Cardiac-specific overexpression of peroxisome proliferator-activated receptor-alpha causes insulin resistance in heart and liver. Journal   Diabetes. Citation   Diabetes. 54(9):2514-24 Publication date   2005 Sep Authors   Park SY Cho YR Finck BN Kim HJ Higashimori T Hong EG Lee MK Danton C Deshmukh S Cline GW Wu JJ Bennett AM Rothermel B Kalinowski A Russell KS Kim YB Kelly DP Kim JK Investigators   Jason K. Kim Grant agencies   National Heart, Lung, and Blood Institute National Institute of Diabetes and Digestive and Kidney Diseases Grants   NHLBI HL-04429 NIDDK U24 DK-59635 MeSH headings   Heart Insulin Resistance Liver Myocardium PPAR alpha MeSH qualifiers   physiopathology physiology metabolism Abstract   Diabetic heart failure may be causally associated with alterations in cardiac energy metabolism and insulin resistance. Mice with heart-specific overexpression of peroxisome proliferator-activated receptor (PPAR)alpha showed a metabolic and cardiomyopathic phenotype similar to the diabetic heart, and we determined tissue-specific glucose metabolism and insulin action in vivo during hyperinsulinemic-euglycemic clamps in awake myosin heavy chain (MHC)-PPARalpha mice (12-14 weeks of age). Basal and insulin-stimulated glucose uptake in heart was significantly reduced in the MHC-PPARalpha mice, and cardiac insulin resistance was mostly attributed to defects in insulin-stimulated activities of insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase, Akt, and tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3). Interestingly, MHC-PPARalpha mice developed hepatic insulin resistance associated with defects in insulin-mediated IRS-2-associated PI 3-kinase activity, increased hepatic triglyceride, and circulating interleukin-6 levels. To determine the underlying mechanism, insulin clamps were conducted in 8-week-old MHC-PPARalpha mice. Insulin-stimulated cardiac glucose uptake was similarly reduced in 8-week-old MHC-PPARalpha mice without changes in cardiac function and hepatic insulin action compared with the age-matched wild-type littermates. Overall, these findings indicate that increased activity of PPARalpha, as occurs in the diabetic heart, leads to cardiac insulin resistance associated with defects in insulin signaling and STAT3 activity, subsequently leading to reduced cardiac function. Additionally, age-associated hepatic insulin resistance develops in MHC-PPARalpha mice that may be due to altered cardiac metabolism, functions, and/or inflammatory cytokines.