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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要雄激素在调节身体脂肪分布方面发挥着有趣的作用，其根本区别在于男性（苹果型、机器人）和女性（梨型、雌性型）之间的脂肪堆积。尽管腹部和臀股脂肪库的差异已被确定内分泌和代谢功能、脂肪细胞大小以及前脂肪细胞的基因调控，其机制哪些性激素调节脂肪组织尚不完全清楚。多囊卵巢综合征经常表现出向心性肥胖、胰岛素抵抗、肝脂肪变性等其他心脏代谢危险因素，具有与女性对男性相似的不良后果因 21- 原因而接受睾酮治疗的变性人。羟化酶缺乏症是一种男性和女性都暴露于过量雄激素的疾病妊娠前三个月以及产后，每 15,000 名活产婴儿中就有 1 人受到影响。典型的CAH，在美国进行普遍的新生儿筛查显着不良的心脏代谢结果可以在儿童早期形成，并在 CAH 个体的整个生命周期中得到确定，包括肥胖、早期肥胖反弹、高血压和胰岛素抵抗，但目前还很少。该提案的目标是针对 CAH 的心脏代谢危险因素进行针对性治疗。通过磁共振 (MR) 侵入性描绘雄激素对脂肪库和异位脂肪的影响 - 我们建议对在成像研究中进行的二次分析。 PI 的 K23 奖通过 MR 成像 (MRI)，我们将量化区域脂肪组织分布（腹部）。内脏和皮下，以及臀股骨）和肝脏脂肪，使用 Dixon 定量化学位移通过质子 (1H) 磁共振波谱 (MRS)，我们将检查甘油三酯成分的差异。（饱和和不饱和脂肪酸）在腹部和臀股脂肪库中，并确定我们发现，我们将发现一种与雄激素相关的中心脂质。分布（腹部与臀股骨相比增加），腹部脂肪中饱和脂肪酸较多，我们还期望在青年人中发现异位脂肪增加，并与雄激素过多有关。我们预测，与性别匹配的对照组相比，CAH 青少年不存在性别差异。目的是：1）评估腹部和臀股脂肪库的脂质分布和成分，通过 MRI 和 MRS 对青年 CAH 与对照组进行非侵入性检查；2) 通过 MRI 评估肝脏中的异位脂质含量这项针对雄激素过多的人类模型的研究可以提供帮助。更好地了解雄激素驱动的对两性脂质分布和代谢风险的影响，并且可能为改善 CAH 的脂质沉积和胰岛素敏感性提供针对性治疗。 NICHD 儿科生长和营养分部的优先领域：脂肪组织的激素调节。