Preeclampsia is a syndrome characterized by hypertension, proteinuria and edema during pregnancy.We have shown that pregnant catechol-O-methyltransferase (COMT) deficient mice display a preeclampsia-like phenotype due to an absence of 2-methoxyestradiol (2-ME), a natural metabolite of estradiol, which is increased during the third trimester of normal human pregnancy.Several single-nucleotide polymorphisms (SNPs) in the human COMT gene have been observed and some of which may result in the depletion of catalytic activity, such as the well-known functional Val158Met isoform.These COMT SNPs have been associated with hypertension, preeclampsia, obesity, increased fat mass and obesity in diabetes.Women with a history of preeclampsia are with the risk of cardiovascular diseases and metabolic syndrome, however molecular links between these diseases conditions are unknown.Here we hypothesized that COMT deficiency could be involved in pathogenesis of metabolic syndromes.COMT protein was suppressed in the liver of high fat diet fed mice.COMT-inhibitor treatment displayed the exacerbation of glucose tolerance defects in mice with a high-fat diet.A significant angiogenesis in the mesenteric fat was also observed in high-fat fed mice treated with COMT-inhibitor.These abnormal adiposity and glucose tolerance defect with the abnormal angiogenesis in COMT-inhibitor treated mice were ameliorated by the 2-ME treatment.Finally we found that the long-term treatment with 2-ME ameliorated glucose intolerance and insulin resistance in mice with high fat diet.These results indicated that COMT/2-ME deficiency could be the shared molecular mechanisms and targets for the intervention both in preeclampsia and in metabolic syndrome.