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1.
Am J Physiol Regul Integr Comp Physiol ; 294(2): R352-61, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18056987

ABSTRACT

Inhibition of brain carnitine palmitoyl-transferase-1 (CPT-1) is reported to decrease food intake and body weight in rats. Yet, the fatty acid synthase (FAS) inhibitor and CPT-1 stimulator C75 produces hypophagia and weight loss when given to rodents intracerebroventricularly (icv). Thus roles and relative contributions of altered brain CPT-1 activity and fatty acid oxidation in these phenomena remain unclarified. We administered compounds that target FAS or CPT-1 to mice by single icv bolus and examined acute and prolonged effects on feeding and body weight. C75 decreased food intake rapidly and potently at all doses (1-56 nmol) and dose dependently inhibited intake on day 1. Dose-dependent weight loss on day 1 persisted through 4 days of postinjection monitoring. The FAS inhibitor cerulenin produced dose-dependent (560 nmol) hypophagia for 1 day, weight loss for 2 days, and weight regain to vehicle control by day 3. The CPT-1 inhibitor etomoxir (32, 320 nmol) did not alter overall day 1 feeding. However, etomoxir attenuated the hypophagia produced by C75, indicating that CPT-1 stimulation is important for C75's effect. A novel compound, C89b, was characterized in vitro as a selective stimulator of CPT-1 that does not affect fatty acid synthesis. C89b (100, 320 nmol) decreased feeding in mice for 3 days and produced persistent weight loss for 6 days without producing conditioned taste aversion. Similarly, intraperitoneal administration decreased feeding and body weight without producing conditioned taste aversion. These results suggest a role for brain CPT-1 in the regulation of energy balance and implicate CPT-1 stimulation as a pharmacological approach to weight loss.


Subject(s)
Body Weight/physiology , Carnitine O-Palmitoyltransferase/metabolism , Eating/physiology , Hypothalamus/enzymology , 4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/pharmacology , Animals , Body Weight/drug effects , Cell Line, Tumor , Dose-Response Relationship, Drug , Eating/drug effects , Energy Metabolism/drug effects , Energy Metabolism/physiology , Enzyme Activation/drug effects , Enzyme Activation/physiology , Enzyme Inhibitors/pharmacology , Epoxy Compounds/pharmacology , Fatty Acid Synthesis Inhibitors/metabolism , Fatty Acids/metabolism , Female , Hypothalamus/cytology , Hypothalamus/drug effects , Injections, Intraventricular , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Neurons/cytology , Neurons/drug effects , Neurons/enzymology , Pregnancy , Rats
2.
Cancer Res ; 67(7): 2964-71, 2007 Apr 01.
Article in English | MEDLINE | ID: mdl-17409402

ABSTRACT

Fatty acid synthase (FAS), the enzyme responsible for the de novo synthesis of fatty acids, is highly expressed in ovarian cancers and most common human carcinomas. Inhibition of FAS and activation of AMP-activated protein kinase (AMPK) have been shown to be cytotoxic to human cancer cells in vitro and in vivo. In this report, we explore the cytotoxic mechanism of action of FAS inhibition and show that C93, a synthetic FAS inhibitor, increases the AMP/ATP ratio, activating AMPK in SKOV3 human ovarian cancer cells, which leads to cytotoxicity. As a physiologic consequence of AMPK activation, acetyl-CoA carboxylase (ACC), the rate-limiting enzyme of fatty acid synthesis, was phosphorylated and inhibited whereas glucose oxidation was increased. Despite these attempts to conserve energy, the AMP/ATP ratio increased with worsening cellular redox status. Pretreatment of SKOV3 cells with compound C, an AMPK inhibitor, substantially rescued the cells from C93 cytotoxicity, indicating its dependence on AMPK activation. 5-(Tetradecyloxy)-2-furoic acid, an ACC inhibitor, did not activate AMPK despite inhibiting fatty acid synthesis pathway activity and was not significantly cytotoxic to SKOV3 cells. This indicates that substrate accumulation from FAS inhibition triggering AMPK activation, not end-product depletion of fatty acids, is likely responsible for AMPK activation. C93 also exhibited significant antitumor activity and apoptosis against SKOV3 xenografts in athymic mice without significant weight loss or cytotoxicity to proliferating cellular compartments such as bone marrow, gastrointestinal tract, or skin. Thus, pharmacologic FAS inhibition selectively activates AMPK in ovarian cancer cells, inducing cytotoxicity while sparing most normal human tissues from the pleiotropic effects of AMPK activation.


