Cardiac-specific overexpression of peroxisome proliferator-activated receptor-alpha 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)-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.
Park
So-Young
SY
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
Cho
You-Ree
YR
Finck
Brian N
BN
Kim
Hyo-Jeong
HJ
Higashimori
Takamasa
T
Hong
Eun-Gyoung
EG
Lee
Mi-Kyung
MK
Danton
Cheryl
C
Deshmukh
Swati
S
Cline
Gary W
GW
Wu
Julie J
JJ
Bennett
Anton M
AM
Rothermel
Beverly
B
Kalinowski
April
A
Russell
Kerry S
KS
Kim
Young-Bum
YB
Kelly
Daniel P
DP
Kim
Jason K
JK
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
D047493:PPAR alpha; D005947:Glucose