Mice lacking melanin-concentrating hormone are hypophagic and lean

Feeding is influenced by hypothalamic neuropeptides that promote (orexigeni c peptides) or inhibit feeding(1). Of these, neuropeptide Y (NPY) in the ar cuate nucleus' and melanin-concentrating hormone (MCH)(3) and orexins/hypoc retins(4,5) in the lateral hypothalamus have received attention because the ir expression is increased during fasting and because they promote feeding when administered centrally. Surprisingly, absence of the orexigenic neurop eptide NPY fails to alter feeding or body weight in normal mice(6). As defi ciency of a single component of the pathway that limits food intake (such a s leptin or receptors for melanocortin-4)(7,8) causes obesity, it has been suggested that orexigenic signals are more redundant than those limiting fo od intake(7,8). To define further the physiological role of MCH and to test the redundancy of orexigenic signals, we generated mice carrying a targete d deletion of the MCH gene. MCH-deficient mice have reduced body weight and leanness due to hypophagia (reduced feeding) and an inappropriately increa sed metabolic rate, despite their reduced amounts of both leptin and arcuat e nucleus pro-opiomelanocortin messenger RNA. Our results show that MCH is a critical regulator of feeding and energy balance which acts downstream of leptin and the melanocortin system, and that deletion of a gene encoding a single orexigenic peptide can result in leanness.