Hypothalamic Agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting

Agouti-related protein (AGRP) is a homologue of the agouti gene product and , when overexpressed, promotes obesity. Like neuropeptide Y (NPY) messenger RNA (mRNA), AGRP mRNA is produced in the hypothalamic arcuate nucleus and is elevated in leptin-deficient ob/ob and leptin-resistant db/db mice. Thes e data suggest that AGRP mRNA might be affected by leptin and nutritional s tatus in parallel with NPY mRNA. To test this hypothesis, we examined if AG RP mRNA would be, like NPY mRNA, inhibited by leptin injections and stimula ted by fasting. AGRP mRNA was elevated in ob/ob mice about 5-fold compared with wild-type controls and was significantly inhibited by leptin treatment , as assessed by Northern blot analysis. In wild-type mice, AGRP mRNA was i ncreased at least 13-fold by a 2-day fast, as assessed both by Northern blo t analysis and in situ hybridization. In ad lib fed db/db mice, AGRP mRNA w as elevated about 8-fold compared with ad rib fed wild-type controls, and w as further increased by fasting in db/db mice. These data suggest that AGRP mRNA and NPY mRNA respond similarly to leptin and fasting.