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© 2001 by the American Diabetes Association, Inc.
Cerulenin Mimics Effects of Leptin on Metabolic Rate, Food Intake, and Body Weight Independent of the Melanocortin System, but Unlike Leptin, Cerulenin Fails to Block Neuroendocrine Effects of Fasting
1 Geriatrics and
2 Anesthesia, the Fishberg Center for Neurobiology, Neurobiology of Aging Laboratories, Mount Sinai School of Medicine, New York, New York
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.
Abbreviations: AGRP, agouti-related peptide; ANOVA, analysis of variance; CART, cocaine- and amphetamine-regulated peptide; FAS, fatty acid synthase; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; RER, respiratory exchange ratio
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