Maternal Feeding of a Synthetic PPARα Agonist Alters Renal Development of Fatty Acid Metabolism in the Neonatal Piglet

Abstract Objectives Clofibrate as a therapeutic agent has been used for controlling hyperlipidemias of humans for more than 50 years. Its action, metabolism, half-life and excretion have been well documented in liver of adult humans and rodent species, but it has not been evaluated well in extrahepatic tissues in neonates as a stimulator of energy utilization. In this study, the role of maternal administration of clofibrate in development of renal fatty acid oxidation was evaluated using swine as a model. Methods A randomized complete block design was used with a total of 27 pregnant sows. The sows were fed standard gestation-lactation diets supplemented with either 0 (control), 0.25% or 0.5% clofibrate (w/w) from d 107 of gestation to d 7 of lactation. Fatty acid oxidation was measured in the presence or absence of carnitine (1 mM) or/and malonate (5 mM) in fresh kidney homogenates from piglets at d1, 7, 14 and 19 of age using 14C-oleic acid (1 mM) as substrate (9.9 mBq/mmol). Results Interactions (P < 0.001) were observed between maternal clofibrate levels and postnatal age on 14C accumulation in CO2 (14CO2), acid soluble products (14C-ASP) and esterified products (14C-ESP). The 14CO2 increased by 1.3 fold from d1 to d7, but showed no differences between d7, 14 and 19 in pigs from the control sows. Maternal supplementation of clofibrate increased 14CO2 in pigs across all ages, but the increase was higher in pigs from sows fed 0.5% versus 0.25% clofibrate at d14. The 14C-ASP was 7-fold higher in d1 pigs from control sows than all other ages. Maternal supplementation of clofibrate increased 14C-ASP by 2 fold in pigs at d1, but had no detectable effect at d 7, 14 and 19. The 14C-ESP increased from d1 to d7 and decreased from d7 to d19 in pigs from control sows. Maternal supplementation of clofibrate had no detectable impact on 14C-ESP at d1, 14 and 19, but decreased 14C-ESP measured in d7 pigs. In vitro carnitine supplementation increased 14CO2 and malonate supplementation decreased 14CO2, but neither carnitine nor malonate altered 14C-ASP or 14C-ESP. Conclusions The stimulatory effect of maternal clofibrate on renal fatty acid metabolism in offspring is associated with the postnatal age, being greater at d1 and d7 than d14 and d19. Funding Sources USDA National Institute of Food and Agriculture.