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.
Highlights
Catechol-o-methyltransferase (COMT) is an enzyme responsible for the metabolism of catechols, such as catecholamines and catechol estrogens
We focused on COMT deficiency-associated defects in glucose tolerance using short-/long-term high fat diet (HFD) and pregnant mice
We found that HFD and pregnancy were associated with COMT suppression in the liver, suggesting that both of these conditions were prone for the onset of COMT deficiency
Summary
Catechol-o-methyltransferase (COMT) is an enzyme responsible for the metabolism of catechols, such as catecholamines and catechol estrogens. Metabolic defects are characteristic of preeclampsia[2, 11], a COMT deficiency-associated disease. Women with a history of preeclampsia have been associated with a future metabolic risk for cardiovascular diseases including type 2 diabetes[17,18,19]. Risk of metabolic diseases in women with a preeclampsia history often has been explained by the hypothesis that vascular damage during pregnancy in preeclamptic women causes endothelial injuries that leads to metabolic defects associated cardiovascular diseases[17,18,19]; the possibility of either a shared genetic background or molecular mechanism has not been investigated. We hypothesized that COMT deficiency is a shared pathogenesis in the onset of the metabolic defects observed in the metabolic syndrome, type 2 diabetes, and preeclampsia
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