Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism

Soo Choi Cheol, Douglas E. Befroy, Roberto Codella, Sheene Kim, Richard M. Reznick, Yu Jin Hwang, Zhen Xiang Liu, Hui Young Lee, Alberto Distefano, Varman T. Samuel, Dongyan Zhang, Gary W. Cline, Christoph Handschin, Jiandie Lin, Kitt F. Petersen, Bruce M. Spiegelman, Gerald I. Shulman

Research output: Contribution to journalArticle

196 Citations (Scopus)

Abstract

Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α has been shown to play critical roles in regulating mitochondria biogenesis, respiration, and muscle oxidative phenotype. Furthermore, reductions in the expression of PGC-1α in muscle have been implicated in the pathogenesis of type 2 diabetes. To determine the effect of increased muscle-specific PGC-1α expression on muscle mitochondrial function and glucose and lipid metabolism in vivo, we examined body composition, energy balance, and liver and muscle insulin sensitivity by hyperinsulinemic-euglycemic clamp studies and muscle energetics by using 31P magnetic resonance spectroscopy in transgenic mice. Increased expression of PGC-1α in muscle resulted in a 2.4-fold increase in mitochondrial density, which was associated with an ≈60% increase in the unidirectional rate of ATP synthesis. Surprisingly, there was no effect of increased muscle PGC-1α expression on whole-body energy expenditure, and PGC-1α transgenic mice were more prone to fat-induced insulin resistance because of decreased insulin-stimulated muscle glucose uptake. The reduced insulin-stimulated muscle glucose uptake could most likely be attributed to a relative increase in fatty acid delivery/triglyceride reesterfication, as reflected by increased expression of CD36, acyl-CoA:diacylglycerol acyltransferase1, and mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase, that may have exceeded mitochondrial fatty acid oxidation, resulting in increased intracellular lipid accumulation and an increase in the membrane to cytosol diacylglycerol content. This, in turn, caused activation of PKCδ, decreased insulin signaling at the level of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and skeletal muscle insulin resistance.

Original languageEnglish (US)
Pages (from-to)19926-19931
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number50
DOIs
StatePublished - Dec 16 2008
Externally publishedYes

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Insulin
Glucose
Muscles
Insulin Resistance
Acyl Coenzyme A
Diglycerides
Transgenic Mice
Fatty Acids
Acyltransferases
Insulin Receptor Substrate Proteins
Peroxisome Proliferator-Activated Receptors
Glucose Clamp Technique
Body Composition
Lipid Metabolism
Cytosol
Type 2 Diabetes Mellitus
Energy Metabolism
Tyrosine
Mitochondria
Respiration

Keywords

  • Diacylglycerol
  • Fatty acid oxidation
  • Insulin resistance
  • Magnetic resonance spectroscopy
  • Mitochondria

ASJC Scopus subject areas

  • General

Cite this

Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism. / Cheol, Soo Choi; Befroy, Douglas E.; Codella, Roberto; Kim, Sheene; Reznick, Richard M.; Hwang, Yu Jin; Liu, Zhen Xiang; Lee, Hui Young; Distefano, Alberto; Samuel, Varman T.; Zhang, Dongyan; Cline, Gary W.; Handschin, Christoph; Lin, Jiandie; Petersen, Kitt F.; Spiegelman, Bruce M.; Shulman, Gerald I.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 50, 16.12.2008, p. 19926-19931.

Research output: Contribution to journalArticle

Cheol, SC, Befroy, DE, Codella, R, Kim, S, Reznick, RM, Hwang, YJ, Liu, ZX, Lee, HY, Distefano, A, Samuel, VT, Zhang, D, Cline, GW, Handschin, C, Lin, J, Petersen, KF, Spiegelman, BM & Shulman, GI 2008, 'Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism', Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 50, pp. 19926-19931. https://doi.org/10.1073/pnas.0810339105
Cheol, Soo Choi ; Befroy, Douglas E. ; Codella, Roberto ; Kim, Sheene ; Reznick, Richard M. ; Hwang, Yu Jin ; Liu, Zhen Xiang ; Lee, Hui Young ; Distefano, Alberto ; Samuel, Varman T. ; Zhang, Dongyan ; Cline, Gary W. ; Handschin, Christoph ; Lin, Jiandie ; Petersen, Kitt F. ; Spiegelman, Bruce M. ; Shulman, Gerald I. / Paradoxical effects of increased expression of PGC-1α on muscle mitochondrial function and insulin-stimulated muscle glucose metabolism. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 50. pp. 19926-19931.
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AU - Cheol, Soo Choi

AU - Befroy, Douglas E.

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AU - Kim, Sheene

AU - Reznick, Richard M.

AU - Hwang, Yu Jin

AU - Liu, Zhen Xiang

AU - Lee, Hui Young

AU - Distefano, Alberto

AU - Samuel, Varman T.

AU - Zhang, Dongyan

AU - Cline, Gary W.

AU - Handschin, Christoph

AU - Lin, Jiandie

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AU - Shulman, Gerald I.

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KW - Magnetic resonance spectroscopy

KW - Mitochondria

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