Hyperleptinemia in Ay/a mice upregulates arcuate cocaine- and amphetamine-regulated transcript expression

Department of Internal Medicine I, School of Medicine, Oita Medical University, Oita 879-5593, Japan The effects of leptin on cocaine- and amphetamine-regulated transcript (CART) and agouti-related protein (AGRP) expression in the hypothalamic arcuate nucleus of obese A y /a mice were investigated. CART mRNA expression was upregulated by 41% and AGRP mRNA downregulated by 78% in hyperleptinemic A y /a mice relative to levels in lean a/a mice. The mRNA expression of these neuropeptides in either young nonobese A y /a mice or rats treated with SHU-9119, a synthetic melanocortin-4 receptor (MC4R) antagonist, did not differ significantly from that in the corresponding controls. After a 72-h fast, which decreased the concentration of serum leptin, CART and AGRP mRNA expression decreased and increased, respectively, in A y /a mice. The expression levels of these neuropeptides in leptin-deficient A y /a ob/ob double mutants were comparable to those in a/a ob/ob mice. Leptin thus modulates both CART and AGRP mRNA expression in obese A y /a mice, whereas leptin signals are blocked at the MCR4R level. Taken together, the present findings indicate that differential expression of these neuropeptides in A y /a and ob/ob mice results in dissimilar progression toward obesity. leptin; lethal yellow mice; agouti-related protein; arcuate nucleus