Subject(s)
Enzyme Inhibitors/pharmacology , Fatty Acid Synthases/antagonists & inhibitors , Multienzyme Complexes/metabolism , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/enzymology , Protein Serine-Threonine Kinases/metabolism , AMP-Activated Protein Kinases , Amino Acid Sequence , Animals , Cell Line, Tumor , Enzyme Activation , Fatty Acids/metabolism , Female , Furans/pharmacology , Glucose/metabolism , Humans , Mice , Mice, Inbred BALB C , Molecular Sequence Data , NAD/metabolism , Ovarian Neoplasms/metabolism , Oxidation-Reduction , Xenograft Model Antitumor Assays
3.
J Med Chem ; 48(4): 946-61, 2005 Feb 24.
Article in English | MEDLINE | ID: mdl-15715465

ABSTRACT

Fatty acid synthase (FAS) catalyzes the synthesis of palmitate from the sequential condensation of an acetyl primer with two carbon units added from malonyl-CoA. Inhibition of the beta-ketoacyl synthase domain of mammalian FAS leads to selective cytotoxicity to various cancer cell lines in vitro and in vivo. Also, inhibitors of FAS can cause reduced food intake and body weight in mice. Naturally occurring thiolactomycin (TLM) was used as a template to develop a new class of type I FAS inhibitors. Using a flexible synthesis, families of TLM structural analogues were obtained that possess selective FAS activity and display anticancer and weight loss effects. Compounds 13a and 13d inhibit pure FAS (ZR-75-1 breast cancer, IC(50) = 50 microg/mL), and display effective weight loss in BalbC mice (>5%). Another subclass of TLM derivatives (23b-d, 31a) exhibits FAS activity (IC(50) = 5%), and is cytotoxic to cancer cells (IC(50) < 38 microg/mL). Finally, a third subclass (16b, 29, 30) is also active against FAS (IC(50) =

Subject(s)
Anti-Obesity Agents/chemical synthesis , Antineoplastic Agents/chemical synthesis , Fatty Acid Synthases/antagonists & inhibitors , Thiophenes/chemical synthesis , Animals , Anti-Obesity Agents/chemistry , Anti-Obesity Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Body Weight/drug effects , Cell Line, Tumor , Drug Screening Assays, Antitumor , Fatty Acid Synthases/chemistry , Humans , Mice , Mice, Inbred BALB C , Models, Molecular , Stereoisomerism , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacology
4.
Endocrinology ; 146(1): 486-93, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15498887

ABSTRACT

C75, a synthetic inhibitor of fatty acid synthase (FAS), causes anorexia and profound weight loss in lean and genetically obese mice. C75 also acts as a stimulator of carnitine palmitoyltransferase-1 to induce fatty acid oxidation. To approximate human obesity, we used a 2-wk C75 treatment model for diet-induced obese (DIO) mice to investigate the central and peripheral effects of C75 on gene expression. C75 treatment decreased food intake, increased energy expenditure, and reduced body weight more effectively in DIO than in lean mice. Analysis of the gene expression changes in hypothalamus demonstrated that the reduced food intake in C75-treated DIO mice might be mediated by inhibition of orexigenic neuropeptide expression and induction of anorexigenic neuropeptide expression. Gene expression changes in peripheral tissues indicated that C75 increased energy expenditure by the induction of genes involved in fatty acid oxidation. C75 also inhibited the expression of genes in peripheral tissues responsible for fatty acid synthesis and accumulation. The patterns of the changes in central and peripheral gene expression that occur with C75 treatment provide mechanisms to explain the reduced food intake and increased energy expenditure observed with C75.


Subject(s)
4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/pharmacology , Eating/drug effects , Energy Metabolism/drug effects , Gene Expression/drug effects , Obesity/genetics , Animals , Body Weight/drug effects , Diet , Eating/genetics , Energy Metabolism/genetics , Fatty Acid Synthases/antagonists & inhibitors , Fatty Acids/metabolism , Hypothalamus/metabolism , Male , Mice , Mice, Inbred C57BL , Neuropeptides/genetics , Neuropeptides/metabolism , Obesity/etiology , Obesity/pathology , Obesity/physiopathology , Oxidation-Reduction/drug effects , Thinness/genetics , Thinness/metabolism , Thinness/pathology
5.
Am J Physiol Endocrinol Metab ; 287(1): E97-E104, 2004 Jul.
Article in English | MEDLINE | ID: mdl-14736702

ABSTRACT

Obesity and its attendant disorders, such as type 2 diabetes, are global health problems. We previously reported that C75, an inhibitor of fatty acid synthase (FAS) and stimulator of carnitine palmitoyltransferase I (CPT I), caused anorexia and profound weight loss in lean and genetically obese mice. To approximate human obesity, we utilized a chronic C75 treatment model for diet-induced obese (DIO) mice. Chronic C75 treatment decreased food consumption and increased energy expenditure due to increased fatty acid oxidation in both DIO and lean mice. There was a substantial loss of adipose tissue and resolution of hepatic steatosis in C75-treated DIO mice. Analysis of changes in the expression of hypothalamic neuropeptides demonstrated that the reduced food consumption in C75-treated DIO mice was accompanied by an increase in cocaine and amphetamine-related transcript expression but not by changes in neuropeptide Y such as seen with acute C75 treatment of lean mice. Inhibition of FAS and stimulation of CPT I provide a means to achieve stable, sustained weight loss in DIO mice.


