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Proc Natl Acad Sci U S A. Jun 7, 2011; 108(23): 9691–9696.
Published online May 18, 2011. doi:  10.1073/pnas.1103267108
PMCID: PMC3111271
Neuroscience

Important roles of brain-specific carnitine palmitoyltransferase and ceramide metabolism in leptin hypothalamic control of feeding

Abstract

Brain-specific carnitine palmitoyltransferase-1 (CPT-1c) is implicated in CNS control of food intake. In this article, we explore the role of hypothalamic CPT-1c in leptin's anorexigenic actions. We first show that adenoviral overexpression of CPT-1c in hypothalamic arcuate nucleus of rats increases food intake and concomitantly up-regulates orexigenic neuropeptide Y (NPY) and Bsx (a transcription factor of NPY). Then, we demonstrate that this overexpression antagonizes the anorectic actions induced by central leptin or compound cerulenin (an inhibitor of fatty acid synthase). The overexpression of CPT-1c also blocks leptin-induced down-regulations of NPY and Bsx. Furthermore, the anorectic actions of central leptin or cerulenin are impaired in mice with brain CPT-1c deleted. Both anorectic effects require elevated levels of hypothalamic arcuate nucleus (Arc) malonyl-CoA, a fatty acid-metabolism intermediate that has emerged as a mediator in hypothalamic control of food intake. Thus, these data suggest that CPT-1c is implicated in malonyl-CoA action in leptin's hypothalamic anorectic signaling pathways. Moreover, ceramide metabolism appears to play a role in leptin's central control of feeding. Leptin treatment decreases Arc ceramide levels, with the decrease being important in leptin-induced anorectic actions and down-regulations of NPY and Bsx. Of interest, our data indicate that leptin impacts ceramide metabolism through malonyl-CoA and CPT-1c, and ceramide de novo biosynthesis acts downstream of both malonyl-CoA and CPT-1c in mediating their effects on feeding and expressions of NPY and Bsx. In summary, we provide insights into the important roles of malonyl-CoA, CPT-1c, and ceramide metabolism in leptin's hypothalamic signaling pathways.

Obesity is a major cause of insulin-resistance and diabetes. An imbalance between food intake and energy expenditure contributes to the development of obesity. The CNS regulates energy homeostasis with the hypothalamus playing a critical role (1, 2). Mounting evidence now shows that fatty acid metabolism in the hypothalamus plays important roles in the central regulation of energy homeostasis (317). In this regard, malonyl-CoA, an intermediate in fatty acid de novo biosynthesis, is emerging as a player in the hypothalamus (3, 5, 6, 813).

Hypothalamic malonyl-CoA metabolism has been implicated in leptin-induced anorectic actions (9, 12, 13). Leptin, an important physiological regulator of food intake and body weight, exerts its anorectic effects partly by inducing an increase in malonyl-CoA level in the hypothalamic arcuate nucleus (Arc) (12). In addition to fatty acid biosynthesis, recent data also suggest a role for carnitine palmitoyltransferase-1 (CPT-1), a key enzyme in mitochondrial fatty acid β-oxidation (7, 18), in hypothalamic regulation of energy balance. Fatty acid biosynthesis and β-oxidation are linked by malonyl-CoA–mediated inhibition of CPT-1 acyltransferase activity (12). In the hypothalamus, the CPT-1 liver isoform (CPT-1a) is the predominant type possessing the prototypical acyltransferase activity (7). Our previous results have demonstrated that leptin treatment does not alter the levels of substrates of CPT-1a, long-chain fatty acyl-CoAs (12). Furthermore, upon leptin treatment, the levels of products of CPT-1a, long-chain acylcarnitines, were also not altered (19). Together, these results show that leptin treatment may not affect CPT-1a activity, although it raises the level of malonyl-CoA (an inhibitor of CPT-1a). It should be noted that the activity of CPT-1–mediated fatty acid β-oxidation is very low in the brain compared with the peripheral tissues (20, 21). As a result, the CPT-1a activity in the hypothalamus may be resistant to further inhibition exerted by malonyl-CoA. This possibility may underlie the difficulties in detecting the expected inhibition of CPT-1a in these experiments. Alternatively, because of the inherently low basal activity, CPT-1a may not be in a position that is subject to the regulation of malonyl-CoA, particularly under the condition that increases malonyl-CoA level. In our subsequent studies (19), we artificially increased the CPT-1a activity in the Arc and were able to detect a leptin-induced inhibition of CPT-1a. However, our data reveal that this CPT-1a inhibition is not implicated in leptin's anorectic actions (19). Thus, despite a significant role of malonyl-CoA, CPT-1a does not seem to be an important player in leptin's hypothalamic control of food intake (12). This dissociation promotes us to identify alternative downstream targets of malonyl-CoA action in leptin's feeding pathways.

