Brain-specific carnitine palmitoyl-transferase-1c: role in CNS fatty acid metabolism, food intake, and body weight.
While the brain does not utilize fatty acids as a primary energy source, recent evidence shows that intermediates of fatty acid metabolism serve as hypothalamic sensors of energy status. Increased hypothalamic malonyl-CoA, an intermediate in fatty acid synthesis, is indicative of energy surplus and leads to the suppression of food intake and increased energy expenditure. Malonyl-CoA functions as an inhibitor of carnitine palmitoyl-transferase 1 (CPT1), a mitochondrial outer membrane enzyme that initiates translocation of fatty acids into mitochondria for oxidation. The mammalian brain expresses a unique homologous CPT1, CPT1c, that binds malonyl-CoA tightly but does not support fatty acid oxidation in vivo, in hypothalamic explants or in heterologous cell culture systems. CPT1c knockout (KO) mice under fasted or refed conditions do not exhibit an altered CNS transcriptome of genes known to be involved in fatty acid metabolism. CPT1c KO mice exhibit normal levels of metabolites and of hypothalamic malonyl-CoA and fatty acyl-CoA levels either in the fasted or refed states. However, CPT1c KO mice exhibit decreased food intake and lower body weight than wild-type littermates. In contrast, CPT1c KO mice gain excessive body weight and body fat when fed a high-fat diet while maintaining lower or equivalent food intake. Heterozygous mice display an intermediate phenotype. These findings provide further evidence that CPT1c plays a role in maintaining energy homeostasis, but not through altered fatty acid oxidation.
Wolfgang
Michael J
MJ
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Cha
Seung Hun
SH
Millington
David S
DS
Cline
Gary
G
Shulman
Gerald I
GI
Suwa
Akira
A
Asaumi
Makoto
M
Kurama
Takeshi
T
Shimokawa
Teruhiko
T
Lane
M Daniel
MD
D000818:Animals; D001835:Body Weight / Q000235:genetics / Q000502:physiology*; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D016466:CHO Cells; D019556:COS Cells; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000502:physiology*; D002490:Central Nervous System / Q000201:enzymology / Q000378:metabolism; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D004435:Eating / Q000235:genetics / Q000502:physiology*; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D005260:Female; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction
D005227:Fatty Acids; D007527:Isoenzymes; D002334:Carnitine O-Palmitoyltransferase