cerulenin and Obesity

Although metabolites and energy balance have long been known to play roles in the regulation of food intake, the potential role of fatty acid metabolism in this process has been considered only recently. Fatty acid synthase (FAS) catalyzes the condensation of acetyl-CoA and malonyl-CoA to generate long-chain fatty acids in the cytoplasm, while the breakdown of fatty acids (beta-oxidation) occurs in mitochondria and is regulated by carnitine palmitoyltransferase-1 (CPT-1), the rate-limiting step for the entry of fatty acids into the mitochondria. Inhibition of FAS using cerulenin or synthetic FAS inhibitors such as C75 reduces food intake and induces profound reversible weight loss. Subsequent studies reveal that C75 also stimulates CPT-1 and increases beta-oxidation. Hypotheses as to the mechanisms by which C75 and cerulenin mediate their effects have been proposed. Centrally, these compounds alter the expression profiles of feeding-related neuropeptides, often inhibiting the expression of orexigenic peptides. Whether through centrally mediated or peripheral mechanisms, C75 also increases energy consumption, which contributes to weight loss. In vitro and in vivo studies demonstrate that at least part of C75's effects is mediated by modulation of AMP-activated protein kinase (AMPK), a known peripheral energy-sensing kinase. Collectively, these data suggest a role for fatty acid metabolism in the perception and regulation of energy balance.

Topics: 4-Butyrolactone; Animals; Body Weight; Carnitine O-Palmitoyltransferase; Cerulenin; Eating; Energy Metabolism; Fatty Acid Synthases; Fatty Acids; Gene Expression; Humans; Models, Biological; Obesity

Topics: 4-Butyrolactone; Animals; Anti-Obesity Agents; Cerulenin; Enzyme Inhibitors; Fatty Acid Synthases; Humans; Hypothalamus; Mice; Mice, Obese; Models, Biological; Obesity

Topics: 4-Butyrolactone; Adipose Tissue; Animals; Carnitine O-Palmitoyltransferase; Cell Size; Cerulenin; Energy Intake; Fatty Acids; Ghrelin; Humans; Malonyl Coenzyme A; Obesity; Peptide Hormones; Peptides

Cerulenin and a related compound, C75, have recently been reported to reduce food intake and body weight independent of leptin through a mechanism hypothesized, like leptin, to involve hypothalamic nutrition-sensitive neurons. To assess whether these inhibitors act through mechanisms similar to mechanisms engaged by leptin, ob/ob and Ay (agouti) mice, as well as fed and fasted wild-type mice, were treated with cerulenin. Like leptin, cerulenin reduced body weight and food intake and increased metabolic rate in ob/ob mice, and cerulenin produced the same effects in wild-type mice, whereas lithium chloride, at doses that produce conditioned taste aversion, reduced metabolic rate. However, in contrast to leptin, cerulenin did not prevent effects of fasting on plasma corticosterone or hypothalamic levels of neuropeptide Y, agouti-related peptide, pro-opiomelanocortin, or cocaine- and amphetamine-related peptide mRNA. Also, in contrast to leptin, cerulenin was highly effective to reduce body weight in Ay mice, in which obesity is caused by blockade of the melanocortin receptor. These data demonstrate that cerulenin produces metabolic effects similar to effects of leptin, but through mechanisms that are independent of, or down-stream from, both leptin and melanocortin receptors.

Topics: Animals; Body Weight; Cerulenin; Drug Resistance; Eating; Endocrine Glands; Fasting; Hypothalamus; Leptin; Male; Melanocyte-Stimulating Hormones; Metabolism; Mice; Mice, Inbred CBA; Mice, Inbred Strains; Neurosecretory Systems; Obesity