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Proc Natl Acad Sci U S A. 2002 Jul 9; 99(14): 9498–9502.
Published online 2002 Jun 11. doi:  10.1073/pnas.132128899
PMCID: PMC123169
Medical Sciences

C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity


C75, a known inhibitor of fatty acid synthase is postulated to cause significant weight loss through decreased hypothalamic neuropeptide Y (NPY) production. Peripherally, C75, an α-methylene-γ-butyrolactone, reduces adipose tissue and fatty liver, despite high levels of malonyl-CoA. To investigate this paradox, we studied the effect of C75 on fatty acid oxidation and energy production in diet-induced obese (DIO) mice and cellular models. Whole-animal calorimetry showed that C75-treated DIO mice had a 50% greater weight loss, and a 32.9% increased production of energy because of fatty acid oxidation, compared with paired-fed controls. Etomoxir, an inhibitor of carnitine O-palmitoyltransferase-1 (CPT-1), reversed the increased energy expenditure in DIO mice by inhibiting fatty acid oxidation. C75 treatment of rodent adipocytes and hepatocytes and human breast cancer cells increased fatty acid oxidation and ATP levels by increasing CPT-1 activity, even in the presence of elevated concentrations of malonyl-CoA. Studies in human cancer cells showed that C75 competed with malonyl-CoA, as measured by CPT-1 activity assays. Thus, C75 acts both centrally to reduce food intake and peripherally to increase fatty acid oxidation, leading to rapid and profound weight loss, loss of adipose mass, and resolution of fatty liver. The pharmacological stimulation of CPT-1 activity is a novel finding. The dual action of the C75 class of compounds as fatty acid synthase inhibitors and CPT-1 agonists has therapeutic implications in the treatment of obesity and type II diabetes.

C75 and its family of α-methylene-γ-butyrolactones are known inhibitors of fatty acid synthase (FAS) (1). Treatment of mice with C75 alters the expression of hypothalamic neuropeptides, leading to reversible inanition and weight loss (24). In addition to its central action, C75 treatment caused changes in peripheral tissues, including inhibition of hepatic fatty acid synthesis, reduction of fatty liver, diminished adipose tissue mass, and high levels of malonyl-CoA (2, 4, 5).

Malonyl-CoA, in addition to its role as a substrate for FAS, is pivotal to energy regulation through its reversible inhibition of O-carnitine palmitoyltransferase-1 (CPT-1) (6). CPT-1 catalyzes the esterification of long-chain acyl-CoAs to l-carnitine for transport into mitochondria for fatty acid oxidation. During energy excess, the increased malonyl-CoA generated for fatty acid synthesis inhibits CPT-1 activity, preventing the oxidation of newly formed fatty acids bound for energy storage. During starvation, malonyl-CoA levels fall to permit the oxidation of fatty acids for energy. When FAS is pharmacologically inhibited, malonyl-CoA levels abruptly rise (2, 5).

Taken together, the peripheral effects of C75 gave rise to a paradox. How could there be a selective reduction in adipocyte mass and fatty liver in the setting of elevated levels of malonyl-CoA as a result of FAS inhibition? We hypothesized that C75 might have additional effects on fatty acid oxidation and CPT-1 activity.

Specifically, our study addressed this potential action of C75 through metabolic investigations of C75 on fatty acid oxidation in diet-induced obese (DIO) mice and in cellular models. It is demonstrated that C75 has a dual role as a malonyl-CoA “mimetic”—a FAS inhibitor and a CPT-1 agonist leading to central and peripheral effects in DIO mice. In DIO mice, we found that C75 reduced food consumption and increased both fatty acid oxidation and energy expenditure, resulting in sustained weight loss. Cellular studies revealed that C75 effects on fatty acid oxidation and energy metabolism were mediated through the stimulation of CPT-1 activity, even in the presence of inhibitory concentrations of malonyl-CoA.

Experimental Procedures

DIO Mouse Model.

Twelve-week-old DIO C57BL6J male mice were obtained from The Jackson Laboratory. Mice were fed a synthetic diet composed of 60% calories from fat (D12492i, Research Diets, New Brunswick, NJ ) postweaning through the experimental procedures. Mice were maintained in a 12-h light-dark cycle at 25°C. After a 1-week acclimatization, animals were treated as described. C75 and etomoxir were dissolved in RPMI medium 1640 and injected i.p at doses indicated.

