Hepatic de novo synthesis of glucose-6- phosphate is not affected in PPARα-deficient mice but is preferentially directed towards hepatic glycogen stores after a short-term fast

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 9h fast mice were infused with [U-C] glucose, [2-C]glycerol, [1-H]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 hr of fasting in WT and Pparα mice, respectively. The gluconeogenic flux towards 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 towards plasma glucose, however, was decreased in Pparα mice, i.e., 142 ± 9 vs 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 to 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 upregulate β-oxidation. However, this gluconeogenic flux was directed more towards glycogen leading to a decreased hepatic glucose output. This was associated with a downregulation of the expression of G6ph in Pparα-deficient mice. Role of PPARα in gluconeogenesis 133