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

PLoS One. 2013 Sep 17;8(9):e74869. doi: 10.1371/journal.pone.0074869. eCollection 2013.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxybutyric Acid / blood
  • Animals
  • Carnitine O-Palmitoyltransferase / genetics
  • Carnitine O-Palmitoyltransferase / metabolism
  • Diet, High-Fat
  • Energy Metabolism / drug effects
  • Fatty Acids / metabolism*
  • Feeding Behavior / drug effects*
  • Gene Expression Regulation / drug effects
  • Hydroxymethylglutaryl-CoA Synthase / genetics
  • Hydroxymethylglutaryl-CoA Synthase / metabolism
  • Intestinal Mucosa / metabolism*
  • Jejunum / drug effects
  • Jejunum / metabolism
  • Lipid Metabolism / drug effects
  • Male
  • Oxidation-Reduction
  • PPAR alpha / agonists*
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacology*
  • Rats

Substances

  • Fatty Acids
  • PPAR alpha
  • Pyrimidines
  • pirinixic acid
  • Carnitine O-Palmitoyltransferase
  • carnitine palmitoyltransferase-1a, rat
  • Hydroxymethylglutaryl-CoA Synthase
  • 3-Hydroxybutyric Acid

Grant support

The project was funded by Swiss National Science Foundation Grant No. 31_130665 WL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.