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Melanin-concentrating hormone is a critical mediator of the leptin-deficient phenotype

2003; National Academy of Sciences; Volume: 100; Issue: 17 Linguagem: Inglês

10.1073/pnas.1633636100

1091-6490

Gabriella Segal‐Lieberman, Richard L. Bradley, Efi Kokkotou, Michael Carlson, Daniel J. Trombly, Xiaomei Wang, Sarah H. Bates, Martin G. Myers, Jeffrey S. Flier, Eleftheria Maratos–Flier,

Biochemical Analysis and Sensing Techniques

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.