title: Cardiac-specific overexpression of peroxisome proliferator-activated receptor-alpha causes insulin resistance in heart and liver.
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.
authors.affiliation: Yale University School of Medicine, Department of Internal Medicine, Section of Endocrinology and Metabolism, The Anlyan Center, S269C, P.O. Box 208020, 300 Cedar St., New Haven, CT 06520-8020, USA. jason.k.kim@yale.edu
authors.forename: So-Young
authors.initials: SY
authors.lastname: Park
authors.forename: You-Ree
authors.initials: YR
authors.lastname: Cho
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
authors.forename: Hyo-Jeong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Takamasa
authors.initials: T
authors.lastname: Higashimori
authors.forename: Eun-Gyoung
authors.initials: EG
authors.lastname: Hong
authors.forename: Mi-Kyung
authors.initials: MK
authors.lastname: Lee
authors.forename: Cheryl
authors.initials: C
authors.lastname: Danton
authors.forename: Swati
authors.initials: S
authors.lastname: Deshmukh
authors.forename: Gary W
authors.initials: GW
authors.lastname: Cline
authors.forename: Julie J
authors.initials: JJ
authors.lastname: Wu
authors.forename: Anton M
authors.initials: AM
authors.lastname: Bennett
authors.forename: Beverly
authors.initials: B
authors.lastname: Rothermel
authors.forename: April
authors.initials: A
authors.lastname: Kalinowski
authors.forename: Kerry S
authors.initials: KS
authors.lastname: Russell
authors.forename: Young-Bum
authors.initials: YB
authors.lastname: Kim
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
mesh_terms: D000818:Animals; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006321:Heart / Q000503:physiopathology*; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D047493:PPAR alpha; D005947:Glucose