Brain‐specific carnitine palmitoyl‐transferase‐1c: role in CNS fatty acid metabolism, food intake, and body weight

Abstract

Cytokines and endocrine hormones control food intake and energy expenditure and are critical for maintaining homeostasis and averting serious health problems such as those associated with obesity. In addition, a recently identified system for maintaining energy balance utilizes an ancient nutrient-sensing pathway with which the CNS monitors energy needs by assessing current energy surplus/deficit and responding by modulating appetite and peripheral energy expenditure (Wolfgang and Lane 2006b AbstractWhile 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 palmitoyltransferase 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 malonylCoA 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.

Neuronal decanoic acid oxidation is markedly lower than that of octanoic acid: A mechanistic insight into the medium‐chain triglyceride ketogenic diet

“…2). CPT1 activity in brain is low, and although there is also a brain-specific isoform of CPT1 (CPT1c), this isoform has not been found to demonstrate any significant enzymatic activity 21,[36][37][38][39] . This hypothesis is further supported by the recent observation that reports, in astrocytes, that C8 is ketogenic whilst C10 is not 40 .…”

BMP signaling pathway is required for commitment of C3H10T1/2 pluripotent stem cells to the adipocyte lineage

“…Immunoblotting and RT-PCR were performed as described (34). Primers for detecting endogenous types 1A, 1B, and 2 BMP receptors were as follows.…”

“…The PCR products were cloned into MSCV retroviral vectors with BglII and XhoI and added to the C3H10T1/2 stem cells with polybrene at a final concentration of 8 g/mL as described (34).…”

Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model

“…However, the mice show a higher tendency to obesity on a high-fat diet when compared with wild-type mice. 8,9 Conversely, using a transgenic mouse model, Cpt1c gain-of-function results in postnatal microcephaly and when fed a high-fat diet, these mice are protected from weight gain. 10 These data suggest a role for CPT1C in feeding behavior or metabolic sensing in the brain.…”