The brain-specific isoform of CPT-1 (CPT-1c), with the sequence similar to the other CPT-1 isozymes (1a and 1b), is expressed in the hypothalamus (22, 23). The molecular function of CPT-1c has not been well defined and the initial studies suggested that CPT-1c did not have the prototypical acyltransferase activity (22, 23). A later study using a more sensitive activity assay identified a very weak acyltransferase activity (20–300 times lower than CPT-1a and -1b) (24). This activity of CPT-1c is atypical as it preferentially uses palmitoyl-CoA as substrate (24). Of interest, CPT-1c is expressed in Arc neurons (25) and CPT-1c knockout animals manifest reduced food intake and weight gain (23). These findings demonstrate that null function of CPT-1c is associated with the anorectic effect, an action in the same direction as the feeding effect produced by exogenous leptin. We further predict that inhibition of CPT-1c functions is a step in leptin's anorectic signaling pathways. Moreover, it has recently been shown that a significant portion of CPT-1c is localized in the endoplasmic reticulum (ER) (24), suggesting that CPT-1c is involved in ER functions. Taken together, these data lead to our hypothesis that CPT-1c acts to modulate leptin's anorectic actions by impacting certain ER functions. In this article, we examined the roles of CPT-1c in leptin's Arc signaling pathways. We further explored how CPT-1c interacts with one of the many functions of the ER, ceramide metabolism (24), to impact leptin's hypothalamic control of food intake.

Results

CPT-1c Modulates the Anorectic Actions of Leptin and Cerulenin.

CPT-1c is widely distributed in CNS neurons (25). To address the arcuate-specific role of CPT-1c, we delivered a recombinant adenoviral vector encoding wild-type human CPT-1c into the arcuate nucleus of rats using stereotaxic surgery. Arc delivery of the virus resulted in an increased Arc level of CPT-1c without altering the level of CPT-1a or CPT-2 (Fig. 1A). The levels of long-chain acylcarnitines, products and a reliable indicator of CPT-1 acyltransferase activity (24, 26), were not changed following the overexpression (Fig. 1A), which is consistent with the prediction that CPT-1c has a very low CPT-1 activity in vivo (21). However, this lack of change of acylcarnitine levels indicates that CPT-1c overexpression did not interfere with CPT-1a activity. Consistent with a previous report (25), Arc overexpression of CPT-1c did not produce significant changes of daily food consumption or body weight gain under ad libitum-fed condition (Fig. S1). However, following an overnight fast, the rats with Arc overexpression of CPT-1c consumed more food than the null rats (Fig. 1B). This overexpression also induced an increase in the level of the Arc orexigenic neuropeptide Y (NPY) (Fig. 1B), an important mediator in central control of feeding (1). In addition, the brain-specific homeobox factor (Bsx), a transcription factor of NPY expression (27), was up-regulated following the overexpression of CPT-1c (Fig. 1B). The levels of other Arc neuropeptides involved in food intake, such as agouti-related peptide (AgRP) and preopiomelanocortin (POMC), were not altered (Fig. 1B). Next, we assessed the role for CPT-1c in leptin's action on food intake by infusing leptin directly into the Arc overexpressing CPT-1c. In these rats, leptin-induced anorectic effects (under ad libitum conditions) were significantly attenuated compared with the null condition (Fig. 1C). To evaluate the role of CPT-1c in the specific context of Arc malonyl-CoA feeding mechanisms, we disrupted the activity of fatty acid synthase (FAS) by infusing cerulenin, a FAS inhibitor (3, 6), into the Arc overexpressing CPT-1c. FAS uses malonyl-CoA as a substrate and central cerulenin treatment exerts anorectic actions by increasing hypothalamic malonyl-CoA level (3, 6). Similar to our findings with leptin, the anorectic actions by cerulenin were antagonized by Arc overexpression of CPT-1c (Fig. 1C). Leptin reduces feeding and body weight partly through down-regulating NPY and Bsx levels (1, 12). Our data showed that these leptin-induced changes were attenuated in the animals with Arc overexpression of CPT-1c (Fig. 1D). We previously reported that leptin treatment in the similar experimental setting did not affect the level of AgRP or POMC (by both real-time PCR and in situ hybridization) (12), so their responses to leptin were not examined in the current study.

