Inhibition of hypothalamic fatty acid synthase triggers rapid activation of fatty acid oxidation in skeletal muscle.
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.
Cha
Seung Hun
SH
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Hu
Zhiyuan
Z
Chohnan
Shigeru
S
Lane
M Daniel
MD
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
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