Sex differences in obesity and metabolic disease

描述(申请人提供)：男性和女性表现出不同的肥胖发病率和模式，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。这个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，即“四种核心基因类型”(FCG)，其中包括睾丸具有XX或XY性染色体的小鼠，以及卵巢也具有XX或XY性染色体的小鼠。因此，FCG模型在区分几类导致性别差异的生物因素方面具有显著优势，这些因素包括性腺激素的组织和激活效应，以及在XX和XY细胞的功能中产生固有性别偏见的X和Y基因的直接影响。我们建议使用FCG模型来梳理性激素(睾丸或卵巢分泌物)和性染色体(XX型和XY型)对能量平衡、脂肪组织功能、葡萄糖和脂肪稳态以及代谢的其他方面的影响。生理变量将在性腺切除和激素替代后性腺激素水平的操作过程中进行测量。引起性染色体肥胖的X连锁基因将通过连锁研究、基因表达和转基因小鼠的分析来确定。这一结果将阐明肥胖和代谢性疾病的基本性别差异，从而更好地理解缓解或加剧疾病的性别因素。

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.