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.

摘要 Klinefelter综合征（KS）是一种遗传性疾病，每600名男性中就有1名患有额外的X染色体 染色体（47，XXY）与多系统表现和继发于 胰岛素抵抗性疾病。KS的标志性特征之一是原发性睾丸功能衰竭， 性腺功能减退症，到目前为止，雄激素治疗一直是唯一的治疗干预研究，在这些 个体然而，胰岛素抵抗和代谢异常已观察到青年与KS事先 睾丸性腺功能减退症的发病此外，睾酮替代并不能改善这些症状。 这些人中的大多数都经历过心脏代谢缺陷。潜在的分子 在KS中观察到的胰岛素抵抗和运动不耐受的高患病率的机制是 未知该申请提出，额外的X染色体导致代谢畸变， 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 调节控制脂肪酸代谢、炎症和炎症的基因表达的转录因子， 氧化应激低PPAR-α活性与心脏代谢特征相关，与KS中观察到的相似， 包括肥胖症、血脂异常和运动不耐受。我们的初步数据显示 和转录组与KS男性中PPAR-α复合物活性不足一致。中央 本研究假设较低的PPAR-α活性有助于KS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上调， 这将改善心脏代谢生理。在这个概念验证试验中，我们将首先比较 青少年和年轻成年男性中全血和骨骼肌中的PPAR-α调节基因， 没有KS，以及在次极量长时间运动和组织特异性 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间进行比较。KS队列将接受干预 与PPAR- α激动剂（非诺贝特）治疗一个月，并将重新评估所有结局。这项研究将奠定 为未来研究首次非雄激素治疗改善胰岛素抵抗奠定了基础， KS男性患者的运动不耐受。该研究旨在支持NIDDK的使命和优先领域， 预计对KS患者有直接的临床意义。