabolism by suppressing AMP-activated protein kinase in the heart" (2009). Open Access Articles. 2125.