Whole-Animal Calorimetry.

Oxygen consumption and CO2 production were measured in up to four mice simultaneously by using an indirect calorimeter (Oxymax Equal Flow System, Columbus Instruments, Columbus, OH). Measurements were recorded every 15 min over the entire course of the experiments. The respiratory exchange ratio (RER) was calculated by the Oxymax software version 5.9. RER is defined as the ratio of CO2 production (VCO2) to O2 consumption (VO2) at any given time irrespective of whether equilibrium was reached. The Oxymax software, using the following equations, calculated heat: Calorific value = 3.815 + 1.232 × RER. Heat (H) = Calorific value × VO2 × 0.001.

Measurement of Fatty Acid Oxidation.

Fatty acid oxidation was measured as described (7). For MCF-7 cells (American Type Culture Collection) and primary hepatocytes (Clonetics, East Rutherford, NJ), 1 × 106 cells were plated in T-25 flasks in triplicate and incubated overnight at 37°C. For 3T3-L1 adipocytes, experiments commenced at 6–9 days postdifferentiation with ≈5 × 106 cells per flask. Drugs were added as indicated diluted from 5 mg/ml stock in DMSO. After 2 h, medium with drugs was removed and cells were preincubated for 30 min with 1.5 ml of the following buffer: 114 mM NaCl/4.7 mM KCl/1.2 mM KH2PO4/1.2 mM MgSO4/11 mM glucose. After preincubation, 200 μl of assay buffer was added containing 114 mM NaCl, 4.7 mM KCl, 1.2 mM KH2PO4, 1.2 mM MgSO4, 11 mM glucose, 2.5 mM palmitate [containing 10 μCi (1 Ci = 37 GBq of [1-14C]palmitate] bound to albumin, and 0.8 mM l-carnitine, and the cells were incubated at 37°C for 2 h. After the incubation, 400 μl of benzethonium hydrochloride was added to the center well to collect released 14CO2. Immediately, the reaction was stopped by adding 500 μl of 7% perchloric acid to the cells. The flasks with wells were then incubated for 2 h at 37°C, after which the benzethonium hydrochloride was removed and 14C was quantitated. Blanks were prepared by adding 500 μl of 7% perchloric acid to the cells before the incubation with the assay buffer for 2 h.

Measurement of CPT-1 Activity.

CPT-1 was measured by using digitonin-treated permeabilized cells (8). Adipocytes (3T3-L1) were studied 6–9 days postdifferentiation at 4–5 × 105 cells per well. For MCF-7 cells and primary hepatocytes, 1 × 106 cells were plated in DMEM with 10% FBS in six-well plates in triplicate. After overnight incubation, drugs and vehicle controls were added as indicated. After 2 h, the medium was removed, and cells were washed with PBS and then incubated with 700 μl of assay medium consisting of 50 mM imidazole, 70 mM KCl, 80 mM sucrose, 1 mM EGTA, 2 mM MgCl2, 1 mM DTT, 1 mM KCN, 1 mM ATP, 0.1% fatty acid-free BSA, 70 μM palmitoyl-CoA, 0.25 μCi of l-[methyl-14C]-carnitine, and 40 μg of digitonin with or without 20 μM malonyl-CoA. C75 was added as specified for each experiment. After incubation for 6 min at 37°C, the reaction was stopped by the addition of 500 μl of ice-cold 4 M perchloric acid. Cells were then harvested and centrifuged at 13,000 × g for 5 min. The pellet was washed with 500 μl of ice-cold 2 mM perchloric acid and centrifuged again. The resulting pellet was resuspended in 800 μl of deionized H2O and extracted with 400 μl of butanol. The 14C in the butanol phase was quantified and represents the acylcarnitine derivative.

Measurement of ATP.

Adipocytes (3T3-L1) were plated at 1 × 105 per well in 96-well plates. ATP levels were measured in the linear range of detection, by using the ATP Bioluminescence Kit CLS II (Roche, Basel) following the manufacturer's protocol, and were read by a Perkin–Elmer Wallac Victor2 1420 luminometer (Wellesley, MA).

