Department of Maternal and Child Health, School of Public Health, China Medical University, Shenyang, Liaoning, China.
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, Liaoning, China.
Endocrine. 2018 Oct;62(1):195-206. doi: 10.1007/s12020-018-1646-9. Epub 2018 Jun 13.
Obesity may lead to male hypogonadism, the underlying mechanism of which remains unclear. In the present study, we established a murine model of male hypogonadism caused by high-fat diet-induced obesity to verify the following hypotheses: 1) an increased leptin level may be related to decreased secretion of GnRH in obese males, and 2) repression of kisspeptin/GPR54 in the hypothalamus, which is associated with increased leptin levels, may account for the decreased secretion of GnRH and be involved in secondary hypogonadism (SH) in obese males.
Male mice were fed high-fat diet for 19 weeks and divided by body weight gain into diet-induced obesity (DIO) and diet-induced obesity resistant (DIO-R) group. The effect of obesity on the reproductive organs in male mice was observed by measuring sperm count and spermatozoid motility, relative to testis and epididymis weight, testosterone levels, and pathologic changes. Leptin, testosterone, estrogen, and LH in serum were detected by ELISA method. Leptin receptor (Ob-R), Kiss1, GPR54, and GnRH mRNA were measured by real-time PCR in the hypothalamus. Expression of kisspeptin and Ob-R protein was determined by Western blotting. Expression of GnRH and GPR54 protein was determined by immunohistochemical analysis.
We found that diet-induced obesity decreased spermatozoid motility, testis and epididymis relative coefficients, and plasma testosterone and luteinizing hormone levels. An increased number and volume of lipid droplets in Leydig cells were observed in the DIO group compared to the control group. Significantly, higher serum leptin levels were found in the DIO and DIO-R groups. The DIO and DIO-R groups showed significant downregulation of the GnRH, Kiss1, GPR54, and Ob-R genes. We also found decreased levels of GnRH, kisspeptin, GPR54, and Ob-R protein in the DIO and DIO-R groups.
These lines of evidence suggest that downregulation of Ob-R and kisspeptin/GPR54 in the murine hypothalamus may contribute to male hypogonadism caused by high-fat diet-induced obesity.
肥胖可能导致男性性腺功能减退症，其潜在机制尚不清楚。本研究建立了高脂饮食诱导肥胖致雄性性腺功能减退症的小鼠模型，验证以下假说：1）瘦素水平升高可能与肥胖男性 GnRH 分泌减少有关，2）下丘脑 kisspeptin/GPR54 受抑制与瘦素水平升高有关，可能导致 GnRH 分泌减少，并参与肥胖男性的继发性性腺功能减退症（SH）。
雄性小鼠给予高脂饮食 19 周，根据体重增加分为饮食诱导肥胖（DIO）和饮食诱导肥胖抵抗（DIO-R）组。通过测量精子计数和精子活力、睾丸和附睾重量、睾酮水平以及组织病理学变化，观察肥胖对雄性小鼠生殖器官的影响。采用 ELISA 法检测血清瘦素、睾酮、雌激素和 LH 水平。实时 PCR 检测下丘脑瘦素受体（Ob-R）、Kiss1、GPR54 和 GnRH mRNA。Western blot 法检测 kisspeptin 和 Ob-R 蛋白表达。免疫组化分析 GnRH 和 GPR54 蛋白表达。
我们发现饮食诱导肥胖降低了精子活力、睾丸和附睾相对系数以及血浆睾酮和黄体生成素水平。与对照组相比，DIO 组的 Leydig 细胞中脂质滴数量和体积增加。DIO 和 DIO-R 组血清瘦素水平明显升高。DIO 和 DIO-R 组 GnRH、Kiss1、GPR54 和 Ob-R 基因表达显著下调。我们还发现 DIO 和 DIO-R 组 GnRH、kisspeptin、GPR54 和 Ob-R 蛋白水平降低。
这些证据表明，小鼠下丘脑 Ob-R 和 kisspeptin/GPR54 下调可能导致高脂饮食诱导肥胖所致的男性性腺功能减退症。
