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

Research output: Contribution to journalArticle

91 Citations (Scopus)

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

Fingerprint

Peroxisome Proliferator-Activated Receptors
Insulin Resistance
Myosin Heavy Chains
Insulin
Liver
Phosphatidylinositol 3-Kinase
Insulin Receptor Substrate Proteins
STAT3 Transcription Factor
Glucose
Glucose Clamp Technique
Energy Metabolism
Tyrosine
Interleukin-6
Triglycerides
Heart Failure
Phosphorylation
Cytokines
Phenotype

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Park, S. Y., Cho, Y. R., Finck, B. N., Kim, H. J., Higashimori, T., Hong, E. G., ... 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

Cardiac-specific overexpression of peroxisome proliferator-activated receptor-α causes insulin resistance in heart and liver. / Park, So Young; Cho, You Ree; Finck, Brian N.; Kim, Hyo Jeong; Higashimori, Takamasa; Hong, Eun Gyoung; Lee, Mi Kyung; Danton, Cheryl; Deshmukh, Swati; Cline, Gary W.; Wu, Julie J.; Bennett, Anton M.; Rothermel, Beverly; Kalinowski, April; Russell, Kerry S.; Kim, Young Bum; Kelly, Daniel P.; Kim, Jason E.

In: Diabetes, Vol. 54, No. 9, 09.2005, p. 2514-2524.

Research output: Contribution to journalArticle

Park, SY, Cho, YR, Finck, BN, Kim, HJ, Higashimori, T, Hong, EG, Lee, MK, Danton, C, Deshmukh, S, Cline, GW, Wu, JJ, Bennett, AM, Rothermel, B, Kalinowski, A, Russell, KS, Kim, YB, Kelly, DP & Kim, JE 2005, 'Cardiac-specific overexpression of peroxisome proliferator-activated receptor-α causes insulin resistance in heart and liver', Diabetes, vol. 54, no. 9, pp. 2514-2524. https://doi.org/10.2337/diabetes.54.9.2514
Park, So Young ; Cho, You Ree ; Finck, Brian N. ; Kim, Hyo Jeong ; Higashimori, Takamasa ; Hong, Eun Gyoung ; Lee, Mi Kyung ; Danton, Cheryl ; Deshmukh, Swati ; Cline, Gary W. ; Wu, Julie J. ; Bennett, Anton M. ; Rothermel, Beverly ; Kalinowski, April ; Russell, Kerry S. ; Kim, Young Bum ; Kelly, Daniel P. ; Kim, Jason E. / Cardiac-specific overexpression of peroxisome proliferator-activated receptor-α causes insulin resistance in heart and liver. In: Diabetes. 2005 ; Vol. 54, No. 9. pp. 2514-2524.
@article{a916e71524da4118b139f00e76c69938,
title = "Cardiac-specific overexpression of peroxisome proliferator-activated receptor-α 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 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.",
author = "Park, {So Young} and Cho, {You Ree} and Finck, {Brian N.} and Kim, {Hyo Jeong} and Takamasa Higashimori and Hong, {Eun Gyoung} and Lee, {Mi Kyung} and Cheryl Danton and Swati Deshmukh and Cline, {Gary W.} and Wu, {Julie J.} and Bennett, {Anton M.} and Beverly Rothermel and April Kalinowski and Russell, {Kerry S.} and Kim, {Young Bum} and Kelly, {Daniel P.} and Kim, {Jason E.}",
year = "2005",
month = "9",
doi = "10.2337/diabetes.54.9.2514",
language = "English (US)",
volume = "54",
pages = "2514--2524",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "9",

}

TY - JOUR

T1 - Cardiac-specific overexpression of peroxisome proliferator-activated receptor-α causes insulin resistance in heart and liver

AU - Park, So Young

AU - Cho, You Ree

AU - Finck, Brian N.

AU - Kim, Hyo Jeong

AU - Higashimori, Takamasa

AU - Hong, Eun Gyoung

AU - Lee, Mi Kyung

AU - Danton, Cheryl

AU - Deshmukh, Swati

AU - Cline, Gary W.

AU - Wu, Julie J.

AU - Bennett, Anton M.

AU - Rothermel, Beverly

AU - Kalinowski, April

AU - Russell, Kerry S.

AU - Kim, Young Bum

AU - Kelly, Daniel P.

AU - Kim, Jason E.

PY - 2005/9

Y1 - 2005/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=24144490615&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=24144490615&partnerID=8YFLogxK

U2 - 10.2337/diabetes.54.9.2514

DO - 10.2337/diabetes.54.9.2514

M3 - Article

C2 - 16123338

AN - SCOPUS:24144490615

VL - 54

SP - 2514

EP - 2524

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 9

ER -