PROJECT 1: METABOLIC AND NEUROENDOCRINE RESPONSES TO ANDROGEN AND DIET

项目 1：雄激素和饮食的代谢和神经内分泌反应

• 批准号: 8510085
• 负责人: KEVIN L GROVE
• 金额: $ 24.89万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8510085
• 关键词: 5 year old; Adolescent; Adult; Androgens; Animals; Body fat; Characteristics; Chronic; Clinical; Complement; Congenital adrenal hyperplasia; Consumption; Control Animal; Data; Development; Diet; Disease; Dynorphins; Estradiol; Euglycemic Clamping; Exposure to; Fat-Restricted Diet; Fatty acid glycerol esters; Female; Frequencies; Functional disorder; Gene Expression; Glucose Clamp; Glucose Intolerance; Goals; Hormones; Hypothalamic structure; Implant; Inflammation; Instruction; Insulin Resistance; Intake; Lead; Link; Macaca mulatta; Measurement; Measures; Metabolic; Metabolic syndrome; Modeling; Molecular; Monkeys; Neurokinin B; Neurons; Neurosecretory Systems; Nutrient; Obesity; Ovarian; Ovarian hormone; Pathology; Pattern; Peptides; Physiologic pulse; Pilot Projects; Plasma; Play; Polycystic Ovary Syndrome; Population; Progesterone; Puberty; Reproductive Health; Role; Signal Transduction; Sleep; Sleep Disorders; Structure; Symptoms; Syndrome; System; Testing; Testosterone; Weight Gain; Women' s Group; cytokine; emerging adult; feeding; girls; insulin sensitivity; kisspeptin; prepuberty; proliferative phase Menstrual cycle; relating to nervous system; reproductive; reproductive axis; reproductive function; reproductive hormone; research study; response; treatment effect

PROJECT SUMMARY (See instructions): We recently discovered that a mild elevation in testosterone (T) levels in prepubertal female monkeys led to a significant increase in the frequency of pulsatile LH secretion, as well as an increase in LH response to GnRH, and concluded that chronic exposure to mild hyperandrogenemia over the course of puberty triggers changes in the neural drive to the reproductive axis that resemble those of girls with PCOS in early adulthood. Subsequently, when monkeys were 5 years of age, we fed them a Western Style Diet (WSD) and after 14 months both T-treated and control animals had a faster than normal pulse frequency in the early follicular phase, as well as decreased LH pulse amplitude. T-treated animals also showed a significant decrease in insulin sensitivity compared to control animals (2.6-fold lower), and changes in ovarian structure function, as detailed in Project II. These pilot studies demonstrate that a combination of T+WSD can lead to neuroendocrine, ovarian and metabolic abnormalities clinically associated with hyperandrogenemia and obesity. However, the specific roles that T and WSD played in the development of these abnormalities are unclear, as this pilot study did not include a T alone group, nor a normal monkey chow group. The overall goal of Project I is to use the pubertal female rhesus monkey model to further define the effects of adolescent and early adult (1) T, (2) WSD, and (3) T+ WSD treatment, compared to (4) control conditions, on function of the metabolic and reproductive neuroendocrine axes. Aim 1 will examine the effects of these four treatments on key metabolic systems and sleep patterns, measuring metabolic substrate and hormone levels, ivGTT, ITT, measurement of metabolic rate in a metabolic chamber, hyperinsulinemic/euglycemic clamps, dexascans, and activity. Sleep disorders are linked to both elevated T and obesity in a bi-directional fashion and could be partially responsible for the metabolic pathologies associated with PCOS. Aim 2 will examine the effects of treatments on reproductive neuroendocrine secretion (LH, FSH and responsiveness to GnRH), plus peptide levels and gene expression in KNDy (Kisspeptin, Neurokinin 8, Dynorphin) neurons in the basal hypothalamus. Aim 3 will test whether decreasing circulating T levels by removing T implants and/or reinstating a lower calorie, low fat diet will reverse neurendocrine and metabolic changes occurring with hyperandrogenemia and WSD.

PROJECT SUMMARY (See instructions): We recently discovered that a mild elevation in testosterone (T) levels in prepubertal female monkeys led to a significant increase in the frequency of pulsatile LH secretion, as well as an increase in LH response to GnRH, and concluded that chronic exposure to mild hyperandrogenemia over the course of puberty triggers changes in the neural drive to the reproductive axis that resemble those of girls with成年初期的PCOS。随后，当猴子年满5岁时，我们给它们提供了西方风格的饮食（WSD），在14个月后，T型和对照动物在早期卵泡期的速度比正常脉冲频率快，而LH脉冲振幅降低。与对照动物相比（低2.6倍）和卵巢结构功能的变化，经过T处理的动物也显示出胰岛素敏感性的显着降低，如Project II中所述。这些试点研究表明，T+WSD的组合可以导致神经内分泌，卵巢和代谢异常在临床上与高狂症和肥胖有关。但是，T和WSD在这些异常的发展中扮演的具体角色尚不清楚，因为这项初步研究不包括单独的t组，也不包括正常的猴子食物组。项目I的总体目标是使用青春期女性恒河猴模型与（4）对照条件相比，进一步定义了青少年和早期成人（1）T，（2）WSD和（3）T+ WSD治疗的影响，对代谢和生殖神经内分泌轴的功能。 AIM 1将检查这四种处理对关键代谢系统和睡眠模式的影响，测量代谢性底物和激素水平，IVGTT，ITT，代谢室中代谢率的测量，高胰岛素/euglinemic/euglimential/eugyclememalimemic clamps，dexascans，dexascans和活性。睡眠障碍以双向方式与T升高和肥胖有关，可能部分负责与PCOS相关的代谢病理。 AIM 2将检查治疗对生殖神经内分泌分泌（LH，FSH和对GNRH的反应性）的影响，以及基底下丘脑中KNDY（Kisspeptin，Neurokinin 8，dynorphin）神经元中KNDY中的肽水平和基因表达。 AIM 3将测试是否通过去除T植入物和/或恢复较低卡路里来降低循环水平，低脂饮食会逆转神经内分泌和代谢性变化，而过多雄激素血症和WSD发生。