axis plays important role in the regulation of energy homeostasis (1, 2) via the effects of thyroid hormone to increase oxygen consumption and heat generation (1, 2). Thus, inhibition of the HPT axis during fasting (3-5) would appear to be an important adaptive mechanism to conserve energy stores. The state of central hypothyroidism induced by fasting is orchestrated by changes of circulating levels of a protein, leptin, which declines with fasting and is restored to normal levels by refeeding (4). Thus, if leptin is administered exogenously to fasting animals, the reduction in circulating levels of thyroid hormones, TSH, and hypophysiotropic pro-TRH mRNA in the hypothalamic paraventricular nucleus (PVN) can be prevented (3). The primary action of leptin on the HPT axis is mediated by the hypothalamic arcuate nucleus through direct axonal projections to the PVN. If the arcuate nucleus is ablated, not only is the response of the thyroid axis to fasting abolished, but its response to the exogenous administration of leptin is lost as well (6).One of the most important arcuate nucleus-derived neuropeptides mediating the effects of leptin on energy homeostasis is agouti-related protein (AGRP) (7,8). Central administration of AGRP not only markedly stimulates food intake, but also simultaneously inhibits the hypothalamicpituitary-thyroid axis (HPT) axis, closely replicating the central hypothyroid state associated with fasting (9). Because AGRP is an endogenous antagonist at melanocortin receptors (8), it is presumed that its primary role on the HPT axis may be to prevent the stimulatory effects of ␣-MSH on the TRH gene (9, 10). Although practically all hypophysiotropic TRH neurons receive contacts by axons containing AGRP (10,11), only approximately 30% of TRH neurons in the medial parvocellular subdivision are contacted by axons containing ␣-MSH (10), and only approximately 48% have been shown to express melanocortin 4 receptor (MC4-R) mRNA (12). Furthermore, the MC4-R knockout (KO) mouse retains significant responses to centrally administered AGRP (13). Thus, the possibility that AGRP might exert its actions on the HPT axis by a receptor other than the MC4-R must be considered.To determine the importance of the MC4-R in mediating the inhibitory effects of AGRP on the HPT axis, we compared Abbreviations: aCSF, Artificial cerebrospinal fluid; AGRP, agoutirelated protein; GABA, ␥-aminobutyric acid; HPT, hypothalamic-pituitary-thyroid; KO, knockout; MC4-R, melanocortin 4 receptor; PVN, paraventricular nucleus; WT, wild-type.Endocrinology is published monthly by The Endocrine Society (http:// www.endo-society.org), the foremost professional society serving the endocrine community.