title: Important role of ventromedial hypothalamic carnitine palmitoyltransferase-1a in the control of food intake.
abstract: Carnitine palmitoyltransferase-1 (CPT-1) liver isoform, or CPT-1a, is implicated in CNS control of food intake. However, the exact brain nucleus site(s) in mediating this action of CPT-1a has not been identified. In this report, we assess the role of CPT-1a in hypothalamic ventromedial nucleus (VMN). We stereotaxically injected an adenoviral vector containing CPT-1a coding sequence into the VMN of rats to induce overexpression and activation of CPT-1a. The VMN-selective activation of CPT-1a induced an orexigenic effect, suggesting CPT-1a in the VMN is involved in the central control of feeding. Intracerebroventricular administration of etomoxir, a CPT-1 inhibitor, decreases food intake. Importantly, in the animals with VMN overexpression of a CPT-1a mutant that antagonizes the CPT-1 inhibition by etomoxir, the anorectic response to etomoxir was attenuated. This suggests that VMN is involved in mediating the anorectic effect of central inhibition of CPT-1a. In contrast, arcuate nucleus (Arc) overexpression of the mutant did not alter etomoxir-induced inhibition of food intake, suggesting that Arc CPT-1a does not play significant roles in this anorectic action. Furthermore, in the VMN, CPT-1a appears to act downstream of hypothalamic malonyl-CoA action of feeding. Finally, we show that in the VMN CPT-1 activity was altered in concert with fasting and refeeding states, supporting a physiological role of CPT-1a in mediating the control of feeding. All together, CPT-1a in the hypothalamic VMN appears to play an important role in central control of food intake. VMN-selective modulation of CPT-1a activity may therefore be a promising strategy in controlling food intake and maintaining normal body weight.
authors.affiliation: Department of Pediatrics, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Su
authors.initials: S
authors.lastname: Gao
authors.forename: Dolors
authors.initials: D
authors.lastname: Serra
authors.forename: Wendy
authors.initials: W
authors.lastname: Keung
authors.forename: Fausto G
authors.initials: FG
authors.lastname: Hegardt
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics* / Q000502:physiology*; D000229:Dependovirus; D004435:Eating / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004852:Epoxy Compounds / Q000494:pharmacology; D005215:Fasting / Q000502:physiology; D005822:Genetic Vectors; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007276:Injections, Intraventricular; D008297:Male; D008316:Malonyl Coenzyme A / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014697:Ventromedial Hypothalamic Nucleus / Q000201:enzymology* / Q000502:physiology*
chemical_list: D000214:Acyl Coenzyme A; D001067:Appetite Depressants; D004852:Epoxy Compounds; D007004:Hypoglycemic Agents; C116917:acylcarnitine; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; C583748:carnitine palmitoyltransferase-1a, rat; C054207:etomoxir; D002331:Carnitine