Nutrient Stress Activates Inflammation and Reduces Glucose Metabolism by Suppressing AMP-Activated Protein Kinase in the Heart

  1. Hwi Jin Ko1,2,
  2. Zhiyou Zhang2,
  3. Dae Young Jung1,2,
  4. John Y. Jun2,3,
  5. Zhexi Ma2,
  6. Kelly E. Jones2,
  7. Sook Y. Chan2 and
  8. Jason K. Kim1,2,4
  1. 1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts;
  2. 2Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania;
  3. 3Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Pennsylvania State University College of Medicine, Hershey, Pennsylvania;
  4. 4Department of Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Massachusetts Medical School, Worcester, Massachusetts.
  1. Corresponding author: Jason K. Kim,{at}
  1. H.J.K. and Z.Z. contributed equally to this article and should be considered co–first authors.


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.


  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received October 3, 2008.
    • Accepted August 2, 2009.
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  1. Diabetes vol. 58 no. 11 2536-2546
  1. All Versions of this Article:
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