Melanin-Concentrating Hormone Is a Critical Mediator of the Leptin-Deficient Phenotype

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-08, Vol.100 (17), p.10085-10090
• Main Authors: Segal-Lieberman, Gabriella, Bradley, Richard L., Kokkotou, Efi, Carlson, Michael, Trombly, Daniel J., Wang, Xiaomei, Bates, Sarah, Myers, Martin G., Flier, Jeffrey S., Maratos-Flier, Eleftheria
• Format: Article
• Language: English
• Subjects: Adipose Tissue, Brown - metabolism; Animals; Base Sequence; Biological Sciences; Body Composition; Body Temperature Regulation; Body Weight; Carrier Proteins - metabolism; Corticosterone - metabolism; DNA - genetics; Eating; Energy Metabolism; Food intake; Gene expression regulation; Genes; Hormones; Hyperphagia; Hypothalamic Hormones - deficiency; Hypothalamic Hormones - genetics; Hypothalamic Hormones - physiology; Ion Channels; Leptin - deficiency; Leptin - genetics; Leptin - physiology; Liver; Liver - metabolism; Locomotion; Male; Melanins - deficiency; Melanins - genetics; Melanins - physiology; Membrane Proteins - metabolism; Mice; Mice, Knockout; Mice, Obese; Mitochondrial Proteins; Motor Activity; Neuropeptides; Obesity; Obesity - genetics; Obesity - physiopathology; Phenotype; Phenotypes; Pituitary Hormones - deficiency; Pituitary Hormones - genetics; Pituitary Hormones - physiology; Skin; Stearoyl-CoA Desaturase - genetics; Triglycerides; Triglycerides - metabolism; Uncoupling Protein 1
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1633636100

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 ob/ob mouse, and we hypothesized that ablation of MCH in this animal would lead to attenuation of its obese phenotype. Compared with ob/ob animals, mice lacking both leptin and MCH (double null) had a dramatic reduction in body fat. Surprisingly, the hyperphagia of the ob/ob 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 ob/ob mice. Compared with ob/ob 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.