Energy homeostasis is regulated by a complex network involving peripheral and central signals that determine food intake and energy expenditure. Melanin-concentrating hormone (MCH) plays an essential role in this process. Animals treated with MCH develop hyperphagia and obesity. Ablation of the prepro-MCH gene leads to a lean phenotype, as does ablation of the rodent MCH receptor, MCHR-1. MCH is overexpressed in the leptin-deficient ob͞ob mouse, and we hypothesized that ablation of MCH in this animal would lead to attenuation of its obese phenotype. Compared with ob͞ob animals, mice lacking both leptin and MCH (double null) had a dramatic reduction in body fat. Surprisingly, the hyperphagia of the ob͞ob mouse was unaffected. Instead, leanness was secondary to a marked increase in energy expenditure resulting from both increased resting energy expenditure and locomotor activity. Furthermore, double-null mice showed improvements in other parameters impaired in ob͞ob mice. Compared with ob͞ob mice, double-null animals had increased basal body temperature, improved response to cold exposure, lower plasma glucocorticoid levels, improved glucose tolerance, and reduced expression of stearoyl-CoA desaturase 1 (SCD-1). These results highlight the importance of MCH in integration of energy homeostasis downstream of leptin and, in particular, the role of MCH in regulation of energy expenditure.M elanin-concentrating hormone (MCH), a 19-aa neuropeptide, is the product of the prepro-MCH gene and is expressed exclusively within the lateral hypothalamus. MCH neurons make monosynaptic projections throughout the neuraxis including the cortex and hindbrain, suggesting that MCH regulates complex motivated behaviors (1). A role for MCH in energy homeostasis emerged from studies demonstrating differential MCH gene expression in leptin-deficient ob͞ob mice, where MCH mRNA was overexpressed 2-to 3-fold compared with normal-weight littermates, in both fed and fasted states (2). Furthermore, MCH administration into the lateral ventricle of rats caused an acute and rapid increase in feeding (2, 4). Genetic evidence for a role of MCH in energy balance was derived from a model of MCH gene ablation, which produced a lean phenotype associated with a decrease in feeding and an increase in resting energy expenditure (3), and also from a model of transgene-derived eutopic overexpression, which produced mild obesity (5). Recently, chronic infusions of MCH were shown to produce hyperphagia and obesity in mice (6) and rats (7).Based on the foregoing evidence, we hypothesized that MCH contributed to the hyperphagia seen in ob͞ob mice (8) and predicted that mice lacking both MCH and leptin would show an attenuated obesity phenotype secondary to decreased feeding. Therefore, we performed a series of crosses of MCH Ϫ/Ϫ mice and ob͞ϩ mice to generate mice lacking both leptin and MCH, i.e., MCH Ϫ/Ϫ ob͞ob mice, designated double null. Double-null mice had marked attenuation of obesity and associated metabolic and endocrine abnormalities of leptin deficie...

Neuropeptide Y (NPY) is an orexigenic (appetite-stimulating) peptide that plays an important role in regulating energy balance. When administered directly into the central nervous system, animals exhibit an immediate increase in feeding behavior, and repetitive injections or chronic infusions lead to obesity. Surprisingly, initial studies of Npy−/− mice on a mixed genetic background did not reveal deficits in energy balance, with the exception of an attenuation in obesity seen in ob/ob mice in which the NPY gene was also deleted. Here, we show that, on a C57BL/6 background, NPY ablation is associated with an increase in body weight and adiposity and a significant defect in refeeding after a fast. This impaired refeeding response in Npy−/− mice resulted in a deficit in weight gain in these animals after 24 h of refeeding. These data indicate that genetic background must be taken into account when the biological role of NPY is evaluated. When examined on a C57BL/6 background, NPY is important for the normal refeeding response after starvation, and its absence promotes mild obesity.