Chronic MCH-1 receptor modulation alters appetite, body weight and adiposity in rats.
Central administration of the neuropeptide melanin-concentrating hormone (MCH) stimulates feeding in rodents. We studied the effects of intracerebroventricular (i.c.v.) administration of an MCH-1 receptor agonist (Compound A) and an MCH-1 receptor antagonist (Compound B) on feeding in satiated rats. Compound B (10 microg, i.c.v.) blocked the acute orexigenic effect of Compound A (5 microg, i.c.v.). In an experiment designed to either stimulate or inhibit MCH-1 receptor signaling over an extended period, rats received continuous i.c.v. infusions of vehicle (saline), Compound A (30 microg/day), Compound B (30 or 48 microg/day) or neuropeptide Y (24 microg/day, as positive control) via implantable infusion pumps. Continuous MCH-1 receptor activation recapitulated the obese phenotype of MCH-over-expressor mice, manifest as enhanced feeding (+23%, P<0.001), caloric efficiency and body weight gain (+38%, P<0.005) over the 14-day period relative to controls. Chronic MCH-1 receptor activation also elevated plasma insulin and leptin levels significantly. Conversely, continuous MCH-1 receptor antagonism led to sustained reductions in food intake (-16%, P<0.001), body weight gain (-35%, P<0.01), and body fat gain relative to controls, without an effect on lean mass. Antagonism of the MCH-1 receptor may be an effective approach for the treatment of obesity.
Shearman
Lauren P
LP
Department of Pharmacology, Merck Research Laboratories, PO Box 2000, Building RY80Y-150, Rahway, NJ 07065, USA. lauren_shearman@merck.com
Camacho
Ramon E
RE
Sloan Stribling
D
D
Zhou
Dan
D
Bednarek
Maria A
MA
Hreniuk
Donna L
DL
Feighner
Scott D
SD
Tan
Carina P
CP
Howard
Andrew D
AD
Van der Ploeg
Lex H T
LH
MacIntyre
D Euan
DE
Hickey
Gerard J
GJ
Strack
Alison M
AM
D000273:Adipose Tissue / Q000187:drug effects / Q000502:physiology*; D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D001066:Appetite / Q000187:drug effects / Q000502:physiology*; D001835:Body Weight / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects / Q000502:physiology; D004987:Ethers / Q000008:administration & dosage / Q000737:chemistry; D006845:Hydrocarbons, Fluorinated / Q000008:administration & dosage / Q000737:chemistry; D008297:Male; D008969:Molecular Sequence Data; D051381:Rats; D017207:Rats, Sprague-Dawley; D011979:Receptors, Pituitary Hormone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*
C118183:CH3OCF2CH(CF3)OCH2F; D004987:Ethers; D006845:Hydrocarbons, Fluorinated; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor; C078742:fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether