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S. A. Burchill, S. Ito, and A. J. Thody


Tyrosinase mRNA, synthesis and activity were measured in the skin during the first 2 weeks of life of C3H-HeAvy mice. Tyrosinase mRNA levels were found to peak on days 3–4 and were followed by increases in tyrosinase synthesis and activity which peaked on days 6–7 and 7–8 respectively. These changes in tyrosinase expression were presumably associated with the growth of the first coat of hair that in neonatal C3H-HeAvy mice is yellow in colour as a result of the increased proportion of phaeomelanin. By the time hair growth had ceased there was no expression of tyrosinase at both mRNA and protein levels. Daily administration of α-melanocyte stimulating hormone (α-MSH) enhanced the expression of tyrosinase mRNA transcripts, tyrosinase synthesis and activity. The increase in tyrosinase activity paralleled the change in the amount of tyrosinase, suggesting that the primary action of α-MSH is to stimulate new synthesis of the enzyme. This induction of tyrosinase was associated with the growth of hair that was darker in colour than that of the controls and contained an increased proportion of eumelanin. This increase in eumelanin reflected a decrease in phaeomelanin content. It was concluded that, through its actions on the enzyme tyrosinase, α-MSH is able to switch the synthesis of phaeomelanin to that of eumelanin in hair follicular melanocytes.

Journal of Endocrinology (1993) 137, 189–195

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S. A. Burchill, A. J. Thody, and S. Ito


Skin tyrosinase levels and the eumelanin and phaeomelanin contents of the hair were measured in pubertal and adult C3H–HeA*vy mice that grow dark and golden yellow hair respectively. Hair growth was initiated by plucking and the skin tyrosinase levels, which increased during the growth of new hair and peaked at around 9 days after plucking, were higher during the growth of dark hair in the pubertal mice than during the growth of yellow hair in the adult mice. Although there was only a twofold difference in the phaeomelanin contents of these two types of hair, the dark hair of the pubertal mice contained over 20 times more eumelanin than the golden-yellow hair of the adult mice. These results suggest that the changes in coat colour in C3H–HeA*vy mice are due mainly to changes in eumelanin synthesis by the hair follicular melanocytes and that the production of this pigment requires higher levels of the enzyme tyrosinase than does the production of phaeomelanin. These changes did not appear to be related to plasma α-MSH levels. Nevertheless, administration of α-MSH increased skin tyrosinase activity in the pubertal mice that were growing dark hair and produced a twofold increase in the eumelanin content of the hair. However, it had no such effects in adult mice and also failed to affect the phaeomelanin content of the hair in both groups of mice. In contrast to α-MSH, bromocriptine decreased skin tyrosinase levels and the eumelanin content and increased the phaeomelanin content of the hair in pubertal mice. These effects of bromocriptine were unrelated to plasma immunoreactive α-MSH levels and were not restored when α-MSH was administered together with the dopamine agonist.

Although the present results support the idea that α-MSH increases coat darkening in the C3H–HeA*vy mouse through its actions on tyrosinase activity and eumelanin synthesis, it seems that these actions are more dependent on changes at the melanocyte level than changes in circulating α-MSH. The present results further suggest that dopaminergic mechanisms may also play a direct regulatory role in the control of coat colour in this mouse.

J. Endocr. (1986) 109, 15–21

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M Shimada, J Ito, Y Yamashita, T Okazaki, and N Isobe

In this study, we investigated the mechanisms of protein kinase B (PKB) activation and its role in cumulus cells during in vitro meiotic resumption of porcine oocytes. PKB activity in cumulus cells was significantly decreased by 12 h cultivation of cumulus-oocyte complexes (COCs) in basic medium. However, the addition of phosphodiesterase inhibitors, hypoxanthine or 3-isobutyl-1-methylxanthine, maintained the level of PKB activity in cumulus cells at comparable with that in cumulus cells just after collection from their follicles. When COCs were cultured with phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor, LY294002, PKB activity was significantly decreased, and both caspase 3 activity and the proportion of apoptotic cells were significantly increased as compared with those in cumulus cells just after collection from their follicles. Moreover, the inhibitory effect of hypoxanthine on spontaneous meiotic resumption was overcome by addition of LY294002. On the other hand, markedly high activity of PKB and high intensity of the phosphorylated PKB band were observed in cumulus cells of COCs which were cultured with FSH. The addition of 20 microM LY294002 to FSH-containing medium induced an apoptosis of cumulus cells, whereas little apoptotic-positive signal was detected in COCs cultured with 5 microM LY294002 and FSH. However, the inhibitory effects of LY294002 on progesterone production by cumulus cells and germinal vesicle breakdown in oocytes reached a maximum at 5 microM. Thus, high activity of the PI 3-kinase-PKB pathway in cumulus cells plays an important role in FSH regulation of cell function. Judging from these results, it is estimated that PI 3-kinase in cumulus cells is required for both the suppression of spontaneous meiotic resumption and the induction of gonadotropin-stimulated meiotic resumption.

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Makoto Ito, Akira Gomori, Jun Suzuki, Shigeharu Tsujioka, Minoru Sasaki, Masao Matsuda, Maria A Bednarek, Masahiko Ito, Akane Ishihara, Hisashi Iwaasa, Douglas J MacNeil, and Akio Kanatani

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.