Antagonism of central melanin-concentrating hormone 1 receptor alleviates steatohepatitis in mice.

Abstract

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.

• Authors: Makoto Ito, Akira Gomori, Jun Suzuki, Shigeharu Tsujioka, Minoru Sasaki, Masao Matsuda, Maria A Bednarek, Masahiko Ito, Akane Ishihara, Hisashi Iwaasa, Douglas J Macneil, Akio Kanatani
• Journal: The Journal of endocrinology (J Endocrinol) Vol. 198 Issue 2 Pg. 309-15 (Aug 2008) ISSN: 1479-6805 [Electronic] England
• PMID: 18523032 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ccl2 protein, mouse
• Chemokine CCL2
• Collagen Type I
• Collagen Type I, alpha 1 Chain
• Dietary Fats
• Interleukin-1beta
• Receptors, Pituitary Hormone
• Triglycerides
• Tumor Necrosis Factor-alpha
• melanin-concentrating hormone receptor

Topics

• Animals
• Body Weight (drug effects)
• Chemokine CCL2 (genetics)
• Collagen Type I (genetics)
• Collagen Type I, alpha 1 Chain
• Dietary Fats (pharmacology)
• Disease Models, Animal
• Fatty Liver (chemically induced, drug therapy, metabolism, pathology)
• Gene Expression Regulation (drug effects)
• Interleukin-1beta (genetics)
• Liver (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Obesity (chemically induced, physiopathology)
• Polymerase Chain Reaction
• Receptors, Pituitary Hormone (antagonists & inhibitors)
• Triglycerides (metabolism)
• Tumor Necrosis Factor-alpha (genetics)