Fig. 1.
CPT-1c modulates the anorectic actions of leptin and cerulenin. The adenovirus that encodes human CPT-1c and coexpresses GFP (Ade-CPT-1c) was delivered into the Arc of rats. The adenoviral vector expressing GFP alone was used as the null control (Ade-null). ...

We have shown that ectopical expression of CPT-1c modulates leptin's anorectic actions. The immediate question is whether this effect has physiological relevance in leptin's central feeding mechanisms. To address the issue, we injected leptin to mice with brain CPT-1c deleted and then monitored food intake and body weight. As expected, leptin-induced inhibitions of food intake and weight gain seen in wild-type mice were blocked in the knockout mice (Fig. 1E). To evaluate the role of CPT-1c specifically in the action of malonyl-CoA, we centrally injected cerulenin into these mice and found CPT-1c deletion blocked the anorectic actions of cerulenin (Fig. 1E). Taken together, these data show that CPT-1c may be a necessary component in the malonyl-CoA action in leptin's intracellular signaling pathways.

Arc Ceramide Metabolism Is Required for Leptin's Anorectic Actions.

A significant portion of CPT-1c resides in the ER and CPT-1c preferentially binds palmitoyl-CoA (24). These findings drove us to hypothesize that CPT-1c plays a role in the ceramide metabolism that starts in the ER and uses palmitoyl-CoA as a substrate (24). In support, we found Arc overexpressing CPT-1c (under fasting condition) had an increased ceramide level, and the Arc with CPT-1c deleted had a decreased level (Fig. 2A). Leptin treatment is expected to alter hypothalamic ceramide level because CPT-1c is involved in leptin's hypothalamic actions. Indeed, we found that leptin reduced the ceramide level in the Arc (Fig. 2B), and this reduction was attenuated by CPT-1c overexpression (Fig. 2C). As the increase in Arc malonyl-CoA level is required in leptin's central anorectic effects (12), we also assessed the role of malonyl-CoA in ceramide metabolism. Malonyl-CoA decarboxylase (MCD), an enzyme degrading malonyl-CoA (12), was overexpressed in the Arc and ceramide levels were then measured. Previous results demonstrated that MCD overexpression in the Arc reduces malonyl-CoA level, increases food intake, and blocks leptin-mediated inhibition of feeding (9, 19). Here we showed that MCD overexpression up-regulated ceramide level and blocked leptin-induced down-regulation of Arc ceramide level (Fig. 2D). Together, these data suggest that leptin induces the decrease in Arc ceramide level through the actions of malonyl-CoA and CPT-1c. Next, we evaluated the relevance of ceramide metabolism in leptin's anorectic signaling actions. We found that Arc pretreatment with N-hexanoyl-d-sphingosine, a cell-penetrating analog of natural ceramides (28), blocked leptin-induced anorectic actions (Fig. 2E). In parallel, the ceramide analog blocked or attenuated leptin-mediated down-regulation of NPY and Bsx (Fig. 2F). To determine the specificity of the observed feeding effects of the compounds, we centrally infused ciliary neurotrophic factor (CNTF) into the rats that had received the pretreatment with the ceramide analog or had CPT-1c overexpressed in the Arc. Previous evidence has demonstrated that CNTF produces anorectic actions without affecting the hypothalamic acetyl-CoA carboxylase and malonyl-CoA metabolic pathway.* In our studies, the overexpression of CPT-1c or pretreatment with the ceramide analog did not block CNTF-mediated anorectic actions (Fig. S2). Thus, the effects of both CPT-1c and ceramide appear to be specific for the malonyl-CoA anorectic action.

