Melanin-concentrating hormone is a critical mediator of the leptin-deficient phenotype.
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.
Segal-Lieberman
Gabriella
G
Research Division, Joslin Diabetes Center, 1 Joslin Place, Boston, MA 02215, USA.
Bradley
Richard L
RL
Kokkotou
Efi
E
Carlson
Michael
M
Trombly
Daniel J
DJ
Wang
Xiaomei
X
Bates
Sarah
S
Myers
Martin G
MG
Flier
Jeffrey S
JS
Maratos-Flier
Eleftheria
E
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
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