Sex Differences in Adipose Tissue Biology and Metabolic Disease

描述（由申请人提供）：本申请为糖尿病、内分泌学和代谢疾病跨学科合作研究项目种子申请，将重点研究肥胖和脂肪分布的性别差异及其对T2D风险的影响。绝经前女性患代谢性疾病的风险低于绝经后女性或男性。上半身脂肪的分布会加剧男女患病的风险，而下半身脂肪则有保护作用。我们假设，除了生理性别（-1-/- Y染色体）的影响外，性类固醇还以脂肪库和性别特异性的方式调节脂肪组织炎症和重塑。我们的团队汇集了在脂肪组织生物学（Greenberg, Fried, Smith），性类固醇（Bhasin），临床研究（Smith, Bhasin）和表观遗传学（Choi）方面有着良好记录的科学家。在接下来的一年里，我们将进行初步研究，以证明我们的多机构合作所带来的可行性和跨学科的融合。我们将分享脂肪氧合和血管的生理测量技术，性类固醇的LC质谱分析，脂肪形态和炎症（包括FACS分析），差异仓库特异性基因表达的数据集，以及分析代谢表型的方法。目的是获得性类固醇对男性和女性脂肪组织作用的多层次理解，以及小鼠和细胞培养模型与转化研究的相关性。为了为我们未来的合作奠定基础，我们计划了几个假设生成的初步项目，以解决脂肪组织血管化和氧合的性别差异，人类脂肪组织中雌激素作用靶点的储存差异，脂肪组织中调节性类固醇抗炎作用的信号通路，以及新生儿雄激素的表观遗传效应。我们的目标是全面了解脂肪组织生物学中的性别差异，因为它与代谢风险有关，为转化为靶向治疗提供一个框架。相关性：尽管女性的体脂百分比高于男性，但她们以更“梨形”的模式（臀部和大腿）储存更多的脂肪，这与患糖尿病等慢性疾病的风险较低有关。我们研究的目的是了解性激素（雌激素和睾丸激素）如何影响脂肪分布，以及身体不同部位的脂肪积累如何影响疾病风险。

DESCRIPTION (provided by applicant): This proposal for a Seeding proposal for Collaborative Interdisciplinary Research Program in Diabetes, Endocrinology and Metabolic Diseases will focus on sex differences in obesity and fat distribution and their impact on risk for T2D. Premenopausal women are at lower risk for metabolic disease than post-menopausal women or men. An upper body fat distribution exacerbates risk in both sexes, while lower body fat is protective. We postulate that in addition to effects of biological sex (-1-/- Y chromosomes, sex steroids regulate adipose tissue inflammation and remodeling in a fat depot- and sex- specific fashion. Our team brings together scientists with strong track records in adipose tissue biology (Greenberg, Fried, Smith), sex steroids (Bhasin), clinical investigation (Smith, Bhasin) and epigenetics (Choi). During the next year, we will undertake preliminary studies to demonstrate the feasibility and interdisciplinary S3mergisms afforded by of our multi-institutional collaboration. We will share technologies for physiological measurements of adipose oxygenation and vascularity, LC MS analysis of sex steroids, adipose morphology and inflammation (including FACS analysis), datasets on differences depot-specific gene expression, and methods to analyze metabolic phenotypes. The objective is to gain a multi-level understanding of sex steroid action on adipose tissues of men and women, and the relevance of mouse and cell culture models for translational research. To set the stage for our future collaborations, we plan several hypothesis-generating preliminary projects that address sex differences in adipose tissue vascularization and oxygenation, depot-differences in targets of estrogen action in human adipose tissues, signaling pathways that regulate anti-inflammatory effects of sex steroids in adipose tissue, and epigenetic effects of neonatal androgen. Our goal is to achieve an integrated understanding of sex differences in adipose tissue biology as it relates to metabolic risk, providing a framework for translation into the targeted therapies RELEVANCE (See instmctions): Although percent body fat is higher in women than men, they store more fat in a more 'pear-shaped' pattern (buttocks and thighs) and this is associated with lower risk for developing chronic diseases such as diabetes. The goal of our research is to understand how sex honnones (estrogen and testosterone) affect fat distribution and how fat accumulation in different parts of the body affects risk for disease.