Abstract：
BACKGROUND: Obesity-induced hypogonadism (OIH) is a prevalent, but often neglected condition in men, which aggravates the metabolic complications of overweight. While hypothalamic suppression of Kiss1-encoded kisspeptin has been suggested to contribute to OIH, the molecular mechanisms for such repression in obesity, and the therapeutic implications thereof, remain unknown.
METHODS: A combination of bioinformatic, expression and functional analyses was implemented, assessing the role of the evolutionary-conserved miRNAs, miR-137 and miR-325, in mediating obesity-induced suppression of hypothalamic kisspeptin, as putative mechanism of central hypogonadism and metabolic comorbidities. The implications of such miR-137/325-kisspeptin interplay for therapeutic intervention in obesity were also explored using preclinical OIH models.
RESULTS: MiR-137/325 repressed human KISS1 3\'-UTR in-vitro and inhibited hypothalamic kisspeptin content in male rats, while miR-137/325 expression was up-regulated, and Kiss1/kisspeptin decreased, in the medio-basal hypothalamus of obese rats. Selective over-expression of miR-137 in Kiss1 neurons reduced Kiss1/ kisspeptin and partially replicated reproductive and metabolic alterations of OIH in lean mice. Conversely, interference of the repressive actions of miR-137/325 selectively on Kiss1 3\'-UTR in vivo, using target-site blockers (TSB), enhanced kisspeptin content and reversed central hypogonadism in obese rats, together with improvement of glucose intolerance, insulin resistance and cardiovascular and inflammatory markers, despite persistent exposure to obesogenic diet. Reversal of OIH by TSB miR-137/325 was more effective than chronic kisspeptin or testosterone treatments in obese rats.
CONCLUSIONS: Our data disclose that the miR-137/325-Kisspeptin repressive interaction is a major player in the pathogenesis of obesity-induced hypogonadism and a putative druggable target for improved management of this condition and its metabolic comorbidities in men suffering obesity.
CONCLUSIONS: Up to half of the men suffering obesity display also central hypogonadism, an often neglected complication of overweight that can aggravate the clinical course of obesity and its complications. The mechanisms for such obesity-induced hypogonadism remain poorly defined. We show here that the evolutionary conserved miR137/miR325 tandem centrally mediates obesity-induced hypogonadism via repression of the reproductive-stimulatory signal, kisspeptin; this may represent an amenable druggable target for improved management of hypogonadism and other metabolic complications of obesity.
METHODS: A combination of bioinformatic, expression and functional analyses was implemented, assessing the role of the evolutionary-conserved miRNAs, miR-137 and miR-325, in mediating obesity-induced suppression of hypothalamic kisspeptin, as putative mechanism of central hypogonadism and metabolic comorbidities. The implications of such miR-137/325-kisspeptin interplay for therapeutic intervention in obesity were also explored using preclinical OIH models.
RESULTS: MiR-137/325 repressed human KISS1 3\'-UTR in-vitro and inhibited hypothalamic kisspeptin content in male rats, while miR-137/325 expression was up-regulated, and Kiss1/kisspeptin decreased, in the medio-basal hypothalamus of obese rats. Selective over-expression of miR-137 in Kiss1 neurons reduced Kiss1/ kisspeptin and partially replicated reproductive and metabolic alterations of OIH in lean mice. Conversely, interference of the repressive actions of miR-137/325 selectively on Kiss1 3\'-UTR in vivo, using target-site blockers (TSB), enhanced kisspeptin content and reversed central hypogonadism in obese rats, together with improvement of glucose intolerance, insulin resistance and cardiovascular and inflammatory markers, despite persistent exposure to obesogenic diet. Reversal of OIH by TSB miR-137/325 was more effective than chronic kisspeptin or testosterone treatments in obese rats.
CONCLUSIONS: Our data disclose that the miR-137/325-Kisspeptin repressive interaction is a major player in the pathogenesis of obesity-induced hypogonadism and a putative druggable target for improved management of this condition and its metabolic comorbidities in men suffering obesity.
CONCLUSIONS: Up to half of the men suffering obesity display also central hypogonadism, an often neglected complication of overweight that can aggravate the clinical course of obesity and its complications. The mechanisms for such obesity-induced hypogonadism remain poorly defined. We show here that the evolutionary conserved miR137/miR325 tandem centrally mediates obesity-induced hypogonadism via repression of the reproductive-stimulatory signal, kisspeptin; this may represent an amenable druggable target for improved management of hypogonadism and other metabolic complications of obesity.
