Sex differences in obesity and metabolic disease

描述（由申请人提供）：男性和女性显示出不同的肥胖发生率和模式，肥胖是糖尿病、心血管疾病和其他代谢和生殖疾病的主要风险因素。该项目旨在了解这些性别差异的生物学根源。我们将使用新的小鼠模型，“四个核心基因型”（FCG），其中包括具有XX或XY性染色体的睾丸的小鼠，以及具有XX或XY性染色体的卵巢的小鼠。因此，FCG模型提供了显着的优势，区分几类生物因素，导致性别差异，包括组织和性腺激素的激活作用，和X和Y基因的直接影响，创建一个内在的性别偏见的功能XX和XY细胞。我们建议使用FCG模型来梳理性激素（睾丸或卵巢分泌物）与性染色体（XX与XY基因型）对能量平衡，脂肪组织功能，葡萄糖和脂质稳态以及代谢的其他方面的影响。在性腺切除术和激素替代后，将在性腺激素水平的操作过程中测量生理变量。通过连锁研究、基因表达和转基因小鼠分析，将确定导致性染色体对肥胖影响的X连锁基因。研究结果将揭示肥胖和代谢疾病的基本性别差异，从而更好地理解改善或加剧疾病的性别特异性因素。 公共卫生相关性：男性和女性在肥胖、糖尿病和相关代谢疾病方面存在显著差异。这项研究的目的是了解这种性别差异的生物学起源，特别是那些由X和Y基因的基因组表达的性别差异引起的差异。了解性别差异的分子基础将有助于了解可以预防两性代谢疾病的因素。

DESCRIPTION (provided by applicant): Men and women show different incidence and patterns of obesity, which is a major risk factor for diabetes, cardiovascular disease, and other metabolic and reproductive diseases. This project aims to understand the biological origins of these sex differences. We will use the novel mouse model, the "four core genotypes" (FCG), which includes mice with testes that have XX or XY sex chromosomes, and mice with ovaries that also have either XX or XY sex chromosomes. Thus, the FCG model offers significant advantages for discriminating among several classes of biological factors that lead to sex differences, including organizational and activational effects of gonadal hormones, and direct effects of X and Y genes that create an inherent sex bias in the function of XX and XY cells. We propose to use the FCG model to tease apart the effects of sex hormones (testicular or ovarian secretions) vs. sex chromosomes (XX vs. XY genotype) on energy balance, adipose tissue function, glucose and lipid homeostasis, and other aspects of metabolism. Physiological variables will be measured during manipulations of gonadal hormonal levels after gonadectomy and hormone replacement. The X-linked genes that cause sex chromosome effects on obesity will be identified by linkage studies, gene expression, and analysis of transgenic mice. The results will shed light on fundamental sex differences in obesity and metabolic disease, leading to greater understanding of sex-specific factors that ameliorate or exacerbate disease. PUBLIC HEALTH RELEVANCE: Men and women show significant differences in obesity, diabetes, and related metabolic diseases. The proposed research aims to understand the biological origins of such sex differences, especially those differences that are caused by the sex differences in genomic representation of X and Y genes. Understanding the molecular basis of sex differences will shed light on factors that can prevent metabolic disease in both sexes.