The agouti-related protein (AgRP) is a powerful appetite modulator expressed in the hypothalamus and the adrenal gland and regulated by leptin. Here we report the robust expression of AgRP in epididymal fat and its upregulation in this tissue by feeding rather than by fasting. This was observed in both the obesity-susceptible C57BL/6J and the obesity-resistant CAST/Ei mouse strains. Surprisingly, AgRP expression was higher in the hypothalamus and the adrenal gland in the leaner and obesity-resistant CAST/Ei strain. In vitro leptin treatment upregulated endogenous AgRP in mouse hypothalamus and adrenal cells, after an acute 6-h exposure, but it downregulated AgRP after a long-term 60-h exposure. AgRP, on the other hand, upregulated its own endogenous expression in the hypothalamus and the adrenal cells and also upregulated endogenous leptin in the adrenal cells. These results reveal a novel feedback loop and reciprocal transcriptional regulation between AgRP and leptin centrally and peripherally. (C) 2004 Elsevier Inc. All rights reserved.