Interrogating Fatty Acid Metabolism Impairment andClinical Correlates in Males with Klinefelter Syndrome

摘要 Klinefelter综合征(KS)是一种遗传性疾病，每600名男性中就有1人有额外的X 染色体(47，XXY)与多系统症状和继发性死亡相关 胰岛素抵抗障碍。KS的特征之一是原发睾丸衰竭，导致 性腺功能减退，到目前为止，雄激素治疗一直是这些研究中唯一的治疗干预措施。 个人。然而，在患有KS的年轻人中已经观察到胰岛素抵抗和代谢异常。 导致睾丸性腺功能减退。此外，替代睾丸素并不能改善这些症状。 这些人中的大多数人都经历了心脏代谢缺陷。潜在的分子 在KS中观察到的胰岛素抵抗和运动不耐受高发的机制是 未知。这一应用表明，额外的X染色体会导致代谢异常，从而 成为治疗干预的目标。过氧化物酶体增殖物激活受体α(PPAR-α)是 一种转录因子，调节控制脂肪酸代谢、炎症和 氧化应激。低PPAR-α活性与心脏代谢特征有关，类似于在KS观察到的情况， 包括肥胖、血脂异常和运动不耐受。我们的初步数据显示了一种代谢物 转录组与男性KS患者PPAR-α复合体活性不足一致。中环 这项研究的假设是PPAR-α活性降低与KS和KS的心脏代谢表型有关。 通过PPAR-α激动剂治疗提高PPAR-α活性将导致基因转录上调 这将改善心脏新陈代谢生理学。在这项概念验证试验中，我们将首先比较 PPAR-α调节的青春期和青壮年男性患者全血和骨骼肌中的基因 没有KS，以及在亚极量长时间运动和组织特异性运动中的全身脂肪氧化 线粒体氧化。静息能量消耗、代谢物浓度和以患者为中心 还将获得结果并在不同组之间进行比较。然后，KS队列将接受干预 使用PPAR-α激动剂(非诺贝特)治疗一个月，所有结果将被重新评估。这项研究将为 为未来研究首次非雄激素治疗改善胰岛素抵抗和 男性KS患者的运动不耐受。该研究的目的是支持NIDDK的使命和优先领域以及 预计将对KS患者产生直接的临床影响。

ABSTRACT Klinefelter syndrome (KS) is a genetic condition affecting 1 in 600 males who have an additional X chromosome (47,XXY) associated with multisystem manifestations and increased mortality secondary to disorders of insulin resistance. One of the hallmark features of KS is primary testicular failure resulting in hypogonadism, and to date androgen treatment has been the only therapeutic intervention studied in these individuals. However, insulin resistance and abnormal metabolism have been observed in youth with KS prior to the onset of testicular hypogonadism. Furthermore, testosterone replacement does not ameliorate these cardiometabolic deficits that the majority of these individuals experience. The underlying molecular mechanisms for the high prevalence of insulin resistance and exercise intolerance observed in KS are unknown. This application proposes that the additional X chromosome leads to metabolic aberrations that can be targeted for therapeutic intervention. Peroxisome proliferator-activated receptor alpha (PPAR-α) is transcription factor that regulates the expression of genes controlling fatty acid metabolism, inflammation, and oxidative stress. Low PPAR-α activity is associated with cardiometabolic profiles similar to that observed in KS, including adiposity, dyslipidemia, and exercise intolerance. Our preliminary data have shown a metabolome and transcriptome consistent with insufficient activity of the PPAR-α complex in males with KS. The central hypothesis of this study is that lower PPAR-α activity contributes to the cardiometabolic phenotype in KS and that increasing PPAR-α activity via PPAR-α agonist treatment will result in upregulation of gene transcription that will improve cardiometabolic physiology. In this proof-of-concept trial, we will first compare expression of PPAR-α-regulated genes from whole blood and skeletal muscle in adolescent and young adult males with and without KS, as well as systemic fat oxidation during submaximal prolonged exercise and tissue-specific mitochondrial ß-oxidation. Resting energy expenditure, metabolite concentrations, and patient-centered outcomes will also be obtained and compared between groups. The KS cohort will then receive intervention with a PPAR- α agonist (fenofibrate) for one month, and all outcomes will be reassessed. This study will lay the foundation for future investigation of the first ever non-androgen treatment to improve insulin resistance and exercise intolerance in males with KS. The study aims support the mission and priority areas of the NIDDK and are expected to have direct clinical implications for individuals with KS.