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The Insulin/Insulin‐like Growth Factor signalling connects metabolism with sexual differentiation
Acta Physiologica ( IF 5.6 ) Pub Date : 2020-11-01 , DOI: 10.1111/apha.13576
Benjamin D. Weger 1 , Frédéric Gachon 1
Affiliation  

Sexual differentiation is a complex process, not only dependent on the XY sex‐determination system. The environment, nutrition, metabolic status, sleep and pollutants also play a pivotal role. Correspondingly, the Insulin/Insulin‐like Growth Factor (IGF) pathway has been described as a key player of sexual development and reproduction.1 In this issue, Radovic Pletikosic and colleagues demonstrated that Insulin/IGF signalling exerts its action through the regulation of steroidogenesis in Leydig cells2.

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FIGURE 1
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The regulation of sexual differentiation and reproduction by Insulin/IGF1 signalling. Schematic showing how Insulin/IGF1 signalling reprograms steroidogenesis in Leydig cells and impacts on sexual differentiation and reproduction. External factors such as environmental pollutants, metabolic status, sleep or diet affect insulin/IGF1 signalling. Insulin and IGF1 bind to their respective receptors, the insulin receptor (INSR) and IGF1 receptor (IGF1R) located on the cell membrane of Leydig cells. Both receptors are required to establish the sexual imbalance in steroidogenesis that favours androgen synthesis over oestradiol production in male mice to establish sexual differentiation and affect reproduction or fertility

Using male mice with a tissue‐specific deletion of the Insulin receptor (Insr) and IGF1 receptor (Igf1r) in steroidogenic tissues, including the Leydig cells, the authors showed that the Insulin/IGF1 pathway is required for the normal development of seminiferous tubules and the proliferation and differentiation of Leydig cells. As a consequence, Insr/Igf1r double‐knockout mice showed strongly reduced spermatogenesis and androgenic hormones synthesis and secretion. Defective steroidogenesis correlated with a decreased expression of the enzymes involved in androgen production, but conversely, there was an increased expression in the enzymes involved in the transformation of testosterone into oestrogens including aromatase (CYP19A1). Surprisingly, the observed changes in steroidogenesis are correlated with an increase of both male (Sry, Sox9) and female (Dax1, Arr19) sex‐determination markers in prepubertal animals, challenging the current view about the antagonistic genetic programs underlying gonadal sex determination.

These results provide new insights into the impact of the Insulin/IGF1 pathway on the regulation of testis physiology, reproduction and beyond. Obesity and metabolic syndrome are associated with insulin resistance and a low GH/IGF1 pathway activity.3 Moreover these pathologies are also characterized by hypogonadism and reduced testosterone levels. Weight loss through lifestyle intervention or bariatric surgery can revert the obesity‐associated hypogonadism.4 However, the involved mechanisms are still not completely understood. While a role of a conversion of testosterone into oestrogen by CYP19A1 in adipose tissue has been suggested, a global effect of obesity‐related metabolic disorders including adipose tissue size and inflammation seems to be involved.5 These factors could act directly on Leydig cells to regulate testosterone synthesis and secretion.6, 7 Indeed, Radovic Pletikosic and colleagues showed that the insulin/IGF1 pathway could likely also plays a role in the obesity‐associated hypogonadism. However, it is unclear if the observed changes in sex‐determination markers caused by Insr and Igf1r deletion are the same as in obesity‐associated hypogonadism.

The impact of hypogonadism on obesity‐related disease is still controversial. While the decreased secretion of testosterone has a detrimental effect on reproductive function, low testosterone and increased oestrogen also have a positive effect on food intake, energy balance, and insulin resistance.8 Therefore, a transient decrease of testosterone and increased oestrogen levels could be seen as a natural process to counteract obesity and its related pathology, as observed in animal models.9 Contrarily, from an evolutionary point of view, this could be regarded as a way to decrease fertility and reproduction capacity of “unhealthy” obese males. Example for this scenario exists, male mice infected by the parasite Taenia crassiceps exhibit a drastically feminized sex hormone profile.10 However, a comparable example has not been described for human yet.

In conclusion, the results published by Radovic Pletikosic and colleagues2 suggest that sexual differentiation might involve a direct effect of obesity‐related factors on the testis, and in particular on Leydig cells, through a modification of the expression of sex‐determination factors, even in adult animals . In light of these observations, sexual differentiation is likely more plastic than generally assumed and links the influence of environmental factors, metabolic fitness and health conditions to male physiology, metabolism and reproductive capacity (Figure 1).



