Effects of Androgen Excess on Lipid Distribution in Congenital Adrenal Hyperplasia

雄激素过多对先天性肾上腺增生症脂质分布的影响

• 批准号: 10163889
• 负责人: Mimi Susan Kim
• 金额: $ 9.15万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163889
• 关键词: 21-hydroxylase deficiency; Abdomen; Adipocytes; Adipose tissue; Affect; Age; Androgen Antagonists; Androgen Receptor; Androgens; Animal Model; Apple; Area; Beta Cell; Body Composition; Body Weight decreased; Body fat; Body mass index; CYP21A2 gene; Cardiovascular system; Central obesity; Chemical Shift Imaging; Childhood; Cholesterol; Clinical Trials; Collaborations; Colorado; Congenital adrenal hyperplasia; Deposition; Disease model; Drug or chemical Tissue Distribution; Dual-Energy X-Ray Absorptiometry; Endocrine; Energy Metabolism; Estradiol; Event; Exhibits; Exposure to; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Female; First Pregnancy Trimester; Gene Expression Regulation; Genotype; Goals; Gonadal Steroid Hormones; Growth; Height; Hepatic; High Density Lipoproteins; Hormones; Human; Hypertension; Hypothalamic structure; Imaging Techniques; Individual; Insulin Resistance; Interleukin-6; Intra-abdominal; Investigation; Leptin; Link; Lipids; Live Birth; Liver; Longevity; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Mentored Patient-Oriented Research Career Development Award; Metabolic; Metabolic Diseases; Muscle; National Institute of Child Health and Human Development; Neonatal Screening; Nonesterified Fatty Acids; Obesity; Organ; Outcome; Participant; Pathogenesis; Patients; Pear; Pediatric Hospitals; Pharmaceutical Preparations; Plasminogen Activator Inhibitor 1; Play; Polycystic Ovary Syndrome; Protons; Regulation; Risk; Risk Factors; Role; Saturated Fatty Acids; Severities; Sex Differences; TNF gene; Testing; Testosterone; Tissues; Transaminases; Triglycerides; Unsaturated Fatty Acids; Visceral; Youth; abdominal fat; adipokines; adiponectin; adverse outcome; base; blood glucose regulation; bone age; cardiometabolic risk; cardiometabolism; circulating biomarkers; early childhood; early pregnancy; hormone regulation; human model; imaging study; improved; inflammatory marker; insulin sensitivity; insulin sensitizing drugs; low density lipoprotein triglyceride; male; men; nutrition; postnatal; prenatal; resistin; secondary analysis; sex; spectroscopic imaging; subcutaneous; targeted treatment; transgender; waist circumference

Project Summary Androgens play an intriguing role in the regulation of body fat distribution, with fundamental differences in adipose accumulation between males (apple-shaped, android) and females (pear-shaped, gynoid). Although differences in the abdominal and gluteal-femoral adipose depots have been identified for endocrine and metabolic function, adipocyte size, and gene regulation of preadipocytes, the mechanisms by which sex hormones regulate adipose tissue are not fully understood. Females with androgen excess due to polycystic ovarian syndrome frequently exhibit central obesity, insulin resistance, hepatic steatosis, and other cardiometabolic risk factors, with similar adverse outcomes that can be seen in female-to-male transgender individuals receiving testosterone. Congenital adrenal hyperplasia (CAH) due to 21- hydroxylase deficiency is a condition in which both males and females are exposed to excess androgens as of the first trimester of pregnancy, and to varying degrees postnatally. One in 15,000 live births are affected with classical CAH, with universal newborn screening across the U.S. Significant adverse cardiometabolic outcomes can develop in early childhood and have been identified across the lifespan of CAH individuals, including obesity, early adiposity rebound, hypertension, and insulin resistance. Yet, there is currently little in the way of targeted treatment of cardiometabolic risk factors in CAH. The goal of this proposal is to non- invasively delineate androgen effects on adipose depots and ectopic fat by magnetic resonance (MR)- based imaging techniques. We propose to perform secondary analyses on imaging studies performed in the PI’s K23 award. With MR imaging (MRI), we will quantify regional adipose tissue distribution (abdominal visceral and subcutaneous, and gluteal-femoral) and liver fat, using Dixon quantitative chemical shift imaging. With proton (1H) MR spectroscopy (MRS), we will examine differences in triglyceride composition (saturated and unsaturated fatty acids) in abdominal and gluteal-femoral adipose depots, and determine intra- and extramyocellular lipid content. We hypothesize that we will find an androgen-related, central lipid distribution (increased abdominal vs. gluteal-femoral), with more saturated fatty acids in abdominal fat, in CAH youth. We also expect to find increased ectopic fat, and an association with excess androgens, in CAH. We predict a lack of sex differences in CAH youth, in contrast to sex-matched controls. The specific aims are to: 1) evaluate abdominal and gluteal-femoral adipose depots for lipid distribution and composition, non-invasively, by MRI and MRS in CAH youth vs. controls; 2) evaluate ectopic lipid content in liver by MRI and muscle by MRS in CAH youth vs. controls. This study of a human model of androgen excess can help to better understand androgen-driven effects on lipid distribution and metabolic risk in both sexes, and may inform targeted treatments to improve lipid deposition and insulin sensitivity in CAH. The project supports a priority area of the NICHD Pediatric Growth and Nutrition Branch: the hormonal regulation of adipose tissue.

