The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis

Abstract

Fatty acid synthesis in the central nervous system is implicated in the control of food intake and energy expenditure. An intermediate in this pathway, malonyl-CoA, mediates these effects. Malonyl-CoA is an established inhibitor of carnitine palmitoyltransferase-1 (CPT1), an outer mitochondrial membrane enzyme that controls entry of fatty acids into mitochondria and, thereby, fatty acid oxidation. CPT1c, a brain-specific enzyme with high sequence similarity to CPT1a (liver) and CPT1b (muscle) was recently discovered. All three CPTs bind malonyl-CoA, and CPT1a and CPT1b catalyze acyl transfer from various fatty acyl-CoAs to carnitine, whereas CPT1c does not. These findings suggest that CPT1c has a unique function or activation mechanism. We produced a targeted mouse knockout (KO) of CPT1c to investigate its role in energy homeostasis. CPT1c KO mice have lower body weight and food intake, which is consistent with a role as an energy-sensing malonyl-CoA target. Paradoxically, CPT1c KO mice fed a high-fat diet are more susceptible to obesity, suggesting that CPT1c is protective against the effects of fat feeding. CPT1c KO mice also exhibit decreased rates of fatty acid oxidation, which may contribute to their increased susceptibility to diet-induced obesity. These findings indicate that CPT1c is necessary for the regulation of energy homeostasis.acetyl-CoA carboxylase ͉ fatty acid synthase ͉ food intake ͉ malonyl-CoA ͉ obesity B ody weight is maintained by regulating food intake and energy expenditure. This balance is monitored by the central nervous system (CNS) in response to cytokine and endocrine signals, including leptin, ghrelin, obestatin, insulin, cholecystokinin, and peptide YY secreted by peripheral tissues. Concomitantly, parallel pathways in the CNS regulate energy balance by monitoring the availability of neuronal energy-rich metabolic substrates. Integration of these signals occurs in the hypothalamus and, ultimately, in higher brain centers where feeding behavior and energy expenditure are adjusted. Two primary indicators of energy surplus, glucose and fatty acids, are also monitored by subsets of hypothalamic neurons that modulate feeding behavior and energy expenditure (1). Fatty acids (2) and de novo fatty acid synthesis from glucose (3) are known to mediate these effects. Indeed, food intake and body weight have been shown to be altered by manipulating the activities of the enzymes involved in fatty acid synthesis, e.g., fatty acid synthase (FAS) (3), malonyl-CoA decarboxylase (4, 5), acetyl-CoA carboxylase (ACC) (6, 7), stearoyl-CoA desaturase (8, 9), and 5Ј-AMP kinase (10, 11).Inhibition of FAS in the CNS, for example, reduces body weight by rapidly provoking a reduction in food intake and an increase in peripheral energy expenditure (3,12). This inhibition can reverse the weight gain caused by diet-induced obesity (13,14) or mutations in leptin (ob͞ob) or its receptor (db͞db) (3, 15), suggesting that it acts independently of STAT3, which is known to be essential for leptin 's action (16, 17). I...

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 .…”

“…Whilst this may be the case for C8, there are reports to suggest that C10, in contrast to C8, may require the carnitine system for complete mitochondrial β-oxidation 18 . Carnitine palmitoyltransferase I (CPT1) is responsible for transferring fatty acyl groups to carnitine and is the rate-limiting step in carnitine-dependent β-oxidation in mitochondria [19][20][21] . To evaluate the potential role of CPT1 in C8 and C10 β-oxidation, the well-characterised CPT1 irreversible inhibitor etomoxir was used [22][23][24] .…”

Hypothalamic malonyl-CoA triggers mitochondrial biogenesis and oxidative gene expression in skeletal muscle: Role of PGC-1α

“…Several lines of evidence are consistent with this speculation. First, CPT1c binds malonyl-CoA and is expressed in regions of the ventral hypothalamus, notably the arcuate nucleus, that are critical for the control of energy homeostasis (34). Consistent with a role as an energy-sensing malonyl-CoA target, CPT1c-null mice eat less and are smaller than wild-type mice (34).…”

“…We suggest that the recently discovered brain-specific enzyme, CPT1c (33,34), may be this signaling molecule (Fig. 6).…”

“…First, CPT1c binds malonyl-CoA and is expressed in regions of the ventral hypothalamus, notably the arcuate nucleus, that are critical for the control of energy homeostasis (34). Consistent with a role as an energy-sensing malonyl-CoA target, CPT1c-null mice eat less and are smaller than wild-type mice (34). In contrast, however, CPT1c-null mice gain considerably more weight than wild-type controls when fed a high-fat diet, suggesting that the CPT1c gene product provides resistance to the effects of a high fat intake (34).…”