Reintroducing testosterone in the db/db mouse partially restores normal glucose metabolism and insulin resistance in a leptin-independent manner.
Reintroducing testosterone in the db/db mouse partially restores normal glucose metabolism and insulin resistance in a leptin-independent manner.
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DOI：
10.1186/s12902-018-0266-y
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发表时间：
2018-06-13
影响因子：
2.7
通讯作者：
Tokushige A
中科院分区：
文献类型：
--
作者：
Yabiku K;Nakamoto K;Tokushige A
睾酮信号通过雄激素受体(AR)和AR基因敲除的小鼠发生肥胖，这表明AR和瘦素信号之间存在功能关联。此外，人们还发现，血液中生理浓度的睾酮可以抑制动脉硬化、肥胖和糖尿病的发生。然而，这些发现还没有被动物模型中的睾酮替代所证实，而且睾酮是直接通过激活AR来增强瘦素信号，还是间接地通过将其转化为雌激素仍不清楚。因此，我们研究了外源性补充睾酮对糖脂代谢的影响。四周大的雄性瘦素受体基因敲除的db/db小鼠作为肥胖模型的对照，保持低睾酮。将小鼠分为假手术组、去势组、去势+补充睾丸素组，从5周龄开始给予高脂饮食(HFD)2周。测定睾酮浓度、血糖、血浆胰岛素水平、腹膜糖耐量和胰岛素耐量。7周后，测定肝脏和肌肉中甘油三酯和糖原的含量。肝脏和比目鱼肌的脂肪蓄积用油红O免疫组织化学方法测定，统计分析采用学生t检验或方差分析。Db/db小鼠与野生型(Wt)db/+小鼠相比，睾酮水平较低与糖耐量异常和脂肪肝有关。此外，4周龄的去势雄性db/db小鼠逐渐出现葡萄糖耐量异常，并伴有15%的肝脏脂肪增加。与那些喂食正常饮食的雄性小鼠相比，喂食HFD的雄性小鼠的睾丸激素水平较低。我们发现，在去势的雄性db/db小鼠皮下注射外源性睾酮替代可以缓解脂肪肝和糖耐量减低的恶化，这表明了一种瘦素非依赖的机制。在这个小鼠模型中，这种机制很可能是通过抑制性腺轴来实现的。综上所述，睾酮可能通过补充瘦素信号调节糖脂代谢的新途径，为代谢紊乱的治疗提供新的靶点。本文的在线版本(10.1186/s12902-0180266-y)包含向授权用户提供的补充材料。
Testosterone signals through the androgen receptor (AR) and AR knockout mice develop obesity, suggesting a functional association between AR and leptin signaling. Furthermore, physiological blood concentrations of testosterone have been found to inhibit the development of arteriosclerosis, obesity and diabetes. However, these findings have not been verified by testosterone replacement in animal models and whether or not testosterone acts directly by activating AR to enhance leptin signaling, or indirectly by its conversion into estrogen remains unclear. Therefore, we investigated the effect of exogenously supplemented testosterone on glucose and lipid metabolism. Four-week-old male leptin receptor-knockout db/db mice were used as controls for a model of obesity retaining low testosterone. Mice were divided into sham-operated, castrated, or castrated and testosterone-supplemented groups and fed a high-fat diet (HFD) for 2 weeks from 5 weeks of age. Testosterone concentrations, blood glucose, plasma insulin levels, and intraperitoneal glucose tolerance and insulin tolerance were measured. At 7 weeks, triglyceride and glycogen content were measured in the liver and muscle. Lipid accumulation in the liver and soleus muscle was determined by immunohistochemistry with Oil Red O. Statistical analyses were performed using the Student’s t-test or ANOVA where applicable. Lower testosterone levels in db/db mice compared with wild type (WT) db/+ mice were associated with glucose intolerance and fatty liver. Furthermore, castrated male db/db mice at 4 weeks of age progressively developed glucose intolerance accompanying a 15% increase in liver fat. Male mice fed a HFD had lower levels of testosterone compared with those fed a normal diet. We found that exogenous testosterone replacement injected subcutaneously into castrated male db/db mice alleviated the exacerbation of fatty liver and glucose intolerance, suggesting a leptin-independent mechanism. This mechanism is most likely mediated through gonadal axis suppression in this mouse model. In summary, testosterone may use a novel pathway to complement leptin signaling to regulate glucose and lipid metabolism, and thus offers a new therapeutic target to treat metabolic disorders. The online version of this article (10.1186/s12902-018-0266-y) contains supplementary material, which is available to authorized users.
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影响因子：
15.9
作者：
Le Bacquer, Olivier;Petroulakis, Emmanuel;Sonenberg, Nahum
通讯作者：
Sonenberg, Nahum
DOI：
10.1161/01.atv.0000150041.81963.68
发表时间：
2005-01-01
影响因子：
8.7
作者：
Ivashchenko, Y;Kramer, F;Torzewski, J
通讯作者：
Torzewski, J
影响因子：
82.9
作者：
Brunham, Liam R.;Kruit, Janine K.;Hayden, Michael R.
通讯作者：
Hayden, Michael R.
影响因子：
6.7
作者：
CHAMNESS, SL;RICKER, DD;CHANG, TSK
通讯作者：
CHANG, TSK
影响因子：
5.8
作者：
Higa, M;Shimabukuro, M;Inaba, T
通讯作者：
Inaba, T