Sex Differences in the Metabolic Syndrome

项目总结-总体：代谢综合征的性别差异 我们关于"代谢综合征的性别差异"的评分旨在阐明性别 代谢综合征（MetSyn）组分如肥胖的风险因素和治疗的差异， 胰岛素抵抗/糖尿病、血脂异常和脂肪肝。男女易感性差异 与心脏代谢疾病的关系是众所周知的，但潜在的遗传和生理机制仍然存在， 定义不好。我们的目标是确定决定性别特异性MetSyn风险的因素，这可能会导致更好的 诊断和治疗的性别。我们项目的一个独特之处是对性别差异的调查 在MetSyn从多个角度，包括雌激素的影响，XX与XY性染色体 互补，以及遗传变异。我们的项目由三个研究项目和三个核心组成，并且 将使用临床前模型和人体组织样本。项目1，"性染色体对代谢的影响 综合征的风险和治疗，"将建立在发现XX的存在相比，XY染色体 增加对肥胖和相关性状的易感性。XX效应的大部分可归因于Kdm5c基因， 其逃避X染色体失活并编码组蛋白修饰酶。我们的研究将定义 Kdm 5c剂量对基因表达、能量平衡和脂肪代谢的表观遗传调控的影响 肥胖时的组织重塑他们还将阐明XX染色体对女性风险增加的影响 对于继发于他汀类药物治疗的糖尿病，并测试可能减轻这种性别偏见的饮食联合治疗。 药物不良反应项目2，"线粒体功能和代谢特征中的基因-性别相互作用"， 旨在了解MetSyn性状中遗传和性别的作用。"系统遗传学"的结果 方法涉及特定基因对MetSyn性状的性别和组织特异性作用。我们的研究将 阐明胰岛素抵抗中线粒体功能的性别效应，脂肪因子的性别特异性效应 脂质运载蛋白2对肥胖和胰岛素抵抗的影响，以及PKLR丙酮酸激酶在肝脏中的性别特异性作用 脂肪变性在小鼠中发现的基因与性别的相互作用将在来自人类队列的组织中进行测试。 项目3，"雌激素受体（ER）β在代谢健康中的影响"，将测试肌肉 ER β可防止小鼠和女性的代谢功能障碍，将在小鼠和女性中识别ER β调节位点。 基因组中的女性和男性，并阐明ER β对线粒体功能的调节作用。 结果可能提供概念验证证据，即骨骼肌ER β是一种有效的治疗靶点， 对抗代谢紊乱和2型糖尿病。基因组技术核心将进行RNA测序， 所有三个项目的ChIP-seq和相关技术。职业提升核心将促进研究 通过管理试点和可行性补助金计划，并通过课程， 工作坊和免费视频库。行政核心将确保有效的领导， 管理这个分数。

PROJECT SUMMARY - Overall: Sex Differences in the Metabolic Syndrome The objective of our SCORE on “Sex Differences in the Metabolic Syndrome” is to elucidate sex differences in risk factors and treatments for Metabolic Syndrome (MetSyn) components such as obesity, insulin resistance/diabetes, dyslipidemia, and fatty liver. Differences between men and women in susceptibility to cardio-metabolic disease are well known, but the underlying genetic and physiological mechanisms remain poorly defined. Our goal is to identify factors that determine sex-specific MetSyn risk, which may lead to better diagnosis and treatment for both sexes. A unique feature of our program is the investigation of sex differences in MetSyn from multiple perspectives, including effects of estrogen, of XX vs. XY sex chromosome complement, and of genetic variation. Our program consists of three research projects and three cores, and will use preclinical models and human tissue samples. Project 1, “Sex chromosome effects on metabolic syndrome risk and treatment,” will build on the finding that the presence of XX compared to XY chromosomes increases susceptibility to obesity and related traits. Much of the XX effect is attributable to the Kdm5c gene, which escapes X chromosome inactivation and encodes a histone modifying enzyme. Our studies will define the effects of Kdm5c dose on the epigenetic regulation of gene expression, energy balance, and adipose tissue remodeling during obesity. They will also elucidate the XX chromosome effect on increased female risk for diabetes secondary to statin drug therapy, and test a dietary co-therapy that may alleviate this sex-biased adverse drug response. Project 2, “Gene-by-sex interactions in mitochondrial functions and metabolic traits,” seeks to understand the roles of both genetics and sex in MetSyn traits. Results of a “systems genetics” approach have implicated sex- and tissue-specific action of specific genes on MetSyn traits. Our studies will elucidate sex effects on mitochondrial functions in insulin resistance, sex-specific effects of the adipokine lipocalin 2 on adiposity and insulin resistance, and the sex-specific role of the PKLR pyruvate kinase in hepatic steatosis. The gene-by-sex interactions discovered in the mouse will be tested in tissues from human cohorts. Project 3, “The impact of estrogen receptor (ER)  in metabolic health,” will test the hypothesis that muscle ER protects against metabolic dysfunction in mice and women, will identify ER regulatory sites across the genome in females and males, and elucidate the effect of ER on the regulation of mitochondrial function. Results may provide proof-of-concept evidence that skeletal muscle ER is an effective therapeutic target to combat metabolic dysfunction and type 2 diabetes. The Genomic Technologies Core will perform RNA-seq, ChIP-seq and related technologies for all three projects. The Career Enhancement Core will foster research in sex differences in metabolism by administering a Pilot & Feasibility grant program, and through courses, workshops, and a free library of videos. The Administrative Core will ensure effective leadership and management of this SCORE.