Fig. 2.
Arc ceramide metabolism is required in leptin's anorectic actions. (A) CPT-1c overexpression: the Ade-CPT-1c or Ade-GFP (null) was delivered into the Arc of rats. The rats were killed following 8-h food deprivation and ceramide levels in the Arc were ...

Finally, we examined the independent effects of Arc ceramide on food intake and body weight. The compound myriocin, an inhibitor of ceramide biosynthesis, was used to reduce the ceramide level. Myriocin does so by inhibiting serine palmitoyltransferase (SPT), the key rate-limiting enzyme of ceramide de novo biosynthesis (29, 30). The brain expresses SPT (30) and we found a significant mRNA level of SPT in the Arc (comparable to the levels of AgRP and POMC). We infused myriocin into the Arc and monitored feeding and body weight. We found that Arc administration (two injections separated by 6 h), which effectively reduced ceramide level in the Arc, lowered food intake and weight gain (Fig. 2G). Along with these changes, NPY and Bsx levels were decreased (Fig. 2H). As was the case with CPT-1c, myriocin treatment did not affect the mRNA level of AgRP or POMC (Fig. 2H). We then tested the feeding effect of elevated ceramide level in the Arc. The dosage of the ceramide analog used in the wild-type animals reached a limit beyond which nonspecific or toxic effects will appear. As a result, we infused the compound with the same dosage into the rats with Arc overexpression of CPT-1c (that can be induced to show an increased level of Arc ceramide). As expected, under ad libitum-fed conditions, the compound increased food intake (24 h after the infusion: DMSO: 100 ± 2.9%; the ceramide analog: 110 ± 4.0%; P < 0.05).

Ceramide de Novo Synthesis Mediates Arc Malonyl-CoA and CPT-1c Actions on Food Intake.

We have shown that both malonyl-CoA and CPT-1c affect leptin's actions on ceramide level and food intake. We further hypothesized that ceramide de novo synthesis mediates these effects. In support of the hypothesis, we found that myriocin infusion (single dosage) prevented the increase in ceramide level induced by MCD or CPT-1c (Fig. 3A). These data demonstrate that de novo synthesis of ceramide contributes to the effects of malonyl-CoA and CPT-1c on ceramide metabolism. Next, we evaluated the relevance of ceramide de novo synthesis in the actions of malonyl-CoA and CPT-1c on feeding. We subjected the rats to a period of food deprivation and infused myriocin at the onset of the fast. Arc overexpression of MCD (lowering malonyl-CoA) or CPT-1c increased rebound feeding, and myriocin treatments stopped the developments of the increase in food intake (Fig. 3B). It should be noted that we injected myriocin as a single dosage in this particular experiment, so that myriocin treatment alone did not affect feeding (Fig. 3B). Along with the blockade of food intake, we found that MCD- and CPT-1c–mediated up-regulations of NPY (9) were also blocked by central myriocin (Fig. 3C). The up-regulation of AgRP level by MCD (9) was not affected by myriocin treatment (Fig. 3C), suggesting a NPY-specific effect in the central actions of de novo biosynthesis of ceramide. The MCD or CPT-1c–induced up-regulation of Bsx was also blocked by myriocin treatment (Fig. 3D).

Fig. 3.
Ceramide de novo biosynthesis mediates malonyl-CoA and CPT-1c actions on food intake and body weight. (A and B) The rats with Arc overexpression of MCD (n = 8), CPT-1c (n = 12), or GFP (null, n = 16) received a single intra-Arc infusion of myriocin (4 ...

Finally, we assessed the physiological relevance of the changes of Arc ceramide levels (Fig. S3). We showed that fasting increased the Arc ceramide levels and refeeding reduced the elevated levels. We also demonstrated that the up-regulation of Arc ceramide levels by fasting is CPT-1c–dependent, as the change is negated in the mice with Arc deletion of CPT-1c (Fig. S3).

Discussion

Previous results have challenged the role of CPT-1a in leptin's Arc anorectic signaling pathways (12, 19). Our current studies identify CPT-1c as a potential mediator in leptin's hypothalamic anorectic actions. CPT-1c also appears to be a necessary component in the anorectic actions induced by central cerulenin. Because the anorectic actions of both leptin and cerulenin require the increase in Arc malonyl-CoA level, CPT-1c is likely implicated in the malonyl-CoA signaling action in leptin's Arc intracellular pathways.

