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

研究男性克兰费尔特综合征患者的脂肪酸代谢损伤及其临床相关性

• 批准号: 10501374
• 负责人: Shanlee Davis
• 金额: $ 31.1万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501374
• 关键词: Adipose tissue; Adolescent and Young Adult; Adult; Affect; Age; Agonist; Androgens; Aneuploidy; Area; Binding; Biopsy; Body mass index; Cardiovascular Diseases; Chronic; Clinical; Complex; Data; Defect; Development; Disease; Dyslipidemias; Energy Metabolism; Exercise; Failure; Fasting; Fatigue; Fatty Acids; Fatty acid glycerol esters; Fenofibrate; Fibrates; Foundations; Functional disorder; Future; Gene Expression; Genes; Genetic Diseases; Genetic Materials; Genetic Transcription; Goals; Health; High Density Lipoprotein Cholesterol; High Prevalence; Hyperplasia; Hypertriglyceridemia; Hypogonadism; Impairment; Inborn Errors of Metabolism; Indirect Calorimetry; Individual; Infertility; Inflammation; Insulin Resistance; Intervention; Intervention Studies; Investigation; Klinefelter' s Syndrome; Life; Ligands; Lipids; Measures; Metabolic; Metabolic Pathway; Metabolism; Mission; Mitochondria; Molecular; Morbidity - disease rate; Muscle Mitochondria; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Outcome; Oxidative Phosphorylation; Oxidative Stress; PPAR alpha; Participant; Pathology; Pathway interactions; Patient Self-Report; Patient-Focused Outcomes; Pharmaceutical Preparations; Phenotype; Physiology; Plasma; Protocols documentation; Quality of life; Regulator Genes; Rest; Role; Secondary to; Skeletal Muscle; Testing; Testosterone; Therapeutic Intervention; Tissue-Specific Gene Expression; Tissues; Up-Regulation; Venous blood sampling; Whole Blood; Work; X Chromosome; Youth; base; cardiometabolism; clinical phenotype; cohort; differential expression; early childhood; epidemiology study; exercise intolerance; experience; fatty acid metabolism; functional restoration; improved; improved outcome; male; men; metabolic phenotype; metabolome; mortality; negative affect; novel; oxidation; sex chromosome aneuploidy; targeted treatment; theories; transcription factor; transcriptome; transcriptome sequencing; translational study; uptake

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.

抽象的 KlineFelter综合征（KS）是一种遗传疾病，影响有600名男性中有1个X中有1个 与多系统表现相关的染色体（47，XXY），其继发于继发的死亡率增加 胰岛素抵抗的疾病。 KS的标志性功能之一是主要的实证故障，导致 迄今为止，性能和雄激素治疗一直是其中唯一的治疗干预措施 个人。但是，在KS之前的青年中已经观察到胰岛素抵抗和异常代谢 达到检测性不足的发作。此外，睾丸激素的替换不会改善这些 心脏代谢定义了这些人中的大多数经历。基础分子 在KS中观察到的胰岛素耐药性和运动倒数的高患病率的机制为 未知。此应用程序提出，附加X染色体会导致代谢像差可能 针对治疗干预。过氧化物组增殖物激活的受体α（PPAR-α）为 转录因子调节控制脂肪酸代谢，注射和 氧化应激。低PPAR-α活性与类似于KS中观察到的心脏代谢谱有关 包括肥胖，血脂异常和运动摄入术。我们的初步数据显示了代谢组 和转录组与Ks男性PPAR-α复合物的活性不足。中央 这项研究的假设是，较低的PPAR-α活性有助于KS中的心脏代谢表型 通过PPAR-α激动剂治疗增加PPAR-α活性将导致基因转录的上调 这将改善心脏代谢生理。在这项概念验证的试验中，我们将首先比较 青少年和成年男性的全血和骨骼肌的PPAR-α调节基因， 没有KS，以及在次最大的长时间运动和组织特异性期间的全身性脂肪氧化 线粒体β氧化。静息能量消耗，代谢物浓度和以患者为中心 还将获得结果并在组之间进行比较。然后，KS队列将接受干预 使用PPAR-α激动剂（fenofrate）持续一个月，并且将重新评估所有结果。这项研究将为 未来第一种非原源治疗的未来投资基础，以改善胰岛素抵抗和 与KS男性运动。该研究旨在支持NIDDK的使命和优先领域 预计对KS的个体具有直接的临床意义。