Miscellaneous Methods and Chemicals.

MCF-7 cells were obtained from the American Type Culture Collection (HTB-22). Preadipocytes (3T3-L-1) obtained from M. Daniel Lane, at Johns Hopkins University, were cultured and differentiated as described (9). Primary rat hepatocytes were obtained from Clonetics. C75 was synthesized by C. Townsend and J. McFadden of the Department of Chemistry at the Johns Hopkins University. Etomoxir was purchased from H. P. O. Wolfe, Projekt-Entwicklung, Konstanz, Germany. For animal studies etomoxir and C75 were administered i.p. in RPMI medium 1640 (GIBCO/BRL, and Life Technologies, Rockville, MD). For cellular studies, etomoxir, and C75 were added at the designated concentrations from 5 mg/ml stocks in DMSO. DMSO concentrations in the final cell culture medium never exceeded 0.1%. [1-14C]Palmitate, and l-[methyl-14C]-carnitine were obtained from Amersham Pharmacia Biotech, Piscataway, NJ.

Statistical Analysis.

All data are presented as means ± standard error of the mean from multiple determinations. Data were analyzed by paired or unpaired t tests where applicable using PRISM 3.0 (GraphPad Software, San Diego).


C75 Treatment Resulted in Sustained Weight Loss in DIO Mice.

Prior studies with C75 were conducted with lean or genetically obese animals treated with doses of C75 that largely prevented food consumption, producing dramatic weight loss. To more closely approximate a paradigm for human obesity, we chose DIO mice raised from weaning on a high-fat diet and designed a C75 treatment protocol to induce sustained and stable weight loss. Four DIO mice were treated initially with a vehicle control, or C75, at 20 mg/kg, i.p., followed by maintenance doses of 10–15 mg/kg every 48 h (Fig. (Fig.11A). All mice had access to a high-fat diet, and water ad libitum. After the initial 16% loss of body mass within the first 2 days of C75 treatment, weight loss stabilized at 20–22% of initial body mass over the course of the experiment, whereas the vehicle controls gained about 1% of body mass. Fig. Fig.11B displays the food consumption of C75-treated mice. Food consumption was reduced for 24 h after each dose, and increased during the subsequent 24 h. C75-treated mice ate an average 1.83 ± 0.29 g/day, compared with 2.72 ± 0.21 g/day for controls (not shown). Despite the cyclical variability in food consumption, stable weight was maintained and no tachyphylaxsis to the C75 was observed.

Figure 1
C75 caused sustained weight loss and reduced food consumption in DIO mice. (A) Three mice were treated on day 0 with C75 (20 mg/kg, i.p.; ▴). Subsequent doses were administered as follows: 15 mg/kg, day 2; 10 mg/kg, day ...

C75-Treated Mice Had Increased Caloric Production Compared with Pair-Fed Controls.

Using a dose of C75 (15 mg/kg) that moderated food intake, we performed whole-animal calorimetry to study energy production in C75-treated mice and pair-fed controls. Four DIO mice were maintained in an Oxymax whole mouse calorimeter with a diet that derived 60% of its calories from fat, and water ad libitum. Heat production (kcal/h) and respiratory exchange ratio (RER) were recorded every 15 min for each animal. After a 24-h adaptation period in the Oxymax, two mice received i.p. C75 (15 mg/kg). After 20 h, the C75-treated mice lost 4.4% of their body mass, and ate an average of 1.9 g each. The two remaining mice were each pair-fed with 1.9 g, and lost 2.0% of their body mass after 20 h. Calorimetric analysis (Fig. (Fig.22A) demonstrated that C75 increased energy expenditure (kcal/h) by 32.9%, compared with pair-fed animals (P < 0.0001, unpaired t test). Moreover, RER was unchanged between C75-treated (0.75 ± 0.02,) and pair-fed animals (0.76 ± 0.03), indicating that predominantly fatty acid was oxidized for fuel (Fig. (Fig.22B). Taken together, these data demonstrate that the C75-induced increase in energy production was responsible for most of the weight loss, and that the increased energy expenditure seen with C75 treatment was because of increased fatty acid oxidation.