摘要：
背景：肥胖引起的性腺功能减退症（OIH）是一种普遍存在的，但经常忽视男性的状况，加重了超重的代谢并发症。虽然下丘脑对Kiss1编码的kisspeptin的抑制被认为有助于OIH，抑制肥胖的分子机制，及其治疗意义，仍然未知。
方法：生物信息学，进行了表达和功能分析，评估进化保守的miRNA的作用，miR-137和miR-325在介导肥胖诱导的下丘脑kisspeptin抑制中，作为中枢性腺功能减退和代谢合并症的推定机制。还使用临床前OIH模型探索了此类miR-137/325-kisspeptin相互作用对肥胖的治疗性干预的意义。
结果：MiR-137/325在体外抑制人KISS13'-UTR，并抑制雄性大鼠下丘脑kisspeptin含量，而miR-137/325表达上调，Kiss1/kisspeptin下降，肥胖大鼠中底下丘脑。miR-137在Kiss1神经元中的选择性过表达减少了Kiss1/kisspeptin，并部分复制了瘦小鼠中OIH的生殖和代谢改变。相反，在体内干扰miR-137/325对Kiss13'-UTR的选择性抑制作用，使用目标位点阻断剂(TSB)，肥胖大鼠中kisspeptin含量增加和中枢性腺功能减退症逆转，随着葡萄糖不耐受的改善，胰岛素抵抗和心血管和炎症标志物，尽管持续暴露于肥胖饮食。在肥胖大鼠中，TSBmiR-137/325逆转OIH比慢性kisspeptin或睾酮治疗更有效。
结论：我们的数据表明，miR-137/325-Kisspeptin抑制相互作用是肥胖诱导性腺功能减退症发病机制的主要参与者，也是肥胖男性患者改善这种情况及其代谢合并症治疗的公认药物靶标。
结论：多达一半的肥胖男性也表现出中枢性腺功能减退，经常被忽视的超重并发症，可加重肥胖及其并发症的临床进程。这种肥胖诱导的性腺机能减退的机制仍然不清楚。我们在这里表明，进化保守的miR137/miR325串联通过抑制生殖刺激信号集中介导肥胖诱导的性腺机能减退，kisspeptin;这可能是改善性腺功能减退和肥胖的其他代谢并发症管理的一个可行的药物靶标。
方法：生物信息学，进行了表达和功能分析，评估进化保守的miRNA的作用，miR-137和miR-325在介导肥胖诱导的下丘脑kisspeptin抑制中，作为中枢性腺功能减退和代谢合并症的推定机制。还使用临床前OIH模型探索了此类miR-137/325-kisspeptin相互作用对肥胖的治疗性干预的意义。
结果：MiR-137/325在体外抑制人KISS13'-UTR，并抑制雄性大鼠下丘脑kisspeptin含量，而miR-137/325表达上调，Kiss1/kisspeptin下降，肥胖大鼠中底下丘脑。miR-137在Kiss1神经元中的选择性过表达减少了Kiss1/kisspeptin，并部分复制了瘦小鼠中OIH的生殖和代谢改变。相反，在体内干扰miR-137/325对Kiss13'-UTR的选择性抑制作用，使用目标位点阻断剂(TSB)，肥胖大鼠中kisspeptin含量增加和中枢性腺功能减退症逆转，随着葡萄糖不耐受的改善，胰岛素抵抗和心血管和炎症标志物，尽管持续暴露于肥胖饮食。在肥胖大鼠中，TSBmiR-137/325逆转OIH比慢性kisspeptin或睾酮治疗更有效。
结论：我们的数据表明，miR-137/325-Kisspeptin抑制相互作用是肥胖诱导性腺功能减退症发病机制的主要参与者，也是肥胖男性患者改善这种情况及其代谢合并症治疗的公认药物靶标。
结论：多达一半的肥胖男性也表现出中枢性腺功能减退，经常被忽视的超重并发症，可加重肥胖及其并发症的临床进程。这种肥胖诱导的性腺机能减退的机制仍然不清楚。我们在这里表明，进化保守的miR137/miR325串联通过抑制生殖刺激信号集中介导肥胖诱导的性腺机能减退，kisspeptin;这可能是改善性腺功能减退和肥胖的其他代谢并发症管理的一个可行的药物靶标。
