Peroxisomal Proliferator-Activated Receptor α Deficiency Diminishes Insulin-Responsiveness of Gluconeogenic/Glycolytic/Pentose Gene Expression and Substrate Cycle Flux

Jun Xu, Vicky Chang, Sean B. Joseph, Chuck Trujillo, Sara Bassilian, Mohammed F. Saad, W. N Paul Lee, Irwin J. Kurland

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Our previous work led to the hypothesis that peroxisomal proliferator-activated receptor α (PPARα) modulates insulin action in a compensatory fashion for hepatic glucose balance vs. peripheral glucose disposal. Therefore, we have examined the expression of insulin-dependent gluconeogenic/glycolytic/pentose cycle enzymes and compared these to insulin responsiveness for peripheral vs. hepatic substrate flux and futile cycling in the PPARa knockout mouse. Hepatic gluconeogenic flux, glucose absorption, clearance and recycling, as well as in vivo glucose disposal were evaluated using new mass isotopomer methods. Insulin-dependent gluconeogenic/ glycolytic/pentose cycle enzyme expression and glucose futile cycling were diminished; however, glucose disappearance was increased. This supports the hypothesis of hepatic insulin resistance and increased peripheral glucose uptake as compensatory events secondary to the decrease in fatty acid oxidation characteristic of the PPARa knockout. We conclude that 1) the loss of PPARα results in lower expression levels and diminished response to meal regulation for gluconeogenic/ glycolytic enzyme expression; and 2) consequently, substrate/ futile cycling of glucose is decreased when PPARα is absent despite increased gluconeogenesis. The compensatory changes in liver and peripheral tissue substrate flux and the resultant adaptation for enzyme expression in the liver to have a diminished insulin dependence reflect the loosely linked correlation between phenotype and genotype in hepatic glucose metabolism.

Original languageEnglish (US)
Pages (from-to)1087-1095
Number of pages9
JournalEndocrinology
Volume145
Issue number3
DOIs
StatePublished - Mar 2004
Externally publishedYes

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Pentoses
Insulin
Gene Expression
Glucose
Substrate Cycling
Liver
Enzymes
Gluconeogenesis
Insulin Receptor
Genetic Association Studies
Recycling
Knockout Mice
Meals
Insulin Resistance
Fatty Acids

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Peroxisomal Proliferator-Activated Receptor α Deficiency Diminishes Insulin-Responsiveness of Gluconeogenic/Glycolytic/Pentose Gene Expression and Substrate Cycle Flux. / Xu, Jun; Chang, Vicky; Joseph, Sean B.; Trujillo, Chuck; Bassilian, Sara; Saad, Mohammed F.; Lee, W. N Paul; Kurland, Irwin J.

In: Endocrinology, Vol. 145, No. 3, 03.2004, p. 1087-1095.

Research output: Contribution to journalArticle

Xu, Jun ; Chang, Vicky ; Joseph, Sean B. ; Trujillo, Chuck ; Bassilian, Sara ; Saad, Mohammed F. ; Lee, W. N Paul ; Kurland, Irwin J. / Peroxisomal Proliferator-Activated Receptor α Deficiency Diminishes Insulin-Responsiveness of Gluconeogenic/Glycolytic/Pentose Gene Expression and Substrate Cycle Flux. In: Endocrinology. 2004 ; Vol. 145, No. 3. pp. 1087-1095.
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