Abstract
The importance of estrogens for glucose homeostasis has been demonstrated by clinical, pharmacological, and experimental studies. Male mice lacking the aromatase gene (ArKO mice), which encodes an enzyme involved in estrogen synthesis, develop glucose- and insulin-intolerance. However, it remains unclear whether insulin signaling is actually impaired in the liver and muscle of ArKO mice. We examined the effects of estrogen-deficiency on insulin signaling by quantifying phosphorylation levels of protein kinase B (Akt) in the liver and muscle and by examining the expression levels of insulin-target genes in the liver. Insulin administration enhanced phosphorylation levels of Akt in the liver and muscle of wild-type (WT) mice, ArKO mice, and ArKO mice supplemented with 17β-estradiol (E2), but insulin was less effective in ArKO mice. Gene expression analysis revealed that alterations induced by insulin in WT liver were also observed in ArKO liver, but the degree of altered expression in a subset of genes was smaller in ArKO mice than in WT mice. E2 supplementation improved the insulin responses of some genes in ArKO mice. Thus, these findings suggest that insulin signaling in the liver and muscle of ArKO mice is less efficient than in WT mice, which contributes to whole-body glucose intolerance in ArKO mice.
Highlights
Metabolic abnormalities, such as dyslipidemia and hyperglycemia, are a major health concern worldwide
The effects of estrogens on the regulation of insulin action and glucose metabolism have been underscored by studies of genetically engineered murine models, such as estrogen receptor (ER) a gene (ESR1) knockout mice (ERaKO mice) (Heine et al, 2000) or mice deficient in the aromatase gene (Cyp19a1), which encodes an enzyme responsible for estrogen synthesis (ArKO mice) (Nemoto et al, 2000; Takeda et al, 2003; Van Sinderen et al, 2014)
We examined phosphorylation levels of Thr308 and Ser473 in Akt 10 or 60 min after insulin administration as proximal insulin signaling events to determine whether ArKO mice respond to insulin properly in two insulin target tissues, liver and muscle
Summary
Metabolic abnormalities, such as dyslipidemia and hyperglycemia, are a major health concern worldwide. The effects of estrogens on the regulation of insulin action and glucose metabolism have been underscored by studies of genetically engineered murine models, such as estrogen receptor (ER) a gene (ESR1) knockout mice (ERaKO mice) (Heine et al, 2000) or mice deficient in the aromatase gene (Cyp19a1), which encodes an enzyme responsible for estrogen synthesis (ArKO mice) (Nemoto et al, 2000; Takeda et al, 2003; Van Sinderen et al, 2014). We examined the responses of insulin-target tissues, such as liver and muscle, using matured ArKO male mice, which develop systemic insulin resistance (Takeda et al, 2003; Van Sinderen et al, 2014)
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