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.
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© 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details.
DOI of Published Version
Diabetes. 2009 Nov;58(11):2536-46. Epub 2009 Aug 18. Link to article on publisher's site
Ko HJ, Zhang Z, Jung D, Jun JY, Ma Z, Jones KE, Chan SY, Kim JK. (2009). Nutrient stress activates inflammation and reduces glucose metabolism by suppressing AMP-activated protein kinase in the heart. Open Access Articles. https://doi.org/10.2337/db08-1361. Retrieved from https://escholarship.umassmed.edu/oapubs/2125
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