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This version published online on December 11, 2003
Endocrinology, doi:10.1210/en.2003-1173
A more recent version of this article appeared on March 1, 2004
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Submitted on September 5, 2003
Accepted on November 17, 2003

PPAR{alpha} deficiency diminishes insulin-responsiveness of gluconeogenic/glycolytic/pentose gene expression and substrate cycle flux

Jun Xu1, Vicky Chang1, Sean B. Joseph1, Chuck Trujillo1, Sara Bassilian1, Mohammed F. Saad1, W. N.Paul Lee1, and Irwin J. Kurland1*

1 Department of Medicine, and Laboratory of Metabolomics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095; Department of Biological Chemistry, Department of Pathology, and Molecular Biology Institute, UCLA, Los Angeles, CA 90095; Department of Pediatrics, Harbor-UCLA Research and Education Institute, Torrance, CA 90502

* To whom correspondence should be addressed. E-mail: irwinjk{at}earthlink.net.

Our previous work led to the hypothesis that PPAR{alpha} 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 PPAR{alpha} KO mouse. Hepatic gluconeogenic flux, glucose absorption, clearance and re-cycling, 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 PPAR{alpha} KO. We conclude: 1) The loss of PPAR{alpha} 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 PPAR{alpha} is absent despite increased gluconeogenesis. The compensatory changes of liver and peripheral tissues substrate flux, and the resultant adaptation for enzyme expression in the liver to have a diminished insulin dependence, reflects the loosely linked correlation between phenotype and genotype in hepatic glucose metabolism.
Key words: mass isotopomer distribution analysis (MIDA) • PPAR{alpha} • glucose clearance • insulin sensitivity • futile cycles • metabolism • glycolysis • gluconeogenesis • stable isotope-based dynamic metabolic profiling (SIDMAP)




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