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 雄激素在调节身体脂肪分布方面起着有趣的作用， 雄性（苹果形，android）和雌性（梨形，gynoid）之间的脂肪积累。 虽然腹部和臀股脂肪库的差异已被确定为 内分泌和代谢功能，脂肪细胞大小，前脂肪细胞的基因调控， 哪些性激素调节脂肪组织还不完全清楚。雄激素过多的女性 多囊卵巢综合征患者经常表现出向心性肥胖、胰岛素抵抗、肝脂肪变性， 其他心脏代谢风险因素，在女性与男性中观察到相似的不良结局 接受睾酮的变性人先天性肾上腺皮质增生症（CAH）由于21- 羟化酶缺乏是一种病症，其中男性和女性都暴露于过量的雄激素， 在怀孕的前三个月，以及出生后不同程度的。每15，000名活产婴儿中就有一人受到影响 与经典的CAH，与美国的普遍新生儿筛查， 结果可以在幼儿期发展，并已在CAH个体的整个生命周期中确定， 包括肥胖、早期肥胖反弹、高血压和胰岛素抵抗。然而，目前几乎没有 在CAH心脏代谢危险因素的靶向治疗方面。这项提案的目的是为了不-- 通过磁共振（MR）侵入性描述雄激素对脂肪库和异位脂肪影响- 基于成像技术。我们建议对在以下研究中进行的成像研究进行二次分析： PI的K23奖通过磁共振成像（MRI），我们将量化局部脂肪组织分布（腹部） 内脏和皮下，和臀股）和肝脏脂肪，使用狄克逊定量化学位移 显像利用质子（1H）磁共振波谱（MRS），我们将检查甘油三酯组成的差异 （饱和和不饱和脂肪酸）在腹部和臀股脂肪库，并确定 肌细胞内外脂质含量。我们假设我们会发现一种雄激素相关的， 分布（腹部与臀股相比增加），腹部脂肪中的饱和脂肪酸更多， CAH青年。我们还希望发现异位脂肪的增加，以及与过量雄激素的相关性， CAH。我们预测，与性别匹配的对照组相比，CAH青少年缺乏性别差异。具体 目的是：1）评估腹部和臀股脂肪库的脂质分布和组成， 非侵入性地，通过MRI和MRS在CAH青年与对照组中进行; 2）通过MRI评估肝脏中的异位脂质含量 和肌肉MRS在CAH青年与对照组。这项对雄激素过多的人类模型的研究可以帮助 为了更好地了解雄激素驱动对男女脂质分布和代谢风险的影响， 为有针对性的治疗提供信息，以改善CAH的脂质沉积和胰岛素敏感性。该项目支持一个 NICHD儿科生长和营养分支的优先领域：脂肪组织的激素调节。