Hepatic de Novo Synthesis of Glucose 6-Phosphate Is Not Affected in Peroxisome Proliferator-activated Receptor α-Deficient Mice but Is Preferentially Directed toward Hepatic Glycogen Stores after a Short Term Fast

Abstract

Apart from impaired β-oxidation, Pparα-deficient (Pparα-/-) mice suffer from hypoglycemia during prolonged fasting, suggesting alterations in hepatic glucose metabolism. We compared hepatic glucose metabolism in vivo in wild type WT) and Pparα -/- mice after a short term fast, applying novel isotopic methods. After a 9-h fast, mice were infused with [U-13C]glucose, [2- 13C]glyecerol, [1-2H]galactose, and paracetamol for 6 h, and blood and urine was collected in timed intervals. Plasma glucose concentrations remained constant and were not different between the groups. Hepatic glycogen content was 69 ± 11 and 90 ± 31 μmol/g liver after 15 h of fasting in WT and Pparα-/- mice, respectively. The gluconeogenic flux toward glucose 6-phosphate was not different between the groups (i.e. 157 ± 9 and 153 ± 9 μmol/kg/min in WT and Pparα-/- mice, respectively). The gluconeogenic flux toward plasma glucose, however, was decreased in PPARα-/- mice (i.e. 142 ± 9 versus 124 ± 13 μmol/kg/min) (p < 0.05), accounting for the observed decrease (-15%) in hepatic glucose production in Pparα-/- mice. Expression of the gene encoding glucose-6-phosphate hydrolase (G6ph) was lower in the PPARα-/- mice compared with WT mice. In conclusion, Pparα-/- mice were able to maintain a normal total gluconeogenic flux to glucose 6-phosphate during moderate fasting, despite their inability to up-regulate β-oxidation. However, this gluconeogenic flux was directed more toward glycogen, leading to a decreased hepatic glucose output. This was associated with a down-regulation of the expression of G6ph in PPARα-deficient mice.