title: Melanin-concentrating hormone is a critical mediator of the leptin-deficient phenotype.
abstract: 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.
authors.affiliation: Research Division, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215, USA.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Segal-Lieberman
authors.forename: Richard L
authors.initials: RL
authors.lastname: Bradley
authors.forename: Efi
authors.initials: E
authors.lastname: Kokkotou
authors.forename: Michael
authors.initials: M
authors.lastname: Carlson
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Trombly
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Wang
authors.forename: Sarah
authors.initials: S
authors.lastname: Bates
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Flier
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Maratos-Flier
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001823:Body Composition; D001833:Body Temperature Regulation; D001835:Body Weight; D002352:Carrier Proteins / Q000378:metabolism; D003345:Corticosterone / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004435:Eating; D004734:Energy Metabolism; D007028:Hypothalamic Hormones / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007473:Ion Channels; D020738:Leptin / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D008099:Liver / Q000378:metabolism; D008297:Male; D008543:Melanins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D024101:Mitochondrial Proteins; D009043:Motor Activity; D009765:Obesity / Q000235:genetics / Q000503:physiopathology; D010641:Phenotype; D010907:Pituitary Hormones / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013230:Stearoyl-CoA Desaturase / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism; D000071256:Uncoupling Protein 1
chemical_list: D002352:Carrier Proteins; D007028:Hypothalamic Hormones; D007473:Ion Channels; D020738:Leptin; D008543:Melanins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D010907:Pituitary Hormones; D014280:Triglycerides; D000071256:Uncoupling Protein 1; C019463:melanin-concentrating hormone; D004247:DNA; D013230:Stearoyl-CoA Desaturase; D003345:Corticosterone