Induction of overlapping genes by fasting and a peroxisome proliferator in pigs: evidence of functional PPAR alpha in nonproliferating species
ABSTRACT Peroxisome proliferator-activated receptor alpha (PPARalpha), a key regulator of fatty acid oxidation, is essential for adaptation to fasting in rats and mice. However, physiological functions of PPARalpha in other species, including humans, are controversial. A group of PPARalpha ligands called peroxisome proliferators (PPs) causes peroxisome proliferation and hepatocarcinogenesis only in rats and mice. To elucidate the role of PPARalpha in adaptation to fasting in nonproliferating species, we compared gene expressions in pig liver from fasted and clofibric acid (a PP)-fed groups against a control diet-fed group. As in rats and mice, fasting induced genes involved with mitochondrial fatty acid oxidation and ketogenesis in pigs. Those genes were also induced by clofibric acid feeding, indicating that PPARalpha mediates the induction of these genes. In contrast to rats and mice, little or no induction of genes for peroxisomal or microsomal fatty acid oxidation was observed in clofibric acid-fed pigs. Histology showed no significant hyperplasia or hepatomegaly in the clofibric acid-fed pigs, whereas it showed a reduction of glycogen by clofibric acid, an effect of PPs also observed in rats. Copy number of PPARalpha mRNA was higher in pigs than in mice and rats, suggesting that peroxisomal proliferation and hyperresponse of several genes to PPs seen only in rats and mice are unrelated to the abundance of PPARalpha. In conclusion, PPARalpha is likely to play a central role in adaptation to fasting in pig liver as in rats and mice.
SourceAvailable from: Denise K Gessner[Show abstract] [Hide abstract]
ABSTRACT: In rats, it has been observed that treatment with activators of peroxisome proliferator-activated receptor α (PPARα) disturbs metabolic adaptations during lactation, which in turn lead to a reduction of milk fat content and gains of litters during the suckling period. It has not yet been investigated whether agonists of PPARα are impairing milk production of lactating sows in a similar manner as in rats. Therefore, the present study aimed to investigate the effect of treatment with clofibrate, a strong synthetic agonist of PPARα, on milk composition and litter gains in lactating sows. Twenty lactating sows received either a basal diet (control group) or the same diet with supplementation of 2 g of clofibrate per kg of diet (clofibrate group). In the clofibrate group, mRNA concentrations of various PPARα target genes involved in fatty acid utilization in liver and skeletal muscle were moderately up-regulated. Fat and energy content of the milk and gains of litters during the suckling period were not different between the control group and the clofibrate group. It is shown that treatment with clofibrate induces only a moderate up-regulation of PPARα target genes in liver and muscle of lactating sows and in turn might have limited effect on whole body fatty acid utilization. This may be the reason why clofibrate treatment did not influence milk fat content and gains of litters during the suckling period. Thus, the present study indicates that activation of PPARα induced either by native agonists such as dietary polyunsaturated fatty acids or a by negative energy balance might be largely uncritical in lactating sows with respect to milk production and litter gains in lactating sows.BMC Veterinary Research 12/2015; 11(1):368. DOI:10.1186/s12917-015-0368-y · 1.74 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: To induce peroxisomal proliferator-activated receptor α (PPARα) expression and increase milk fat utilization in pigs at birth, the effect of maternal feeding of the PPARα agonist, clofibrate (2-(4-chlorophenoxy)-2-methyl-propanoic acid, ethyl ester), on fatty acid oxidation was examined at full-term delivery (0 h) and 24 h after delivery in this study. Each group of pigs (n = 10) was delivered from pregnant sows fed a commercial diet with or without 0.8% clofibrate for the last 7 d of gestation. Blood samples were collected from the utero-ovarian artery of the sows and the umbilical cords of the pigs as they were removed from the sows by C-section on day 113 of gestation. HPLC analysis identified that clofibric acid was present in the plasma of the clofibrate-fed sow (~4.2 μg/mL) and its offspring (~1.5 μg/mL). Furthermore, the maternal-fed clofibrate had no impact on the liver weight of the pigs at 0 h and 24 h, but hepatic fatty acid oxidation examined in fresh homogenates showed that clofibrate increased (P < 0.01) (14)C-accumulation in CO2 and acid soluble products 2.9-fold from [1-(14)C]-oleic acid and 1.6-fold from [1-(14)C]-lignoceric acid respectively. Correspondingly, clofibrate increased fetal hepatic carnitine palmitoyltransferase (CPT) and acyl-CoA oxidase (ACO) activities by 36% and 42% over controls (P < 0.036). The mRNA abundance of CPT I was 20-fold higher in pigs exposed to clofibrate (P < 0.0001) but no differences were detected for ACO and PPARα mRNA between the two groups. These data demonstrate that dietary clofibrate is absorbed by the sow, crosses the placental membrane, and enters fetal circulation to induce hepatic fatty acid oxidation by increasing the CPT and ACO activities of the newborn.03/2015; 6(1):11. DOI:10.1186/s40104-015-0010-7
[Show abstract] [Hide abstract]
ABSTRACT: The neonatal pig ranks among the most prominent research models for the study of pediatric nutrition and metabolism. Its precocial development at birth affords ready adaptation to artificial rearing systems, and research using this model spans a wide array of nutrients. Sophisticated in vitro and in vivo methodologies supporting both invasive, reduction-science research as well as whole-animal preclinical investigations have been developed. Potential applications may dually benefit both agricultural and medical sciences (e.g., "agrimedical research"). The broad scope of this review is to outline the fundamental elements of the piglet model and to highlight key aspects of relevance to various macronutrients, including lipids, carbohydrates, proteins/amino acids, and calcium/phosphorus. The review examines similarities between piglets and infants and also piglet idiosyncrasies, concluding that, overall, the piglet represents an adaptable and robust model for pediatric nutrition and metabolism research.02/2014; 2(1):419-44. DOI:10.1146/annurev-animal-022513-114158