Mechanism of the anti-obesity effects induced by a novel melanin-concentrating hormone 1-receptor antagonist in mice.
OBJECTIVE
Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide expressed in the lateral hypothalamus that is involved in feeding and body weight regulation. Intracerebroventricular infusion of a peptidic MCH1 receptor antagonist ameliorated obesity in murine models. Recently, small molecule MCH1 receptor antagonists have been developed and characterized for the treatment of obesity. However, little is known of the mechanism of the anti-obesity effects of MCH1 receptor antagonists.


METHODS
To examine the mechanisms of action of the anti-obesity effect of MCH1 receptor antagonists more precisely, we conducted a pair-feeding study in mice with diet-induced obesity (DIO), chronically treated with an orally active and highly selective MCH1 receptor antagonist and examined changes in mRNA expression levels in liver, brown and white adipose tissues. We also assessed the acute effects of the MCH1 receptor antagonist in energy expenditure under thermoneutral conditions.


RESULTS
Treatment with the MCH1 receptor antagonist at 30 mg.kg(-1) for 1 month moderately suppressed feeding and significantly reduced body weight by 24%. In contrast, pair-feeding resulted in a smaller weight reduction of 10%. Treatment with the MCH1 receptor antagonist resulted in a higher body temperature compared with the pair-fed group. TaqMan and calorimetry data suggested that the MCH1 receptor antagonist also stimulated thermogenesis.


CONCLUSIONS
Our results indicate that an MCH1 receptor antagonist caused anti-obesity effects im mice by acting on both energy intake and energy expenditure.
Ito
Masahiko
M
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Japan.
Ishihara
A
A
Gomori
A
A
Matsushita
H
H
Ito
Makoto
M
Metzger
J M
JM
Marsh
D J
DJ
Haga
Y
Y
Iwaasa
H
H
Tokita
S
S
Takenaga
N
N
Sato
N
N
MacNeil
D J
DJ
Moriya
M
M
Kanatani
A
A
D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D019440:Anti-Obesity Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011728:Pyridones / Q000493:pharmacokinetics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D011869:Radioligand Assay; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D022722:Thermogenesis / Q000187:drug effects
C549221:4-(benzyloxy)-1-(4-(2-pyrrolidin-1-ylethoxy)phenyl)pyridin-2(3H)-one; D019440:Anti-Obesity Agents; C103263:MCHR1 protein, human; D011728:Pyridones; D011759:Pyrrolidines; D012333:RNA, Messenger; D017481:Receptors, Somatostatin