Testosterone is sequestered in dysfunctional adipose tissue, modifying androgen-responsive genes.,International Journal of Obesity

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Testosterone is sequestered in dysfunctional adipose tissue, modifying androgen-responsive genes.
International Journal of Obesity ( IF 4.2 ) Pub Date : 2020-03-17 , DOI: 10.1038/s41366-020-0568-9
Andrea Di Nisio ₁ , Iva Sabovic ₁ , Luca De Toni ₁ , Maria Santa Rocca ₂ , Stefano Dall'Acqua ₃ , Bruno Azzena ₄ , Maurizio De Rocco Ponce ₁ , Carlo Foresta ₁

Affiliation

Background/objective

The recognized association between male hypogonadism and obesity has multifactorial implications on adipose tissue (AT) physiology. The fat solubility of testosterone (T) suggests a sequestration process in fat depots, leading to reduced circulating levels of T in obesity. Several evidence suggest that steroids play a two-sided inhibitory role on adipogenesis by locally decreasing lipid accumulation and by stimulating lipolysis. The current study investigates T trafficking and activity in dysfunctional AT.

Subjects/methods

Samples of subcutaneous AT (SAT) were obtained from explants from lipoaspirate plastic surgery in six obese and six normal weight male patients. Experimental procedures on both SAT explants and insulin-resistant (IR) 3T3-L1 adipocytes were performed, including real-time PCR and mass-spectrometry quantification.

Results

A significant deregulation of gene responsiveness to androgens in IR cells and obese SAT was observed (all p < 0.05), together with reduced T release after adrenergic stimulation (−10% compared with −55% in lean SAT, p = 0.021). Higher concentrations of intracellular T and estradiol in obese SAT were also observed (2.4 vs. 1.3 ng/g, p = 0.013 and 0.075 vs. 0.22 ng/g, p = 0.004, respectively). Testosterone accumulation resulted in even lower expression in androgen-responsive genes involved in lipolytic and anti-adipogenic pathways from both in vitro and ex vivo experiments.

Conclusions

These results suggest an altered response of dysfunctional fat cells to testosterone stimulation, which normally favors lipolysis and induces an anti-adipogenic effect. The considerable reduction of lipolytic T release after adrenergic stimulation in obese SAT contributes to AT dysfunction, in a feedforward loop further reducing T levels in obese hypogonadal males.

中文翻译：

睾酮隔离在功能失调的脂肪组织中，修饰雄激素反应基因。

背景/目标

男性性腺机能减退和肥胖之间公认的关联对脂肪组织 (AT) 生理学具有多因素影响。睾酮 (T) 的脂溶性表明脂肪库中有一个隔离过程，导致肥胖中 T 的循环水平降低。一些证据表明，类固醇通过局部减少脂质积累和刺激脂肪分解，对脂肪生成具有双重抑制作用。当前的研究调查了功能失调的 AT 中的 T 贩运和活动。

课题/方法

皮下 AT (SAT) 样本是从 6 名肥胖男性和 6 名正常体重男性患者的脂肪抽吸整形手术的外植体中获得的。对 SAT 外植体和胰岛素抵抗 (IR) 3T3-L1 脂肪细胞进行了实验程序，包括实时 PCR 和质谱定量。

结果

观察到 IR 细胞和肥胖 SAT 中对雄激素的基因反应性显着失调（所有p < 0.05），以及肾上腺素能刺激后 T 释放减少（-10% 与瘦 SAT 中的 -55% 相比，p = 0.021）。在肥胖 SAT 中还观察到更高浓度的细胞内 T 和雌二醇（分别为 2.4 对 1.3 ng/g，p = 0.013 和 0.075 对 0.22 ng/g，p = 0.004）。在体外和离体实验中，睾酮积累导致参与脂解和抗脂肪生成途径的雄激素反应基因的表达甚至更低。