Cardiac-specific overexpression of peroxisome proliferator-activated receptor-α causes insulin resistance in heart and liver

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)-PPAR alpha mice (12-14 weeks of age). Basal and insulin-stimulated glucose uptake in heart was significantly reduced fin the MHC-PPAR alpha 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-PPAR alpha 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-PPAR alpha mice. Insulin-stimulated cardiac glucose uptake was similarly reduced in 8-week-old MHC-PPAR alpha 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 PPAR alpha, 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-PPAR alpha mice that may be due to altered cardiac metabolism, functions, and/or inflammatory cytokines.