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

So Young Park, You Ree Cho, Brian N. Finck, Hyo Jeong Kim, Takamasa Higashimori, Eun Gyoung Hong, Mi Kyung Lee, Cheryl Danton, Swati Deshmukh, Gary W. Cline, Julie J. Wu, Anton M. Bennett, Beverly Rothermel, April Kalinowski, Kerry S. Russell, Young Bum Kim, Daniel P. Kelly, Jason E. Kim

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92 Scopus citations

Abstract

Diabetic heart failure may be causally associated with alterations in cardiac energy metabolism and insulin resistance. Mice with heart-specific overexpression of perorisome proliferator-activated receptor (PPAR)α 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)-PPARα mice (12-14 weeks of age). Basal and insulin-stimulated glucose uptake in heart was significantly reduced in the MHC-PPARα 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-PPARα 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-PPARα mice. Insulin-stimulated cardiac glucose uptake was similarly reduced in 8-week-old MHC-PPARα 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 PPARα, 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-PPARα mice that may be due to altered cardiac metabolism, functions, and/or inflammatory cytokines.

Original languageEnglish
Pages (from-to)2514-2524
Number of pages11
JournalDiabetes
Volume54
Issue number9
DOIs
StatePublished - Sep 1 2005

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    Park, S. Y., Cho, Y. R., Finck, B. N., Kim, H. J., Higashimori, T., Hong, E. G., Lee, M. K., Danton, C., Deshmukh, S., Cline, G. W., Wu, J. J., Bennett, A. M., Rothermel, B., Kalinowski, A., Russell, K. S., Kim, Y. B., Kelly, D. P., & Kim, J. E. (2005). Cardiac-specific overexpression of peroxisome proliferator-activated receptor-α causes insulin resistance in heart and liver. Diabetes, 54(9), 2514-2524. https://doi.org/10.2337/diabetes.54.9.2514