The Regulation ACRP30 and Adult Reproductive Development

ACRP30 法规与成人生殖发育

• 批准号: 6616838
• 负责人: Terry P. Combs
• 金额: $ 4.99万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6616838
• 关键词: adipocytes; adipose tissue; bioenergetics; blood circulation; body weight; endocrinology; gender difference; glucose metabolism; hormone regulation /control mechanism; human puberty; hypothalamic pituitary axis; insulin sensitivity /resistance; laboratory mouse; messenger RNA; peptides; pituitary hormones; postdoctoral investigator; protein structure function; reproductive development; sex differentiation; testicular feminization

DESCRIPTION (provided by applicant): ACRP3O is a circulating protein produced in adipose tissue. Plasma levels of ACRP3O are inversely related to adipose mass in humans and mice. ACRP3O levels in FVB mice increase from approximately 3 mg/mI at 1-week of age to 10 mg/mi and 30 mg/mI at 5-weeks of age in males and females, respectively. Several groups recently showed that ACRP3O is an important regulator of glucose homeostasis. The elevation of ACRP3O may therefore be associated with changes in glucose homeostasis that occur during sexual maturation. Furthermore, elevated levels of ACRP3O in adult females may be associated with their increased insulin sensitivity compared to males. The studies described in this proposal are focused on three specific aims. (1) Demonstrate the activity of a negative-feedback loop that regulates circulating levels of ACRP3O. Elevating ACRP3O exposure and studying the effects on endogenous ACRP3O production will test the hypothesis in the first aim. Feminization of adult males by neonatal castration may uncover the basis for the sexual dimorphism in circulating ACRP3O. (2) Demonstrate that the ACRP3O negative-feedback loop involves the hypothalamic-pituitary axis. Studying the effects of elevated ACRP3O on pituitary peptides as well as their effects on ACRP3O will test the hypothesis in the second aim and determine if the regulation of ACRP3O might involve a centrally mediated pathway. (3) Demonstrate that sexual maturation is associated with the rise of ACRP3O. Studying the rise of ACRP3O during puberty and comparing the timing with the onset of adulthood will test the hypothesis in the third aim. Accelerating or delaying the onset of adulthood by regulating the rise of ACRP3O during puberty might identify a novel role for ACRP3O in reproductive development.

描述（由申请人提供）：ACRP3O是在脂肪组织中产生的循环蛋白。 AcRP3O的血浆水平与人类和小鼠的脂肪质量成反比。 FVB小鼠中的ACRP3O水平从大约3 mg/mi的年龄在10 mg/mi时增加到10 mg/mi和30 mg/mi的男性和女性。最近几个小组表明，ACRP3O是葡萄糖稳态的重要调节剂。因此，ACRP3O的升高可能与性成熟过程中发生的葡萄糖稳态变化有关。此外，与男性相比，成年女性的ACR3O水平升高可能与其胰岛素敏感性提高有关。该提案中描述的研究集中在三个特定目标上。 （1）证明了调节ACRP3O循环水平的负反馈环的活性。提高ACRP3O暴露并研究对内源性ACRP3O产生的影响将在第一个目标中检验该假设。通过新生儿cast割对成年男性的女性化可能会揭示循环ACR3O中性二态性的基础。 （2）证明ACRP3O负反馈回路涉及下丘脑 - 垂体轴。研究ACRP3O升高对垂体肽的影响以及它们对ACRP3O的影响将在第二个目标中检验假设，并确定ACRP3O的调节是否可能涉及中央介导的途径。 （3）证明性成熟与ACRP3O的兴起有关。在青春期研究ACRP3O的兴起并将时间与成年开始进行比较将在第三个目标中检验假设。通过调节青春期中ACRP3O的兴起，加速或延迟成年的发作可能会确定Acr3O在生殖发展中的新作用。