No 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...

Previous studies showed that i.p. administration of C75, a potent inhibitor of fatty acid synthase (FAS), blocked fasting-induced up-regulation of orexigenic neuropeptides and down-regulation of anorexigenic neuropeptides in the hypothalami of mice. As a result, food intake and body weight were drastically reduced. Here we provide evidence supporting the hypothesis that hypothalamic malonyl-CoA, a substrate of FAS, is an indicator of global energy status and mediates the feeding behavior of mice. We use a sensitive recycling assay to quantify malonyl-CoA to show that the hypothalamic malonyl-CoA level is low in fasted mice and rapidly (<2 h) increases (Ϸ5-fold) on refeeding. Intracerebroventricular C75 ͉ acetyl-CoA carboxylase ͉ fatty acid synthase ͉ neuropeptides ͉ obesity T he hypothalamus monitors global energy status in higher animals (1-4). Specific regions within the hypothalamus, notably the arcuate nucleus, respond to changes in energy status by altering the expression͞secretion of neuropeptides that affect energy intake and expenditure. Thus, when energy intake exceeds expenditure expression of the orexigenic neuropeptides, i.e., NPY and AgRP, decreases whereas the expression of anorexigenic neuropeptides, i.e., proopiomelanocortin (POMC) and CART, increases (1). Signals triggered by these changes are transmitted to higher brain centers through second-order neurons that affect behavior leading to decreased food intake. Conversely, when energy expenditure exceeds intake, the inverse response occurs. Despite considerable progress in identifying many of the neuropeptides and circuits involved (1-4), the signaling mechanisms by which energy status is initially monitored by neurons of the hypothalamus are incompletely understood.Recent evidence (5, 6) has implicated malonyl-CoA, an intermediate in fatty acid biosynthesis, as a possible mediator in the hypothalamic signaling pathway that monitors energy status. We and others have detected both acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) (6, 7), enzymes that catalyze the formation and utilization of malonyl-CoA, respectively, in a subset of hypothalamic neurons. A potent inhibitor of FAS, i.e., C75 (8), that would be expected to increase cellular malonyl-CoA, suppresses food intake and appropriately alters expression of the hypothalamic neuropeptide mRNAs described above (9). Also consistent with the ''malonyl-CoA hypothesis'' is a recent report of Gilbert et al. (10), who found that carotid infusion of obese (Zucker) rats with glucose and insulin suppressed food intake and this effect was prevented by the ACC inhibitor, 5-(tetradecyloxy)-2-furoic acid (TOFA), administered intracerebroventricularly (i.c.v.). Although these indirect lines of evidence support the hypothesis that malonyl-CoA participates in monitoring energy status in the hypothalamus, direct proof is still lacking.Most previous studies (5-7, 9, 11) compared the effects of C75 administered by i.p. injection to mice that had been fasted to increase appetite when presented with food....