中文翻译:

胰岛素/类胰岛素生长因子信号传导将新陈代谢与性别分化联系起来

性别分化是一个复杂的过程,不仅取决于XY性别决定系统。环境,营养,代谢状态,睡眠和污染物也起着关键作用。相应地,胰岛素/类胰岛素生长因子(IGF)途径被描述为性发育和生殖的关键因素。1在本期杂志中,Radovic Pletikosic及其同事证明了胰岛素/ IGF信号传导通过调节Leydig细胞中类固醇生成来发挥其作用2

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图1
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胰岛素/ IGF1信号传导对性分化和生殖的调节。示意图显示胰岛素/ IGF1信号传导如何重新编程Leydig细胞中的类固醇生成及其对性分化和生殖的影响。外部因素(例如环境污染物,代谢状态,睡眠或饮食)会影响胰岛素/ IGF1信号传导。胰岛素和IGF1与其各自的受体结合,即位于Leydig细胞细胞膜上的胰岛素受体(INSR)和IGF1受体(IGF1R)。需要两种受体来建立类固醇生成中的性失衡,从而促进雄性小鼠中雄激素合成而不是雌二醇生成,从而建立性别分化并影响生殖或生育能力

作者使用在类固醇生成组织(包括Leydig细胞)中具有胰岛素特异性受体(Insr)和IGF1受体(Igf1r)的组织特异性缺失的雄性小鼠,作者表明胰岛素/ IGF1途径对于细精管和白细胞的正常发育是必需的。 Leydig细胞的增殖和分化。因此,Insr / Igf1r双基因敲除小鼠的精子发生和雄激素的合成与分泌都大大减少。不良的类固醇生成与雄激素产生所涉及的酶的表达降低相关,但相反,参与睾丸激素向包括芳香化酶(CYP19A1)的雌激素转化的酶的表达升高。令人惊讶地,在类固醇生成所观察到的变化与增加男性(的相关Sry基因Sox9的)和雌性(DAX1Arr19在青春期前的动物)性别决定标记,挑战大约底层性腺性别决定的拮抗的遗传程序的当前视图。

这些结果提供了有关胰岛素/ IGF1途径对睾丸生理,生殖及其他调控的影响的新见解。肥胖和代谢综合征与胰岛素抵抗和低GH / IGF1通路活性有关。3此外,这些病理特征还在于性腺功能低下和睾丸激素水平降低。通过生活方式干预或减肥手术减轻体重,可以减轻与肥胖相关的性腺功能减退。4但是,所涉及的机制仍未完全理解。尽管有人提出通过CYP19A1在脂肪组织中将睾丸激素转化为雌激素的作用,但似乎涉及与肥胖相关的代谢紊乱的整体影响,包括脂肪组织的大小和炎症。5这些因子可以直接作用于Leydig细胞,以调节睾丸激素的合成和分泌。[6,7]的确,Radovic Pletikosic及其同事表明,胰岛素/ IGF1途径也可能在肥胖相关性腺功能减退症中起作用。但是,尚不清楚由InsrIgf1r缺失引起的性别决定标志的观察到的变化与肥胖相关性腺功能减退是否相同。

性腺功能减退对肥胖相关疾病的影响仍存在争议。睾丸激素分泌减少对生殖功能有不利影响,而睾丸激素水平低和雌激素增加对食物摄入,能量平衡和胰岛素抵抗也有积极作用。8因此,如在动物模型中所观察到的,睾丸激素的短暂降低和雌激素水平的升高可被视为抵抗肥胖及其相关病理的自然过程。9相反,从进化的角度来看,这可以被视为降低“不健康”肥胖男性生育能力和繁殖能力的一种方式。存在这种情况的示例,被寄生虫Taenia crassiceps感染的雄性小鼠表现出急剧女性化的性激素特征。10然而,还没有为人类描述一个可比较的例子。

总之,Radovic Pletikosic及其同事[ 2]公布的结果表明,性别差异可能通过改变性别决定因子的表达,甚至可能与肥胖相关因素对睾丸,尤其是对睾丸间质细胞的直接作用有关。在成年动物中。根据这些观察结果,性别分化可能比普遍认为的更具可塑性,并将环境因素,代谢适应性和健康状况的影响与男性生理,代谢和生殖能力联系起来(图1)。

更新日期:2020-11-01
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