Possible role of intestinal fatty acid oxidation in the eating-inhibitory effect of the PPAR-α agonist Wy-14643 in high-fat diet fed rats.
PPAR-α plays a key role in lipid metabolism; it enhances fatty acid oxidation (FAO) and ketogenesis. Pharmacological PPAR-α activation improves insulin sensitivity and reduces food intake, but its mechanisms of action remain unknown. We here report that intraperitoneal (IP) administration of the PPAR-α agonist Wy-14643 (40 mg/kg BW) reduced food intake in adult male rats fed a high-fat diet (HFD, 49% of the energy) mainly through an increase in the latency to eat after injection, and without inducing a conditioned taste avoidance. Also, IP administered Wy-14643 caused an acute (the first 60 min) decrease in the respiratory quotient (RQ) and an increase in hepatic portal vein β-hydroxybutyrate level (at 35 min) without affecting plasma non-esterified fatty acids. Given the known stimulatory effect of PPAR-α on FAO and ketogenesis, we measured the protein expression level of carnitine palmitoyltransferase-1 (CPT 1A) and mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase (HMG-CoAS2), two key enzymes for FAO and ketogenesis, respectively, in liver, duodenum and jejunum. Wy-14643 induced a significant increase in the expression of CPT 1A in the jejunum and duodenum and of HMG-CoAS2 in the jejunum, but neither CPT 1A nor HMG-CoAS2 expression was increased in the liver. The induction of CPT 1A and HMG-CoAS2 expression was associated with a decrease in the lipid droplet content selectively in the jejunum. Our findings indicate that Wy-14643 stimulates FAO and ketogenesis in the intestine, in particular in the jejunum, rather than in the liver, thus supporting the hypothesis that PPAR-α activation inhibits eating by stimulating intestinal FAO.
Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland.
Elnaz
E
Karimian Azari
Claudia
C
Leitner
Thomas
T
Jaggi
Wolfgang
W
Langhans
Abdelhak
A
Mansouri
D020155:3-Hydroxybutyric Acid / Q000097:blood; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism*; D005247:Feeding Behavior / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000819:agonists*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats
D005227:Fatty Acids; D047493:PPAR alpha; D011743:Pyrimidines; C006253:pirinixic acid; D002334:Carnitine O-Palmitoyltransferase; C583748:carnitine palmitoyltransferase-1a, rat; D006904:Hydroxymethylglutaryl-CoA Synthase; D020155:3-Hydroxybutyric Acid