malonyl-coenzyme-a and Weight-Loss

Fatty acid metabolism in the hypothalamus has recently been shown to regulate feeding. The selective estrogen receptor modulator tamoxifen (TMX) exerts a potent anorectic effect. Here, we show that the anorectic effect of TMX is associated with the accumulation of malonyl-CoA in the hypothalamus and inhibition of fatty acid synthase (FAS) expression specifically in the ventromedial nucleus of the hypothalamus (VMN). Furthermore, we demonstrate that FAS mRNA expression is physiologically regulated by fasting and refeeding in the VMN but not in other hypothalamic nuclei. Thus, the VMN appears to be the hypothalamic site where regulation of FAS and feeding converge. Supporting the potential clinical relevance of these observations, reanalysis of a primary breast cancer prevention study showed that obese women treated with TMX gained significantly less body weight over a 6-year period than obese women given placebo. The finding that TMX can modulate appetite through alterations in FAS expression and malonyl-CoA levels suggests a link between hypothalamic sex steroid receptors, fatty acid metabolism, and feeding behavior.

Topics: Animals; Anorexia; Body Weight; Energy Intake; Fatty Acid Synthases; Feeding Behavior; Malonyl Coenzyme A; Pro-Opiomelanocortin; Rats; Rats, Wistar; Tamoxifen; Ventromedial Hypothalamic Nucleus; Weight Loss

A relationship between free fatty acids, intramuscular triglycerides (TG(M)s), and insulin resistance is widely accepted. The intracellular level of malonyl-coenzyme A (CoA) was suggested to be the possible link. Acetyl-CoA carboxylase (ACC) is a key enzyme in fatty acid metabolism, catalyzing the synthesis of malonyl-CoA, a fatty acid acyl-chain elongation unit, from acetyl-CoA. We assessed ACC2 mRNA expression variations in skeletal muscle of subjects who have undergone biliopancreatic diversion (BPD) operation. BPD, in fact inducing a massive lipid malabsorption, leads to a reversion of insulin resistance.. Twelve obese women (BMI > 40 kg/m(2)) were enrolled in the study. Body composition, euglycemic-hyperinsulinemic clamp, and muscle biopsies for lipid analysis and reverse transcription-competitive polymerase chain reaction were performed before and 3 years after BPD.. The average weight loss was around 37%. A significant inverse linear relation was observed between glucose uptake and TG(M) (y = -5.62x - 142.82, R(2) = 0.50, p = 0.01). The reduced amount of ACC2 mRNA directly correlated with both TG(M) (y = 2.11x +69.85, R(2) = 0.70, p = 0.01) and fasting insulin (y = 1.49x + 57.17, R(2) = 0.69, p < 0.01) concentrations.. In conclusion, down-regulation of ACC2 mRNA, induced by the lowering of plasma insulin concentration, is related to improvement of insulin sensitivity. We hypothesize that reduced amount of malonyl-CoA, consequent to reduced ACC2 mRNA, enhancing fatty acid oxidation, causes lowering of the intramyocitic triglyceride depot.

Topics: Acetyl-CoA Carboxylase; Biliopancreatic Diversion; Biopsy; Body Composition; Fasting; Female; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Isoenzymes; Male; Malonyl Coenzyme A; Muscle, Skeletal; Obesity, Morbid; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Triglycerides; Weight Loss

Topics: Animals; Down-Regulation; Eating; Energy Metabolism; Humans; Hypothalamus; Liver; Malonyl Coenzyme A; Obesity; Oxidative Stress; Reactive Oxygen Species; Stearoyl-CoA Desaturase; Weight Loss

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.

Topics: 3T3 Cells; 4-Butyrolactone; Adenosine Triphosphate; Adipocytes; Animals; Carnitine O-Palmitoyltransferase; Diet; Energy Metabolism; Enzyme Inhibitors; Epoxy Compounds; Fatty Acid Synthases; Fatty Acids; Humans; Male; Malonyl Coenzyme A; Mice; Mice, Inbred C57BL; Obesity; Oxidation-Reduction; Tumor Cells, Cultured; Weight Loss

With the escalation of obesity-related disease, there is great interest in defining the mechanisms that control appetite and body weight. We have identified a link between anabolic energy metabolism and appetite control. Both systemic and intracerebroventricular treatment of mice with fatty acid synthase (FAS) inhibitors (cerulenin and a synthetic compound C75) led to inhibition of feeding and dramatic weight loss. C75 inhibited expression of the prophagic signal neuropeptide Y in the hypothalamus and acted in a leptin-independent manner that appears to be mediated by malonyl-coenzyme A. Thus, FAS may represent an important link in feeding regulation and may be a potential therapeutic target.

Topics: Acetyl-CoA Carboxylase; Animals; Appetite; Appetite Depressants; Cerulenin; Dose-Response Relationship, Drug; Eating; Enzyme Inhibitors; Fasting; Fatty Acid Synthases; Female; Hypothalamus; Injections, Intraventricular; Leptin; Liver; Male; Malonyl Coenzyme A; Mice; Mice, Inbred BALB C; Neurons; Neuropeptide Y; RNA, Messenger; Weight Loss

A multidisciplinary team may have discovered an important new weapon in the battle of the bulge. On page 2379 of this issue, the team reports that a molecule that is needed for fat synthesis in the body may play a key role in appetite signaling in the brain. Moreover, the investigators produced a synthetic inhibitor of this molecule that spurred a dramatic drop in appetite and weight in mice.

Topics: Animals; Appetite; Appetite Depressants; Brain; Enzyme Inhibitors; Fasting; Fatty Acid Synthases; Humans; Liver; Malonyl Coenzyme A; Mice; Neuropeptide Y; Obesity; RNA, Messenger; Weight Loss