Deficiency in catechol-o-methyltransferase is linked to a disruption of glucose homeostasis in mice
Abstract 2-methoxyestradiol (2-ME), an estrogen metabolite generated via catechol-o-methyltransferase (COMT), is multifunctional methoxy-catechol. Here, we report that COMT deficiency leads to glucose intolerance and 2-ME rescues COMT-deficient-associated metabolic defects. Liver COMT protein was su...
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Nature Portfolio
2017
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oai:doaj.org-article:b583bc08d06d4a32b024507f7393df702021-12-02T12:32:57ZDeficiency in catechol-o-methyltransferase is linked to a disruption of glucose homeostasis in mice10.1038/s41598-017-08513-w2045-2322https://doaj.org/article/b583bc08d06d4a32b024507f7393df702017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08513-whttps://doaj.org/toc/2045-2322Abstract 2-methoxyestradiol (2-ME), an estrogen metabolite generated via catechol-o-methyltransferase (COMT), is multifunctional methoxy-catechol. Here, we report that COMT deficiency leads to glucose intolerance and 2-ME rescues COMT-deficient-associated metabolic defects. Liver COMT protein was suppressed in high fat diet (HFD)-fed or in pregnant mice. COMT suppression, by Ro41-0960 or siRNA, in HFD fed mice or in pregnant mice exacerbated glucose intolerance; 2-ME intervention ameliorated these defects. 2-ME effects on glucose tolerance were associated with AMPK phosphorylation in the liver and in islet cells. Metformin restored liver COMT protein levels, and metformin-induced liver AMPK phosphorylation was abolished by COMT inhibition. The amelioration in glucose tolerance by 2-ME was associated with biphasic insulin secretion in an environment-dependent manner. 2-ME-induced insulin secretion was associated with the AMPK phosphorylation, PDX-1 phosphorylation, and MST-1 suppression in MIN-6 cells. Furthermore 2-ME displayed PPARγ agonist-like activity. These results suggest that COMT is an enzyme to maintain glucose homeostasis and 2-ME is a potential endogenous multi-target anti-diabetic candidate.Megumi KanasakiSwayam Prakash SrivastavaFan YangLing XuSumiyo KudohMunehiro KitadaNorikazu UekiHyoh KimJinpeng LiSatoru TakedaKeizo KanasakiDaisuke KoyaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017) |
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Medicine R Science Q |
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Medicine R Science Q Megumi Kanasaki Swayam Prakash Srivastava Fan Yang Ling Xu Sumiyo Kudoh Munehiro Kitada Norikazu Ueki Hyoh Kim Jinpeng Li Satoru Takeda Keizo Kanasaki Daisuke Koya Deficiency in catechol-o-methyltransferase is linked to a disruption of glucose homeostasis in mice |
| description |
Abstract 2-methoxyestradiol (2-ME), an estrogen metabolite generated via catechol-o-methyltransferase (COMT), is multifunctional methoxy-catechol. Here, we report that COMT deficiency leads to glucose intolerance and 2-ME rescues COMT-deficient-associated metabolic defects. Liver COMT protein was suppressed in high fat diet (HFD)-fed or in pregnant mice. COMT suppression, by Ro41-0960 or siRNA, in HFD fed mice or in pregnant mice exacerbated glucose intolerance; 2-ME intervention ameliorated these defects. 2-ME effects on glucose tolerance were associated with AMPK phosphorylation in the liver and in islet cells. Metformin restored liver COMT protein levels, and metformin-induced liver AMPK phosphorylation was abolished by COMT inhibition. The amelioration in glucose tolerance by 2-ME was associated with biphasic insulin secretion in an environment-dependent manner. 2-ME-induced insulin secretion was associated with the AMPK phosphorylation, PDX-1 phosphorylation, and MST-1 suppression in MIN-6 cells. Furthermore 2-ME displayed PPARγ agonist-like activity. These results suggest that COMT is an enzyme to maintain glucose homeostasis and 2-ME is a potential endogenous multi-target anti-diabetic candidate. |
| format |
article |
| author |
Megumi Kanasaki Swayam Prakash Srivastava Fan Yang Ling Xu Sumiyo Kudoh Munehiro Kitada Norikazu Ueki Hyoh Kim Jinpeng Li Satoru Takeda Keizo Kanasaki Daisuke Koya |
| author_facet |
Megumi Kanasaki Swayam Prakash Srivastava Fan Yang Ling Xu Sumiyo Kudoh Munehiro Kitada Norikazu Ueki Hyoh Kim Jinpeng Li Satoru Takeda Keizo Kanasaki Daisuke Koya |
| author_sort |
Megumi Kanasaki |
| title |
Deficiency in catechol-o-methyltransferase is linked to a disruption of glucose homeostasis in mice |
| title_short |
Deficiency in catechol-o-methyltransferase is linked to a disruption of glucose homeostasis in mice |
| title_full |
Deficiency in catechol-o-methyltransferase is linked to a disruption of glucose homeostasis in mice |
| title_fullStr |
Deficiency in catechol-o-methyltransferase is linked to a disruption of glucose homeostasis in mice |
| title_full_unstemmed |
Deficiency in catechol-o-methyltransferase is linked to a disruption of glucose homeostasis in mice |
| title_sort |
deficiency in catechol-o-methyltransferase is linked to a disruption of glucose homeostasis in mice |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/b583bc08d06d4a32b024507f7393df70 |
| work_keys_str_mv |
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1718393942055059456 |