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

Department of Medicine (J.X., V.C., C.T., M.F.S., I.J.K.) and Laboratory of Metabolomics (J.X., V.C., C.T., I.J.K.), David Geffen School of Medicine, and Departments of Biological Chemistry (J.X.) and Pathology (S.B.J.) and Molecular Biology Institute (I.J.K.), University of California, Los Angeles, California 90095; and Department of Pediatrics, Harbor-University of California-Los Angeles Research and Education Institute (S.B., W.N.P.L.), Torrance, California 90502

Address all correspondence and requests for reprints to: Dr. Irwin J. Kurland, Molecular Biology Institute, University of California, Los Angeles, California 90095. E-mail: irwinjk{at}earthlink.net.

Our previous work led to the hypothesis that peroxisomal proliferator-activated receptor (PPAR) 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 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 PPAR knockout. We conclude that 1) the loss of PPAR 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 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.

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