Effects of a selective melanin-concentrating hormone 1 receptor antagonist on food intake and energy homeostasis in diet-induced obese mice.
Melanin concentrating hormone (MCH) is a cyclic neuropeptide expressed in the lateral hypothalamus that plays an important role in energy homeostasis. To investigate the pharmacological consequences of inhibiting MCH signaling in murine obesity models, we examined the effect of acute and chronic administration of a selective MCH1 receptor antagonist (SCH-A) in diet-induced obese (DIO) and Lep(ob/ob) mice. Oral administration of SCH-A for 5 consecutive days (30 mg/kg q.d.) produced hypophagia, a loss of body weight and adiposity, and decreased plasma leptin levels in DIO mice, and hypophagia and reduced weight gain in Lep(ob/ob) mice. Chronic administration of SCH-A to DIO mice decreased food intake, body weight and adiposity, and plasma leptin and free fatty acids. These effects were accompanied by increases in several hypothalamic neuropeptides. Acute administration of SCH-A (30 mg/kg) prevented the decrease in energy expenditure associated with food restriction. These results indicate that MCH1 receptor antagonists may be effective in the treatment of obesity.
Kowalski
Timothy J
TJ
Department of CV/Metabolic Diseases, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. timothy.kowalski@spcorp.com
Spar
Brian D
BD
Weig
Blair
B
Farley
Constance
C
Cook
John
J
Ghibaudi
Lorraine
L
Fried
Steve
S
O'Neill
Kim
K
Del Vecchio
Robert A
RA
McBriar
Mark
M
Guzik
Henry
H
Clader
John
J
Hawes
Brian E
BE
Hwa
Joyce
J
D000273:Adipose Tissue / Q000187:drug effects; D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004041:Dietary Fats / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D004734:Energy Metabolism / Q000187:drug effects*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D019004:Galanin / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D007028:Hypothalamic Hormones / Q000235:genetics; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000097:blood; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D007457:Iodine Radioisotopes; D020738:Leptin / Q000097:blood; D008297:Male; D008543:Melanins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009478:Neuropeptide Y / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology*; D009765:Obesity / Q000209:etiology / Q000503:physiopathology*; D009842:Oligopeptides / Q000378:metabolism; D064446:Orexin Receptors; D000068797:Orexins; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D010907:Pituitary Hormones / Q000235:genetics; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000097:blood; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
C433463:3-iodotyrosyl-8-amino-3,6-dioxyoctanoyl-arginyl-cysteinyl-methionyl-leucyl-glycyl-arginyl-valyl-phenylalanyl-arginyl-prolyl-cysteinyltryptophan; D004041:Dietary Fats; D005230:Fatty Acids, Nonesterified; D007028:Hypothalamic Hormones; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D007457:Iodine Radioisotopes; D020738:Leptin; C491209:Mchr1 protein, mouse; D008543:Melanins; D009478:Neuropeptide Y; D009479:Neuropeptides; D009570:Nitriles; D009842:Oligopeptides; D064446:Orexin Receptors; D000068797:Orexins; D010879:Piperazines; D010907:Pituitary Hormones; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D017481:Receptors, Somatostatin; C511125:SCH-A compound; D014280:Triglycerides; C019463:melanin-concentrating hormone; D019004:Galanin; D014508:Urea