Antagonism of central melanin-concentrating hormone 1 receptor alleviates steatohepatitis in mice.
Blockade of brain melanin-concentrating hormone 1 receptor (MCH1R) significantly ameliorates fatty liver as well as obesity. However, the mode of action of this effect is unknown. This study examined the effect of a MCH1R antagonist in murine steatohepatitis models with and without obesity and clarified whether these pharmacological effects were attributed to anti-obesity effects. Steatohepatitis with concomitant obese phenotypes was developed after 52-week exposure to a high-fat diet, and steatohepatitis with reduced body weight was developed by exposure to a methionine- and choline-deficient diet for 10 days. Chronic intracerebroventricular infusion of a peptidic MCH1R antagonist reduced hepatic triglyceride contents and ameliorated steatohepatitis on histological observations in both mice models. Improvement of steatohepatitis was concomitant with amelioration of obese phenotypes such as hyperinsulinemia and hyperleptinemia in the case of the obese model, whereas body weight reduction was not associated with amelioration of steatohepatitis by the antagonist in the lean model. Reduction of hepatic gene expressions encoding cytochromes P450 4A was identified by treatment with the antagonist in both the obese and lean models. These results suggest that brain blockade of MCH1R could alleviate steatohepatitis independently from anti-obesity effects. In conclusion, MCH1R antagonist could have a new therapeutic potential for the treatment of human nonalcoholic steatohepatitis.
Tsukuba Research Institute Tsukuba Safety Assessment Laboratories, Banyu Pharmaceutical Co., Ltd, 3 Okubo, Tsukuba 300-2611, Japan.
Makoto
M
Ito
Akira
A
Gomori
Jun
J
Suzuki
Shigeharu
S
Tsujioka
Minoru
M
Sasaki
Masao
M
Matsuda
Maria A
MA
Bednarek
Masahiko
M
Ito
Akane
A
Ishihara
Hisashi
H
Iwaasa
Douglas J
DJ
Macneil
Akio
A
Kanatani
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D004041:Dietary Fats / Q000494:pharmacology*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D053583:Interleukin-1beta / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000139:chemically induced / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors*; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D004041:Dietary Fats; D053583:Interleukin-1beta; D011979:Receptors, Pituitary Hormone; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; C092274:melanin-concentrating hormone receptor