Figure 2
C75-treated mice expended more energy than pair-fed controls by increasing fatty acid oxidation. (A) C75-treated mice maintained an average caloric expenditure of 0.79 kcal/h (red) compared with 0.53 kcal/h (black) in the pair-fed mice ...

Inhibition of Fatty Acid Oxidation Blocked the Increased Energy Expenditure and the Enhanced Weight Loss in C75-Treated Mice.

If the increased energy expenditure with C75 was because of increased fatty acid oxidation, etomoxir, an irreversible CPT-1 inhibitor (10) should block the C75-induced increase in energy expenditure in vivo. For each dose of etomoxir tested, mice were maintained in the calorimeter and treated with either C75 (15 mg/kg, i.p.) (two mice), or C75 (15 mg/kg, i.p.) and etomoxir (20, 15, 10, or 5 mg/kg, i.p.) (two mice per dose). In the experiments illustrated in Fig. Fig.22 B and C, all animals were treated initially with C75 at time 0. After 2 h, two mice were treated with etomoxir, and two received vehicle alone. RER and energy expenditure were recorded.

Heat production was similar between all groups of C75-treated animals during the first 24 h of the experiment (Fig. (Fig.22C). A statistically significant dose-dependent reduction in heat production occurred 2 hours after etomoxir treatment, indicating that the increased energy expenditure seen during C75 could be blocked by the inhibition of fatty acid oxidation. Fig. Fig.22D shows the average reduction in heat computed from the initial dose of C75 until the end of the experiment. There were no consistent changes in RER among controls or etomoxir doses, as the average RER remained between 0.75 and 0.78 throughout the course of the experiments (data not shown). These data further corroborate the pair-feeding studies indicating that increased fatty acid oxidation by C75 was the mechanism responsible for the weight loss seen above that caused by decreased food consumption.

C75 Increases Fatty Acid Oxidation and ATP Levels by Enhancing CPT-1 Activity.

Because the liver is the site of substantial fatty acid oxidation, and DIO mice preferentially lost adipose tissue with C75 (4), mouse 3T3-L1 adipocytes and primary rat hepatocytes were used to further address the mechanism underpinning the observation that C75 stimulated fatty acid oxidation (Fig. (Fig.3).3). In mouse adipocytes, C75 dramatically increased fatty acid oxidation in a concentration-dependent manner, within 2 h. At concentrations of 30 and 40 μg/ml, fatty acid oxidation increased by 203% (P < 0.02) and 358% (P < 0.003), respectively (Fig. (Fig.33A). Similarly, ATP levels increased after 2 h of C75 [40 μg/ml] up to 420% of control (P < 0.002) (Fig. (Fig.33B).

Figure 3
C75 increased fatty acid oxidation, ATP production, and CPT-1 activity in mouse 3T3-L1 adipocytes. (A) C75 caused a concentration-dependent increase in fatty acid oxidation. At doses of 30 and 40 μg/ml, C75 significantly increased fatty ...

Because in vivo inhibition of CPT-1 by etomoxir reversed the C75 increase in energy production, we hypothesized that C75 may directly enhance CPT-1 activity. In adipocytes (Fig. (Fig.33C), C75 (20 μg/ml) increased CPT-1 activity (P < 0.0001) by 213%, whereas malonyl-CoA inhibited CPT-1 activity to 46% of control. In primary rat hepatocytes, the C75 effect was greatest (Fig. (Fig.4).4). C75 induced a dose-dependent increase in fatty acid oxidation to approximately 800% of control (Fig. (Fig.44A; P < 0.0001), and an increase in CPT-1 activity to 475% of control (Fig. (Fig.44B; P < 0.0001). Thus, C75 may directly activate CPT-1 to increase fatty acid oxidation, increase ATP levels, and thus increase energy production.

Figure 4
C75 increased fatty acid oxidation and CPT-1 activity in primary rat hepatocytes. (Left) C75 treatment caused a dose-dependent increase in fatty acid oxidation up to 839% of control at 40 μg/ml (P < 0.0001, unpaired t test, ...

C75 Increased Human CPT-1 Activity in the Presence of Inhibitory Concentrations of Malonyl-CoA.