项目摘要 雄激素在调节体内脂肪分布中起着有趣的作用，在 雄性（苹果形，Android）和雌性（梨形，甲状腺）之间的脂肪积累。 尽管已经确定了腹部和臀肌脂肪沉积物的差异 内分泌和代谢功能，脂肪细胞的大小和基因调节前脂肪细胞，机制 哪些性骑马调节脂肪组织尚不完全了解。雄激素的女性超过应有的 多囊性卵巢综合征经常暴露于中枢性肥胖，胰岛素抵抗，肝脂肪变性和 其他心脏代谢危险因素，具有相似的不良结果，可以在女性到男性中看到 跨性别者接受睾丸激素。先天性肾上腺增生（CAH）由于21- 羟化酶缺乏症是男性和女性都暴露于多余的雄激素的疾病 15,000分之一的活产影响 与经典CAH一起，在美国各地进行了通用新生儿筛查 结局可以在幼儿时期发展，并且在CAH个体的整个生命周期中都被发现 包括肥胖，早期肥胖反弹，高血压和胰岛素抵抗。但是，目前几乎没有 在CAH中针对心脏代谢危险因素的靶向治疗方式。该提议的目的是非 通过磁共振（MR） - 侵入性地描绘雄激素对脂肪沉积物和生态脂肪的影响 - 基于成像技术。我们建议对在成像研究中进行次要分析 PI的K23奖。使用MR成像（MRI），我们将量化区域脂肪组织分布（腹部 内脏和皮下，以及使用迪克森定量化学移位 成像。使用质子（1H）MR光谱法（MRS），我们将检查甘油三酸酯组成的差异 （饱和和不饱和脂肪酸）在腹部和臀肌脂肪沉积中，并确定 内和细胞外脂质含量。我们假设我们会发现与雄激素有关的中央脂质 分布（增加腹部与谷腔妇女），腹部脂肪中有更多饱和脂肪酸， CAH青年。我们还期望发现生态脂肪增加，并且与超过雄激素的关联 CAH。与性别匹配的对照相比，我们预测CAH青年缺乏性别差异。具体 目的是：1）评估腹部和臀肌脂肪沉积物的脂质分布和组成， 非侵入性的，由CAH青年与对照组中的MRI和MRS； 2）通过MRI评估肝脏中的Ecopic脂质含量 和MRS在CAH青年与对照组中的肌肉。这项对雄激素模型的研究超过了 更好地理解雄激素驱动对男女脂质分布和代谢风险的影响，并且可能 告知有针对性的治疗方法以改善CAH中的脂质沉积和胰岛素敏感性。该项目支持 NICHD小儿生长和营养分支的优先区域：脂肪组织的激素调节。