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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....

AMP-activated protein kinase (AMPK) plays an important role in regulating whole body energy homeostasis. Recently, it has been demonstrated that berberine (BBR) exerts antiobesity and antidiabetic effects in obese and diabetic rodent models through the activation of AMPK in peripheral tissues. Here we show that BBR improves lipid dysregulation and fatty liver in obese mice through central and peripheral actions. In obese db/db and ob/ob mice, BBR treatment reduced liver weight, hepatic and plasma triglyceride, and cholesterol contents. In the liver and muscle of db/db mice, BBR promoted AMPK activity and fatty acid oxidation and changed expression of genes involved in lipid metabolism. Additionally, intracerebroventricular administration of BBR decreased the level of malonyl-CoA and stimulated the expression of fatty acid oxidation genes in skeletal muscle. Together, these data suggest that BBR would improve fatty liver in obese subjects, which is probably mediated not only by peripheral AMPK activation but also by neural signaling from the central nervous system.

SUMMARY mTOR Complex 1 (mTORC1; mammalian target of rapamycin (mTOR) in complex with raptor) is a key regulator of protein synthesis and cell growth in response to nutrient amino acids. Here we report that inositol polyphosphate multikinase (IPMK), which possesses both inositol phosphate kinase and lipid kinase activities, regulates amino acid signaling to mTORC1. This regulation is independent of IPMK's catalytic function, instead reflecting its binding with mTOR and raptor, which maintains the mTOR-raptor association. Thus, IPMK appears to be a physiologic mTOR cofactor, serving as a determinant of mTORC1 stability and amino acid-induced mTOR signaling. Substances that block IPMK-mTORC1 binding may afford therapeutic benefit in nutrient amino acid-regulated conditions such as obesity and diabetes.

The American diet, especially that of adolescents, contains highly palatable foods of high-energy content and large amounts of high-fructose sweeteners. These factors are believed to contribute to the obesity epidemic and insulin resistance. Previous investigations revealed that the central metabolism of glucose suppresses food intake mediated by the hypothalamic AMP-kinase/malonylCoA signaling system. Unlike glucose, centrally administered fructose increases food intake. Evidence presented herein indicates that the more rapid initial steps of central fructose metabolism deplete hypothalamic ATP level, whereas the slower regulated steps of glucose metabolism elevate hypothalamic ATP level. Consistent with effects on the [ATP]/[AMP] ratio, fructose increases phosphorylation/activation of hypothalamic AMP kinase causing phosphorylation/inactivation of acetyl-CoA carboxylase, whereas glucose has the inverse effects. The changes provoked by central fructose administration reduce hypothalamic malonyl-CoA level and thereby increase food intake. These findings explain the paradoxical fructose effect on food intake and lend credence to the malonyl-CoA hypothesis.acetyl-CoA carboxylase ͉ AMP kinase ͉ high-fructose corn syrup ͉ hypothalamic ATP ͉ obesity O ver the past three decades there has been an alarming increase in the incidence of obesity and type 2 diabetes in the United States (1). Particularly troubling is the rise of these conditions in youth (2). Paralleling this rise has been the extensive use of high-fructose sweeteners in the diet and increasing evidence that fructose may be a contributing factor to the obesity epidemic (3). These correlations are consistent with the finding that high-fructose diets promote insulin resistance, glucose intolerance, and increased rates of hepatic lipogenesis in laboratory animals (4).Although both glucose and fructose enter metabolism via the glycolytic pathway, the initial steps of hepatic fructose metabolism differ from those of glucose. Likewise, recent evidence suggests that sugar metabolism in regions of the central nervous system (CNS) that control food intake and energy expenditure, fructose metabolism also differs from that of glucose. It is known that the initial steps of hepatic fructose metabolism use a different set of enzymes that allow this sugar to bypass the rate-limiting step [catalyzed by phosphofructokinase (PFK)] in the glycolytic pathway. Similar enzymes of fructose metabolism are found in regions of the CNS that play an important role in monitoring energy balance and satiety control (5-7). These findings are consistent with a recent report (ref. 8 and findings reported herein) that centrally-administered fructose provokes feeding. In contrast, the central administration of glucose causes satiety (8,9). In this article, we provide a molecular basis for these differences. It should be noted, however, that uncertainty remains regarding the extent to which fructose in systemic circulation can cross the blood-brain barrier to enter these regions of the brain ...

