title: Nutrient stress activates inflammation and reduces glucose metabolism by suppressing AMP-activated protein kinase in the heart.
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.
  
  
  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.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Hwi Jin
authors.initials: HJ
authors.lastname: Ko
authors.forename: Zhiyou
authors.initials: Z
authors.lastname: Zhang
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Jung
authors.forename: John Y
authors.initials: JY
authors.lastname: Jun
authors.forename: Zhexi
authors.initials: Z
authors.lastname: Ma
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Jones
authors.forename: Sook Y
authors.initials: SY
authors.lastname: Chan
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D000818:Animals; D003925:Diabetic Angiopathies / Q000401:mortality / Q000503:physiopathology*; D004041:Dietary Fats / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000378:metabolism; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000401:mortality / Q000503:physiopathology; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D007262:Infusions, Intravenous; D015850:Interleukin-6 / Q000172:deficiency / Q000494:pharmacology; D008055:Lipids / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*
chemical_list: D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D015850:Interleukin-6; D008055:Lipids; D055372:AMP-Activated Protein Kinases; D005947:Glucose
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