Although the exact biochemical functions of CPT-1c have not been uncovered in the present study, our data suggest that CPT-1c regulates ceramide metabolism. Importantly, ceramide metabolism appears to play a role in CPT-1c's effect on food intake. In particular, we provide evidence supporting a role of ceramide de novo biosynthesis in mediating CPT-1c action on feeding. Based on these data, we propose that CPT-1c would act to intervene with ER ceramide de novo biosynthesis. There are several potential mechanisms underlying this proposal. First, because CPT-1c is localized in the ER (24) where SPT resides, it is possible that CPT-1c physically interacts with SPT to modulate the activity of ceramide de novo biosynthesis. Second, as it has a preferential affinity for palmitoyl-CoA (24), CPT-1c may increase the local availability of palmitoyl-CoA for use by SPT to synthesize ceramide. Finally, CPT-1c may act as a transporter for shuttling palmitoyl-CoA into the ER for use in ceramide synthesis. This potential mechanism is effective in interpreting the observed changes in ceramide levels when malonyl-CoA levels alter concomitantly (e.g., MCD overexpression). By the inhibitory effect on mitochondrial CPT-1a, malonyl-CoA can affect the availability of palmitoyl-CoA to SPT, and thus the subsequent ceramide de novo biosynthesis. However, once palmitoyl-CoA is shuttled into the ER, ceramide biosynthesis will be free of the intervention by malonyl-CoA–mediated inhibition of CPT-1a. This scenario sets an ideal subcellular environment for the de novo biosynthetic pathway of ceramide to exert a regulatory signaling role. The potential interaction of CPT-1c with ceramide metabolism appears to have physiological relevance as our data also suggest that CPT-1c is required in fasting-induced increase in ceramide levels.

Ceramide metabolism plays roles in the signaling mechanisms underlying a variety of physiological functions, such as apoptosis, cell growth, and cell differentiation (29). Of relevance, elevated ceramide biosynthesis in the periphery has been implicated in the pathogenesis of obesity and type-2 diabetes (29). Our data suggest a role for ceramide metabolism in the hypothalamic controls of feeding and body weight. Of interest in leptin's signaling actions, we show that leptin reduces ceramide level in the Arc, which is a significant step in leptin-mediated anorectic effects and down-regulations of NPY and Bsx. In leptin's action on ceramide metabolism, it seems that both malonyl-CoA and CPT-1c are involved. Our data indicate that, in addition to CPT-1c, malonyl-CoA action can also impact Arc ceramide metabolism. Moreover, similar to CPT-1c, the downstream signaling actions of malonyl-CoA's effect on feeding also involve ceramide de novo synthesis. Because malonyl-CoA and CPT-1c play roles in leptin's actions on feeding, ceramide de novo synthesis may be a component in leptin's hypothalamic anorectic signaling pathways. Taking these data together, we propose a model that leptin reduces ceramide level and food intake via increasing malonyl-CoA and inducing CPT-1c inhibition, resulting in the decreased ceramide de novo synthesis (Fig. S4). Because CPT-1c can bind malonyl-CoA, malonyl-CoA might directly inhibit CPT-1c functions (Fig. S4, pathway-1). Our data are indeed consistent with this proposed pathway. Reduced malonyl-CoA level (under either fasting or MCD overexpression), which is anticipated to activate CPT-1c, is associated with the increases in ceramide levels and food intake. However, it should be particularly noted that malonyl-CoA may also interact with other yet-to-be identified mediators to modulate ceramide metabolism and food intake (Fig. S4, pathway-2). In this case, malonyl-CoA and CPT-1c can act in parallel, as they converge on ceramide de novo synthesis, to control food intake. A definitive answer would depend on identifying the range of the molecular functions of CPT-1c, which is fully warranted. In this model, our results identify NPY, among the major Arc neuropeptides, as a common effector in the actions of malonyl-CoA, CPT-1c, and ceramide metabolism on food intake. These data may suggest that the CPT-1c/ceramide pathway has greater effects on the expression of NPY than the other neuropeptides, such as AgRP and POMC. In addition, CPT-1c might regulate ceramide metabolism in the neurons that specifically express NPY.

