Peroxisome Proliferator-activated Receptor α (PPARα) Influences Substrate Utilization for Hepatic Glucose Production

Jun Xu,Gary Xiao,Chuck Trujillo,Vicky Chang,Lilia Blanco,Sean B Joseph,Sara Bassilian,Mohammed F Saad,Peter Tontonoz,W N Paul Lee,Irwin J Kurland

doi:10.1074/jbc.m201208200

Abstract

The hypoglycemia seen in the fasting PPARalpha null mouse is thought to be due to impaired liver fatty acid beta-oxidation. The etiology of hypoglycemia in the PPARalpha null mouse was determined via stable isotope studies. Glucose, lactate, and glycerol flux was assessed in the fasted and fed states in 4-month-old PPARalpha null mice and in C57BL/6 WT maintained on standard chow using a new protocol for flux assessment in the fasted and fed states. Hepatic glucose production (HGP) and glucose carbon recycling were estimated using [U-(13)C(6)]glucose, and HGP, lactate, and glycerol turnover was estimated utilizing either [U-(13)C(3)]lactate or [2-(13)C]glycerol infused subcutaneously via Alza miniosmotic pumps. At the end of a 17-h fast, HGP was higher in the PPARalpha null mice than in WT by 37% (p < 0.01). However, recycling of glucose carbon from lactate back to glucose was lower in the PPARalpha null than in WT (39% versus 51%, p < 0.02). The lack of conversion of lactate to glucose was confirmed using an [U-(13)C(3)]lactate infusion. In the fasted state, HGP from lactate and lactate production were decreased by 65 and 55%, respectively (p < 0.05) in PPARalpha null mice. In contrast, when [2-(13)C]glycerol was infused, glycerol production and HGP from glycerol increased by 80 and 250%, respectively (p < 0.01), in the fasted state of PPARalpha null mice. The increased HGP from glycerol was not suppressed in the fed state. While little change was evident for phosphoenolpyruvate carboxykinase (PEPCK) expression, pyruvate kinase expression was decreased 16-fold in fasted PPARalpha null mice as compared with the wild-type control. The fasted and fed insulin levels were comparable, but blood glucose levels were lower in the PPARalpha null mice than in controls. In conclusion, PPARalpha receptor function creates a setpoint for a metabolic network that regulates the rate and route of HGP in the fasted and fed states, in part, by controlling the flux of glycerol and lactate between the triose-phosphate and pyruvate/lactate pools.

Highlights

§§ Assistant investigator of the Howard Hughes Medical Institute at the University of California, Los Angeles, CA 90095
We report here a study of the regulation of Hepatic glucose production (HGP) and substrate utilization for peroxisome-proliferatoractivated receptors (PPARs)␣ null mice maintained on a chow diet, during the physiologic situation of a moderate overnight fast (17 h) and refeeding (5 h), using 13C-mass isotopomer distribution analysis (MIDA)
As noted by Beylot and co-workers in their recent paper [14] in the rat, glycerol turnover rate as well as the percent contribution of glycerol to total glucose production is higher in the A-V mode than those obtained from the V-A mode

Summary

Introduction

The etiology for the hypoglycemia seen in the fasting PPAR␣ null mouse is believed to reflect a depletion of liver glycogen and a decrease in gluconeogenesis secondary to impaired liver fatty acid ␤-oxidation [3, 4]. We report here a study of the regulation of HGP and substrate utilization for PPAR␣ null mice maintained on a chow diet, during the physiologic situation of a moderate overnight fast (17 h) and refeeding (5 h), using 13C-mass isotopomer distribution analysis (MIDA). This form of metabolomic profiling uncovers the “silent” phenotype not seen in previous studies of PPAR␣ KO mice and insulin action and indicates that PPAR␣ is an important element regulating metabolic transition from fed to fasted states. The data indicate that the actions of PPAR␣ intersect with those of insulin in the regulation of substrate utilization for hepatic glucose production

Methods

Results

Conclusion