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

Cerulenin and a related compound, C75, have recently been reported to reduc e food intake and body weight independent of leptin through a mechanism hyp othesized, like leptin, to involve hypothalamic nutrition-sensitive neurons . To assess whether these inhibitors act through mechanisms similar to mech anisms engaged by leptin, ob/ob and A(y) (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 m ice, and cerulenin produced the same effects in wild-type mice, whereas lit hium chloride, at doses that produce conditioned taste aversion, reduced me tabolic rate. However, in contrast to leptin, cerulenin did not prevent eff ects of fasting on plasma corticosterone or hypothalamic levels of neuropep tide Y, agouti-related peptide, pro-opiomefanocortin, or cocaine- and amphe tamine-related peptide mRNA. Also, in contrast to leptin, cerulenin was hig hly effective to reduce body weight in A(y) mice, in which obesity is cause d by blockade of the melanocortin receptor. These data demonstrate that cer ulenin produces metabolic effects similar to effects of leptin, but through mechanisms that are independent of, or down-stream from, both leptin and m elanocortin receptors.