Segal-Lieberman, GabriellaBradley, Richard L.Kokkotou, EfiCarlson, MichaelTrombly, Daniel J.Wang, XiaomeiBates, SarahMyers, Martin G. Jr.Flier, Jeffrey S.Maratos-Flier, Eleftheria2019-10-052003Segal-Lieberman, G., R. L. Bradley, E. Kokkotou, M. Carlson, D. J. Trombly, X. Wang, S. Bates, M. G. Myers, J. S. Flier, and E. Maratos-Flier. 2003. “Melanin-Concentrating Hormone Is a Critical Mediator of the Leptin-Deficient Phenotype.” Proceedings of the National Academy of Sciences 100 (17): 10085–90. https://doi.org/10.1073/pnas.1633636100.0027-84240744-28311091-6490http://nrs.harvard.edu/urn-3:HUL.InstRepos:41483252Energy 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.en-USJournal Article2019-10-0510.1073/pnas.1633636100