Hypothalamic malonyl-CoA has been shown to function in global energy homeostasis by modulating food intake and energy expenditure. Little is known, however, about the regulation of malonyl-CoA concentration in the central nervous system. To address this issue we investigated the response of putative intermediates in the malonyl-CoA pathway to metabolic and endocrine cues, notably those provoked by glucose and leptin. Hypothalamic malonyl-CoA rises in proportion to the carbohydrate content of the diet consumed after food deprivation. Malonyl-CoA concentration peaks 1 h after refeeding or after peripheral glucose administration. This response depends on the dose of glucose administered and is blocked by the i.c.v. administration of an inhibitor of glucose metabolism, 2-deoxyglucose (2-DG). The kinetics of change in hypothalamic malonyl-CoA after glucose administration is coincident with the suppression of phosphorylation of AMP kinase and acetyl-CoA carboxylase. Blockade of glucose utilization in the CNS by i.c.v. 2-DG prevented the effects of glucose on 5AMP-activated protein kinase, malonyl-CoA, hypothalamic neuropeptide expression, and food intake. Finally, we showed that leptin can increase hypothalamic malonyl-CoA and that the increase is additive with glucose administration. Leptin-deficient ob/ob mice, however, showed no defect in the glucose-or refeeding-induced rise in hypothalamic malonyl-CoA after food deprivation, demonstrating that leptin was not required for this effect. These studies show that hypothalamic malonyl-CoA responds to the level of circulating glucose and leptin, both of which affect energy homeostasis.acetyl-CoA carboxylase ͉ AMP kinase ͉ carnitine palmitoyl-transferase 1c ͉ fatty acid synthase A n interconnected endocrine and neuroendocrine system controls food intake and energy expenditure (1). Recently, a new pathway for maintaining energy homeostasis has become evident that relies on an ancient nutrient-sensing pathway whereby the CNS directly monitors energy needs by sampling cellular adenine nucleotide levels and responds by directing hunger and peripheral energy expenditure (2, 3). Neural cellular energy status is monitored through AMPK, which directly senses the [AMP]/[ATP] ratio. The AMPK system provides a rapid means of detecting energy status not reliant directly on endocrine signals. The activation of AMPK leads to the inhibition of the key regulatory enzyme of fatty acid synthesis, acetyl-CoA carboxylase (ACC). The activity of this enzyme is an indicator of energy surplus and is thought to be one of the mechanisms by which energy homeostasis is mediated. Several enzymes that are involved in fatty acid metabolism have been implicated in the CNS control of energy homeostasis including AMPK (4-7), ACC (8, 9), fatty acid synthase (FAS) (8, 10), carnitine palmitoyltransferase 1 (CPT1) (11, 12), and stearoyl-CoA desaturase 1 (13). Because fatty acid synthesis is a process that occurs primarily during energy surplus, it is not surprising that this system has evolved as a means to r...

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 phosphorylation͞inactivation of acetyl-CoA carboxylase, which leads to reduced malonyl-CoA concentration. Lowering muscle malonyl-CoA, a potent inhibitor of carnitine͞ palmitoyl-CoA transferase 1 (CPT1), releases CPT1 from inhibitory constraint, facilitating the entry of fatty acids into mitochondria for ␤ oxidation. Also correlated with these events are C75-induced increases in the expression of skeletal muscle peroxisome proliferator-activated receptor ␣ (PPAR␣), a transcriptional activator of fatty acid oxidizing enzymes, and uncoupling protein 3 (UCP3), a thermogenic mitochondrial uncoupling protein. Phentolamine, an ␣-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 PPAR␣ is the concomitant increase in the expression of PGC1␣, transcriptional coactivator of the UCP3 and PPAR␣-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.acetyl-CoA carboxylase ͉ malonyl-CoA ͉ obesity ͉ uncoupling protein 3 T he hypothalamus monitors peripheral neural and hormonal signals that reflect changes in the energy status of higher animals (1). These signals are transmitted to higher brain centers, where the information is integrated and appropriate adjustments are made to alter feeding behavior. Recent evidence suggests that, in addition to signals that affect food intake, signals are also transmitted from the CNS to peripheral tissues, e.g., liver and skeletal muscle, to alter metabolic pathways involved in energy storage and expenditure (2, 3).Previous investigations have shown that intracerebroventricular (i.c.v.) administration of C75, a potent inhibitor of fatty acid synthase (FAS) (4), rapidly (Ͻ2 h) increases hypothalamic malonyl-CoA concentration (5), suppresses expression of orexigenic neuropeptides (e.g., NPY and AgRP), and activates expression of anorexigenic neuropeptides (e.g., ␣MSH and CART) (6). These changes correlate closely with an abrupt curtailment of food intake and a loss of body weight (7). Compelling evidence indicates that changes in hypothalamic [malonyl-CoA], provoked by inhibition of FAS or by refeeding after fasting, serve as an intermediary in the signaling pathways that...