Subject(s)
4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/administration & dosage , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Diet/adverse effects , Eating/drug effects , Fatty Acids/metabolism , Obesity/drug therapy , Obesity/metabolism , Animals , Body Weight/drug effects , Carnitine O-Palmitoyltransferase/drug effects , Chronic Disease , Fatty Acid Synthases/antagonists & inhibitors , Fatty Liver/etiology , Fatty Liver/metabolism , Fatty Liver/prevention & control , Male , Mice , Mice, Inbred C57BL , Obesity/complications , Obesity/etiology , Oxidation-Reduction , Treatment Outcome
6.
J Biol Chem ; 279(5): 3817-27, 2004 Jan 30.
Article in English | MEDLINE | ID: mdl-14615481

ABSTRACT

C75, a synthetic inhibitor of fatty acid synthase (FAS), is hypothesized to alter the metabolism of neurons in the hypothalamus that regulate feeding behavior to contribute to the decreased food intake and profound weight loss seen with C75 treatment. In the present study, we characterize the suitability of primary cultures of cortical neurons for studies designed to investigate the consequences of C75 treatment and the alteration of fatty acid metabolism in neurons. We demonstrate that in primary cortical neurons, C75 inhibits FAS activity and stimulates carnitine palmitoyltransferase-1 (CPT-1), consistent with its effects in peripheral tissues. C75 alters neuronal ATP levels and AMP-activated protein kinase (AMPK) activity. Neuronal ATP levels are affected in a biphasic manner with C75 treatment, decreasing initially, followed by a prolonged increase above control levels. Cerulenin, a FAS inhibitor, causes a similar biphasic change in ATP levels, although levels do not exceed control. C75 and cerulenin modulate AMPK phosphorylation and activity. TOFA, an inhibitor of acetyl-CoA carboxylase, increases ATP levels, but does not affect AMPK activity. Several downstream pathways are affected by C75 treatment, including glucose metabolism and acetyl-CoA carboxylase (ACC) phosphorylation. These data demonstrate that C75 modulates the levels of energy intermediates, thus, affecting the energy sensor AMPK. Similar effects in hypothalamic neurons could form the basis for the effects of C75 on feeding behavior.


Subject(s)
4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/pharmacology , Fatty Acid Synthases/antagonists & inhibitors , Multienzyme Complexes/metabolism , Neurons/metabolism , Protein Serine-Threonine Kinases/metabolism , AMP-Activated Protein Kinases , Acetyl-CoA Carboxylase/metabolism , Adenosine Triphosphate/metabolism , Animals , Blotting, Western , Carnitine O-Palmitoyltransferase/metabolism , Cell Survival , Cells, Cultured , Chromatography, High Pressure Liquid , Electrophysiology , Fatty Acids/metabolism , Glucose/metabolism , Hypothalamus/metabolism , Hypothalamus/pathology , Immunohistochemistry , Models, Biological , Neurons/drug effects , Phosphorylation , Rats , Rats, Sprague-Dawley , Time Factors
7.
Proc Natl Acad Sci U S A ; 99(14): 9498-502, 2002 Jul 09.
Article in English | MEDLINE | ID: mdl-12060712

ABSTRACT

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 alpha-methylene-gamma-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.


Subject(s)
4-Butyrolactone/analogs & derivatives , 4-Butyrolactone/pharmacology , Energy Metabolism/drug effects , Fatty Acids/metabolism , Obesity/drug therapy , 3T3 Cells , Adenosine Triphosphate/metabolism , Adipocytes/drug effects , Adipocytes/metabolism , Animals , Carnitine O-Palmitoyltransferase/antagonists & inhibitors , Diet/adverse effects , Enzyme Inhibitors/pharmacology , Epoxy Compounds/pharmacology , Fatty Acid Synthases/antagonists & inhibitors , Humans , Male , Malonyl Coenzyme A/pharmacology , Mice , Mice, Inbred C57BL , Obesity/etiology , Oxidation-Reduction , Tumor Cells, Cultured , Weight Loss/drug effects
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