During CPT-1 activity assays, C75 stimulation occurred in permeabilized cells that were essentially devoid of malonyl-CoA. To study the interplay between malonyl-CoA and C75, we used the MCF-7 human breast cancer cell line that has served as our model system in studying the biochemical effects of C75 (11). Similar to the results obtained in adipocytes and hepatocytes, C75 caused a dose-dependent increase in CPT-1 activity (166% at 20 μg/ml) in MCF-7 cells, whereas malonyl-CoA (20 μM) inhibited CPT-1 activity, as expected (Fig. (Fig.55A). When malonyl-CoA (20 μM) was added along with C75 in the incubation buffer, the stimulation of CPT-1 seen with C75 treatment alone persisted (152% at 20 μg/ml). Thus, C75 increased CPT-1 activity, even in the presence of concentrations of malonyl-CoA that would be inhibitory. An immunoblot of MCF-7 cells with polyclonal anti-CPT-1 liver isoform antibody showed no changes in CPT-1 protein levels with or without a 2-h incubation of cells with C75 at 10 μg/ml (data not shown).

Figure 5
C75 increased CPT-1 activity in the presence of inhibitory concentrations of malonyl-CoA and is a competitive CPT-1 agonist. (A) C75 increased CPT-1 activity up to 166% of control at 20 μg/ml (P = 0.0027, unpaired t test), whereas ...

Since C75 is a slow-binding and likely irreversible inhibitor of FAS (1), we wished to determine whether the interaction between C75 and CPT-1 was also irreversible. MCF-7 cells were pretreated with C75 for 2 h, at which time C75 was removed from the assay buffer (middle bar of Fig. Fig.55B). Under these conditions, C75 increased CPT-1 activity to 150% of control similar to that achieved when C75 was continually present in the assay buffer. When duplicate wells were pretreated with C75, after which C75 was replaced with malonyl-CoA in the assay buffer (Fig. (Fig.55B, right bar), CPT-1 activity was significantly reduced to approximately 50% of control. Thus, the interaction between C75 and CPT-1 is likely to be noncovalent, because malonyl-CoA rapidly reversed the stimulatory effect of C75. Without C75 pretreatment, malonyl-CoA alone reduced CPT-1 activity to 25% (left bar). Thus, C75 appears to act as a CPT-1 agonist, preventing malonyl-CoA-mediated inhibition of CPT-1, thereby increasing fatty acid oxidation.


In this study, we describe a peripheral mechanism of action for the dramatic weight loss induced by C75 treatment. A mouse model of diet-induced obesity was used in these studies, as this model more closely represents human obesity than does one with lean or genetically altered animals. Chronic C75 treatment led to sustained, stable weight loss in these DIO mice of about 20% of body mass, with a moderate reduction of food intake. Weight loss was maintained on stable doses of C75, indicating no tachyphylaxsis to this compound. Moreover, reduced food consumption in the setting of a high-fat diet indicated that C75, a FAS inhibitor, was able to mediate its effects despite chronic high levels of dietary fat.

As reported in recent descriptive studies that used a paired-feeding paradigm in DIO mice using doses of C75 that resulted in moderately reduced food intake, it became apparent that the central anorexigenic mechanism proposed for C75 action accounted for only about half of the weight loss achieved (4). Whole-animal calorimetry performed here demonstrated that C75-treated mice actually had increased energy expenditure compared with pair-fed controls. Moreover, the C75-treated animals maintained an RER measurement of 0.7, indicating that fatty acid oxidation was likely responsible for the increased energy production.

Previous studies provided evidence to support the hypothesis that C75 acts centrally to reduce food intake by alterations in the level of hypothalamic neuropeptide Y levels and other hypothalamic peptides, leading to decreased appetite (2, 3). Although this central mechanism explained the reduced food intake, it could not account for the preferential reduction in adipose mass (4) and fatty liver (2) in the setting of increased malonyl-CoA levels following FAS inhibition.

To further probe the mechanism responsible for both increased fatty acid oxidation and increased energy expenditure, DIO mice were first treated with C75 followed by the administration of etomoxir, an inhibitor of CPT-1 and thus fatty acid oxidation. If C75 increased energy production through enhanced fatty acid oxidation, etomoxir should reverse this effect. Indeed, etomoxir reduced the C75-induced energy expenditure in vivo. These data further substantiated a peripheral mechanism linking C75 treatment with increased fatty acid oxidation, increased energy production, and weight loss through increased fatty acid oxidation.

