title: Inhibition of hypothalamic fatty acid synthase triggers rapid activation of fatty acid oxidation in skeletal muscle.
abstract: Malonyl-CoA functions as a mediator in the hypothalamic sensing of energy balance and regulates the neural physiology that governs feeding behavior and energy expenditure. The central administration of C75, a potent inhibitor of the fatty acid synthase (FAS), increases malonyl-CoA concentration in the hypothalamus and suppresses food intake while activating fatty acid oxidation in skeletal muscle. Closely correlated with the increase in muscle fatty acid oxidation is the phosphorylation/inactivation of acetyl-CoA carboxylase, which leads to reduced malonyl-CoA concentration. Lowering muscle malonyl-CoA, a potent inhibitor of carnitine/palmitoyl-CoA transferase 1 (CPT1), releases CPT1 from inhibitory constraint, facilitating the entry of fatty acids into mitochondria for beta oxidation. Also correlated with these events are C75-induced increases in the expression of skeletal muscle peroxisome proliferator-activated receptor alpha (PPARalpha), a transcriptional activator of fatty acid oxidizing enzymes, and uncoupling protein 3 (UCP3), a thermogenic mitochondrial uncoupling protein. Phentolamine, an alpha-adrenergic blocking agent, prevents the C75-induced increases of skeletal muscle UCP3 and whole body fatty acid oxidation and C75-induced decrease of skeletal muscle malonyl-CoA. Thus, the sympathetic nervous system is implicated in the transmission of the "malonyl-CoA signal" from brain to skeletal muscle. Consistent with the up-regulation of UCP3 and PPARalpha is the concomitant increase in the expression of PGC1alpha, transcriptional coactivator of the UCP3 and PPARalpha-activated genes. These findings clarify the mechanism by which the hypothalamic malonyl-CoA signal is communicated to metabolic systems in skeletal muscle that regulate fatty acid oxidation and energy expenditure.
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Seung Hun
authors.initials: SH
authors.lastname: Cha
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Hu
authors.forename: Shigeru
authors.initials: S
authors.lastname: Chohnan
authors.forename: M Daniel
authors.initials: MD
authors.lastname: Lane
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D017931:DNA Primers; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D005227:Fatty Acids / Q000097:blood / Q000378:metabolism*; D007031:Hypothalamus / Q000378:metabolism*; D007473:Ion Channels; D008316:Malonyl Coenzyme A / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins; D018482:Muscle, Skeletal / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D047493:PPAR alpha / Q000378:metabolism; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000378:metabolism / Q000502:physiology*; D000071247:Uncoupling Protein 3
chemical_list: C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D002352:Carrier Proteins; D017931:DNA Primers; D005227:Fatty Acids; D007473:Ion Channels; D024101:Mitochondrial Proteins; D047493:PPAR alpha; C000604393:Ucp3 protein, mouse; D000071247:Uncoupling Protein 3; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D064429:Fatty Acid Synthases; D015107:4-Butyrolactone