Published online before print August 1, 2003, 10.1073/pnas.1633636100
PNAS | August 19, 2003 | vol. 100 | no. 17 | 10085-10090
PHYSIOLOGY
Melanin-concentrating hormone is a critical mediator of the leptin-deficient phenotype
Gabriella Segal-Lieberman * , Richard L. Bradley * , Efi Kokkotou * , Michael Carlson *, Daniel J. Trombly *, Xiaomei Wang *, Sarah Bates * , Martin G. Myers, Jr. * , Jeffrey S. Flier and Eleftheria Maratos-Flier * ¶
*Research Division, Joslin Diabetes Center, Boston, MA 02215; Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA 02215; and Department of Medicine, Harvard Medical School, Boston, MA 02215
Communicated by C. Ronald Kahn, Harvard Medical School, Boston, MA, June 13, 2003 (received for review March 6, 2003)
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.
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Abbreviations: MCH, melanin-concentrating hormone; SCD-1, stearoyl-CoA desaturase 1; MCHR, MCH receptor; VO2, oxygen consumption; UCP-1, uncoupling protein 1; BAT, brown adipose tissue; AgRP, agouti-related peptide; NPY, neuropeptide Y; NEI, neuropeptide EI; NGE, neuropeptide GE. |