In vitro studies using primary culture and cell line models were initiated to probe the biochemical mechanism of C75 on fatty acid oxidation, energy (ATP) production, and CPT-1 activity. In prior studies that used MCF-7 human carcinoma cells to investigate the actions of cerulenin, a natural product FAS inhibitor (12), cerulenin treatment increased malonyl-CoA and decreased fatty acid oxidation (11). Since cerulenin had no effect on CPT-1 activity, the reduction in fatty acid oxidation was likely because of malonyl-CoA inhibition of CPT-1 (11). Although it is an FAS inhibitor, C75 paradoxically increased fatty acid oxidation, ATP levels, and CPT-1 activity in both rodent and human cell lines. Moreover, C75 stimulated CPT-1 activity in the presence of inhibitory concentrations of malonyl-CoA. Although more studies are needed to confirm the nature of the interaction between C75 and CPT-1, both C75 and malonyl-CoA contain dicarbonyl groups that have been shown to be required for the binding of malonyl-CoA and other compounds to CPT-1 (13). Moreover, the amphipathic nature of C75 may account for the stimulation of CPT-1 activity because palmitoyl-CoA, a CPT-1 substrate that is similarly amphipathic, also activates the enzyme, and in excess, can reverse malonyl-CoA inhibition (14). Interestingly, cerulenin, a natural product inhibitor of FAS, has only a single dicarbonyl group in its cyclized form, is not amphipathic, and in contrast to C75, does not increase CPT-1 activity (11, 12).

Thus, we propose a second mechanism of action for C75 that is outlined in Fig. Fig.6.6. In the central nervous system (CNS), C75 inhibits FAS, leading to changes in neuropeptide expression that result in an anorexigenic signal. In the periphery, C75 increases CPT-1 activity, fatty acid oxidation, and energy production, leading to selective reduction of adipose tissue, liver fat, and weight loss. It is unlikely that this peripheral mechanism plays a role in the CNS, as neurons are unable to efficiently oxidize fatty acids (15).

Figure 6
Proposed model for central and peripheral C75 mechanisms of action. Centrally, C75 alters orexigenic and anorexigenic peptides, leading to a net reduction in food consumption. In the peripheral organs such as liver and adipose tissue, C75 increases CPT-1 ...

In addition to delineating a novel mechanism of action of C75, these data describe a pharmacological agonist of CPT-1 and identify CPT-1 as a therapeutic target for obesity and type II diabetes. Recent studies have elucidated the binding site of malonyl-CoA on CPT-1 (1618). It is likely that new malonyl-CoA mimetic structures will be identified enabling specific targeting of the malonyl-CoA binding site on CPT-1 without affecting FAS activity. Thus, it may be possible to specifically target either the central or the peripheral pathway pharmacologically, and modulate weight loss based on appetite control or energy expenditure.


We thank Tim Moran, Susan Aja, Albert H. Owens, Jr., and the FAS Working Group for critical review of this manuscript. We also thank Gebretateos Woldegeorgis for the gift of the anti-CPT-1 antibodies. This work was supported by grants from FASgen, Inc., and National Institutes of Health grants from the National Institute of Neurological Disorders and Stroke and the National Institute on Deafness and Other Communication Disorders (to G.V.R.), National Cancer Institute Grant RO1 CA87850-02 (to F.P.K.), and National Institute of Neurological Disorders and Stroke Grant F32 (to L.E.L.). Under a license agreement between FASgen, Inc., and The Johns Hopkins University, J.N.T., L.E.L., G.V.R., and F.P.K. are entitled to a share in royalty received by the University on sales of products described in this article. F.P.K. owns and G.V.R. has an interest in FASgen, Inc., stock, which is subject to certain restrictions under university policy. The Johns Hopkins University, in accordance with its conflict of interest policies, is managing the terms of this arrangement.


C75an α-methylene-γ-butyrolactone
DIOdiet-induced obese
CPT-1O-carnitine palmitoyltransferase-1
FASfatty acid synthase
RERrespiratory exchange ratio


This paper was submitted directly (Track II) to the PNAS office.

See commentary on page 9096.


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