Objective

Low testosterone in men (hypogonadism) is associated with obesity and type II diabetes. Testosterone replacement therapy has been shown to reverse these effects. However, the mechanisms by which testosterone regulates total fat mass, fat distribution, and metabolic health are unclear. In this study, we clarify the impact of hypogonadism on these parameters, as well as parse the role of testosterone from its downstream metabolites, dihydrotestosterone (DHT), and estradiol, in the regulation of depot-specific adipose tissue mass.

Methods

To achieve this objective, we utilized mouse models of male hypogonadism coupled with hormone replacement therapy, magnetic resonance imaging (MRI), glucose tolerance tests, flow cytometry, and immunohistochemical techniques.

Results

We observed that castrated mice develop increased fat mass, reduced muscle mass, and impaired glucose metabolism compared with gonadally intact males. Interestingly, obesity is further accelerated in castrated mice fed a high-fat diet, suggesting hypogonadism increases susceptibility to obesogenesis when dietary consumption of fat is elevated. By performing hormone replacement therapy in castrated mice, we show that testosterone impedes visceral and subcutaneous fat mass expansion. Testosterone-derived estradiol selectively blocks visceral fat growth, and DHT selectively blocks the growth of subcutaneous fat. These effects are mediated by depot-specific alterations in adipocyte size. We also show that high-fat diet-induced adipogenesis is elevated in castrated mice and that this can be rescued by androgen treatment. Obesogenic adipogenesis is also elevated in mice where androgen receptor activity is inhibited.

Conclusions

These data indicate that hypogonadism impairs glucose metabolism and increases obesogenic fat mass expansion through adipocyte hypertrophy and adipogenesis. In addition, our findings highlight distinct roles for testosterone, DHT, and estradiol in the regulation of total fat mass and fat distribution and reveal that androgen signaling blocks obesogenic adipogenesis in vivo.

中文翻译：

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睾酮代谢物差异调节肥胖和脂肪分布

客观的

男性睾酮水平低（性腺机能减退）与肥胖和 II 型糖尿病有关。睾酮替代疗法已被证明可以逆转这些影响。然而，睾酮调节总脂肪量、脂肪分布和代谢健康的机制尚不清楚。在这项研究中，我们阐明了性腺机能减退对这些参数的影响，并从其下游代谢物、二氢睾酮 (DHT) 和雌二醇中解析了睾酮在调节库特异性脂肪组织质量中的作用。

方法

为了实现这一目标，我们利用雄性性腺功能减退症小鼠模型与激素替代疗法、磁共振成像 (MRI)、葡萄糖耐量测试、流式细胞术和免疫组织化学技术相结合。

结果

我们观察到，与性腺完整的雄性相比，阉割的小鼠脂肪量增加，肌肉量减少，葡萄糖代谢受损。有趣的是，在喂食高脂肪饮食的阉割小鼠中，肥胖进一步加速，这表明当饮食脂肪消耗量增加时，性腺机能减退会增加对肥胖发生的易感性。通过对去势小鼠进行激素替代疗法，我们表明睾酮阻碍内脏和皮下脂肪量的膨胀。睾酮衍生的雌二醇选择性地阻止内脏脂肪的生长，而 DHT 则选择性地阻止皮下脂肪的生长。这些效应是由脂肪细胞大小的仓库特异性改变介导的。我们还表明，高脂肪饮食诱导的脂肪生成在去势小鼠中升高，这可以通过雄激素治疗来挽救。

结论

这些数据表明，性腺机能减退会损害葡萄糖代谢并通过脂肪细胞肥大和脂肪生成增加致胖脂肪量。此外，我们的研究结果强调了睾酮、DHT 和雌二醇在调节总脂肪量和脂肪分布中的不同作用，并揭示雄激素信号在体内阻断致胖脂肪生成。