Iakovleva T V, Kostina N E, Makarova E N, Bazhan N M
Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.
Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, Russia.
Vavilovskii Zhurnal Genet Selektsii. 2020 Jul;24(4):427-434. doi: 10.18699/VJ20.635.
A positive effect of estradiol on insulin sensitivity has been shown for females and males. Insulin sensitivity is higher in females than in males, and males show a greater tendency to develop metabolic disorders. It is believed that these sex differences are due to a protective effect of estradiol in females, but not in males. Estradiol is a steroid hormone, and its effect is due to the modulation of target gene expression, but the effect of estradiol on the expression of genes encoding insulin signal transduction and glucose transport has not been sufficiently studied. The aim of the study was to compare the molecular mechanisms of the estradiol influence on insulin sensitivity in mice of both sexes. The effect of gonadectomy and estradiol (1 μg/animal, three days) on the expression of insulin signaling cascade genes in muscle, adipose tissue, and liver, as well as on the expression of Fgf21, estradiol receptors (Esr1/2), and transcription factor Stat3 in the liver in female and male mice was investigated. Estradiol levels were lower and glucose blood levels and insulin resistance were higher in Sham operated (Sham) males compared to Sham females. Irs2, Pik3cd, and Esr1/2 mRNA levels were lower in the liver of Sham males than in Sham females. In females, gonadectomy reduced the level of estradiol in the blood, increased insulin resistance and blood glucose levels compared to Sham females. Administration of estradiol to gonadectomized females decreased blood insulin levels and insulin resistance. In males, gonadectomy, on the contrary, increased the blood estradiol level, decreased blood insulin level and insulin resistance. Estradiol did not affect the parameters studied in males. The development of insulin resistance in gonadectomized females was associated with a decreased expression of the Irs2 gene in the liver. Increased insulin sensitivity in gonadectomized males was associated with increased levels of Irs2 and Pik3cd mRNA in the liver. It can be assumed that increasing the level of estradiol in the blood activates the expression of the Irs2 gene in the liver regardless of animal sex. Also, estradiol seems to regulate the transport of glucose in adipose tissue regardless of animal sex: in females and males, an increase in the blood estradiol level was associated with a decrease in the expression of the Slc2a4 gene in adipose tissue. Thus, the effects of estradiol on the expression of insulin cascade genes do not seem to depend on animal sex, but have tissue specificity. Since the molecular mechanism of estradiol influence on the expression of insulin cascade genes in females and males is the same, the cause of sexual differences in insulin sensitivity and the rate of development of metabolic disorders may be a decrease in the level of estradiol in the blood, as well as a decrease in the expression of estradiol receptors in the liver in males compared to females.
已证实雌二醇对女性和男性的胰岛素敏感性均有积极作用。女性的胰岛素敏感性高于男性，且男性患代谢紊乱的倾向更大。人们认为这些性别差异是由于雌二醇对女性具有保护作用，而对男性没有。雌二醇是一种类固醇激素，其作用是通过调节靶基因表达来实现的，但雌二醇对胰岛素信号转导和葡萄糖转运相关基因表达的影响尚未得到充分研究。本研究的目的是比较雌二醇对两性小鼠胰岛素敏感性影响的分子机制。研究了去势和雌二醇（1μg/只动物，持续三天）对雌性和雄性小鼠肌肉、脂肪组织和肝脏中胰岛素信号级联基因表达的影响，以及对肝脏中Fgf21、雌二醇受体（Esr1/2）和转录因子Stat3表达的影响。与假手术（Sham）雌性小鼠相比，假手术雄性小鼠的雌二醇水平较低，血糖水平和胰岛素抵抗较高。假手术雄性小鼠肝脏中的Irs2、Pik3cd和Esr1/2 mRNA水平低于假手术雌性小鼠。在雌性小鼠中，与假手术雌性小鼠相比，去势降低了血液中的雌二醇水平，增加了胰岛素抵抗和血糖水平。给去势雌性小鼠注射雌二醇可降低血液胰岛素水平和胰岛素抵抗。相反，在雄性小鼠中，去势增加了血液中的雌二醇水平，降低了血液胰岛素水平和胰岛素抵抗。雌二醇对雄性小鼠所研究的参数没有影响。去势雌性小鼠胰岛素抵抗的发展与肝脏中Irs2基因表达的降低有关。去势雄性小鼠胰岛素敏感性的增加与肝脏中Irs2和Pik3cd mRNA水平的增加有关。可以推测，无论动物性别，血液中雌二醇水平的升高都会激活肝脏中Irs2基因的表达。此外，无论动物性别，雌二醇似乎都能调节脂肪组织中的葡萄糖转运：在雌性和雄性小鼠中，血液中雌二醇水平的升高与脂肪组织中Slc2a4基因表达的降低有关。因此，雌二醇对胰岛素级联基因表达的影响似乎不取决于动物性别，而是具有组织特异性。由于雌二醇对雌性和雄性小鼠胰岛素级联基因表达影响的分子机制相同，胰岛素敏感性性别差异和代谢紊乱发展速度的原因可能是血液中雌二醇水平的降低，以及与雌性相比雄性肝脏中雌二醇受体表达的降低。
