title: Malonyl-CoA mediates leptin hypothalamic control of feeding independent of inhibition of CPT-1a.
abstract: Hypothalamic fatty acid metabolism is involved in central nervous system controls of feeding and energy balance. Malonyl-CoA, an intermediate of fatty acid biosynthesis, is emerging as a significant player in these processes. Notably, hypothalamic malonyl-CoA has been implicated in leptin's feeding effect. Leptin treatment increases malonyl-CoA level in the hypothalamic arcuate nucleus (Arc), and this increase is required for leptin-induced decrease in food intake. However, the intracellular downstream mediators of malonyl-CoA's feeding effect have not been identified. A primary biochemical action of malonyl-CoA is the inhibition of the acyltransferase activity of carnitine palmitoyltransferase-1 (CPT-1). In the hypothalamus, the predominant isoform of CPT-1 that possesses the acyltransferase activity is CPT-1 liver type (CPT-1a). To address the role of CPT-1a in malonyl-CoA's anorectic action, we used a recombinant adenovirus expressing a mutant CPT-1a that is insensitive to malonyl-CoA inhibition. We show that Arc overexpression of the mutant CPT-1a blocked the malonyl-CoA-mediated inhibition of CPT-1 activity. However, the overexpression of this mutant did not affect the anorectic actions of leptin or central cerulenin for which an increase in Arc malonyl-CoA level is also required. Thus, CPT-1a does not appear to be involved in the malonyl-CoA's anorectic actions induced by leptin. Furthermore, long-chain fatty acyl-CoAs, substrates of CPT-1a, dissociate from malonyl-CoA's actions in the Arc under different feeding states. Together, our results suggest that Arc intracellular mechanisms of malonyl-CoA's anorectic actions induced by leptin are independent of CPT-1a. The data suggest that target(s), rather than CPT-1a, mediates malonyl-CoA action on feeding.
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: Wendy
authors.initials: W
authors.lastname: Keung
authors.forename: Dolors
authors.initials: D
authors.lastname: Serra
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Patricia
authors.initials: P
authors.lastname: Carrasco
authors.forename: Nuria
authors.initials: N
authors.lastname: Casals
authors.forename: Fausto G
authors.initials: FG
authors.lastname: Hegardt
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Moran
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
mesh_terms: D000217:Acyltransferases / Q000502:physiology; D000818:Animals; D001069:Appetite Regulation / Q000502:physiology*; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D002569:Cerulenin / Q000378:metabolism; D004734:Energy Metabolism / Q000502:physiology; D007031:Hypothalamus / Q000502:physiology*; D020738:Leptin / Q000502:physiology*; D008297:Male; D008316:Malonyl Coenzyme A / Q000502:physiology*; D023421:Models, Animal; D009154:Mutation / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D020738:Leptin; D002569:Cerulenin; D008316:Malonyl Coenzyme A; D000217:Acyltransferases; D002334:Carnitine O-Palmitoyltransferase