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Cardiac-Specific Overexpression of Peroxisome Proliferator–Activated Receptor- Causes Insulin Resistance in Heart and Liver

¹ Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, Connecticut
² Department of Medicine, Center for Cardiovascular Research, Washington University School of Medicine, St. Louis, Missouri
³ Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut
⁴ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
⁵ Section of Cardiology, Yale University School of Medicine, New Haven, Connecticut
⁶ Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
⁷ Yale Mouse Metabolic Phenotyping Center, Yale University School of Medicine, New Haven, Connecticut

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

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