Increased ceramide level might activate the ER stress cascade (31) and hypothalamic ER stress can impair leptin receptor signaling (32, 33). In our studies, we did not find any evidence to suggest the involvement of ER stress in CPT-1c and ceramide actions (Fig. S5). Moreover, CPT-1c and ceramide metabolism seem to act independent of several other mediators of leptin's intracellular signaling pathways, such as signal transducer and activator of transcription 3 (STAT3), forkhead box protein O1 (FoxO1), and mammalian target of rapamycin (mTOR) (Fig. S6). Notably, our results suggest that the activation of STAT3 by leptin is not affected by either CPT-1c overexpression or ceramide treatment. However, impaired STAT3 signaling plays a critical role in ER stress-induced disruption of leptin signaling (32). Taken together, CPT-1c and ceramide appear to antagonize leptin's anorectic actions through ER stress-independent processes. In addition, the responses of the pathway of AMP-kinase (AMPK)/acetyl-CoA carboxylase (ACC) to leptin are also not affected by CPT-1c and ceramide actions (Fig. S6), which is consistent with the proposed downstream positions of CPT-1 and ceramide metabolism in leptin's malonyl-CoA signaling pathway. Our results suggest that Bsx and NPY lie downstream in the pathway by which CPT-1c and ceramide metabolism mediate leptin anorectic signaling actions (Fig. S4). Consistent with this argument, it has been reported that ceramide can increase glutamate release via enhancing exocytosis (34) and glutamate can up-regulate NPY mRNA levels in CNS neurons (35). A number of the downstream metabolites of ceramide, such as sphingosine and sphigosine-1 phosphate, are implicated in signaling transduction pathways (29), so these metabolites might play roles in ceramide-mediated control of food intake and energy balance.

Finally, we address the specificity of the pharmacological approaches used in our studies. In the anorectic effects of cerulenin, the specific CPT-1c deletion would not block cerulenin-mediated feeding actions if cerulenin used nonspecific targets to reduce food intake. In the ceramide experiments, myriocin and the compound of ceramide analog produced the opposing feeding effects, which is most likely because of their opposing molecular actions on ceramide metabolism rather than other nonspecific effects.

In summary, we provide strong evidence in support of an important role for CPT-1c in leptin's Arc anorectic signaling pathways. CPT-1c may mediate malonyl-CoA's signaling aspect in leptin feeding actions by regulating ceramide de novo synthesis. Targeting CPT-1c and ceramide metabolism in the Arc may offer effective approaches to prevent overweight and development of obesity.

Methods

Following central infusions of the adenoviruses or different compounds, food intake and body weight were monitored. At designated time points, the animals were killed and brains were dissected; then, different biochemical assays were run. Detailed methods are described in the SI Methods.

Supplementary Material

Supporting Information:

Acknowledgments

We thank Prof. Jens Bruening and Dr. Dolors Serra for their critical advice and generous assistance in revising our manuscript, and Dr. Wendy Keung, Ms. Amy Barr, Mr. Ken Strynadka, and Mr. Thomas Panakkezhum for their critical technical assistance. These studies are funded mainly by a grant from the Canadian Diabetes Association and a fellowship of the Heart and Stroke Foundation of Canada (to S.G.). X.G. and D.W. acknowledge grants from the National Basic Research Program of China (973 Program 2011CB504004 and 2010CB945500); F.G.H., N.C., and P.C. acknowledge grants from Ministry of Education and Science, Spain (Grant SAF2007-61926 to F.G.H.), and from Instituto de Salud Carlos III (Grant CIBERobn CB06/03/0026 to F.G.H. and research contract to P.C.); T.H.M. acknowledges National Institutes of Health Grant DK19302; G.D.L. is a scientist of the Alberta Heritage Foundation for Medical Research; technical support was from the Cardiovascular Research Center (CVRC) and ABACUS Research Center in the University of Alberta.

Footnotes

The authors declare no conflict of interest.

*This Direct Submission article had a prearranged editor.

*Wood, et al. The Endocrine Society's 91st Annual Meeting, ENDO 09, June 10–13, 2009, Washington, DC.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1103267108/-/DCSupplemental.

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