Genetic Susceptibility to Adverse Metabolic Consequences of Obesity

肥胖症在美国的流行程度正在迅速上升。因此，与肥胖相关的代谢紊乱 这增加了心血管疾病的风险，包括糖尿病、血脂异常和高血压正在流行。 比例。肥胖对不良代谢后果的易感性在人群中差异很大： 肥胖症的轻微增加会导致一些人严重的代谢失调，而另一些人 即使严重肥胖，也要保持正常的新陈代谢。该项目的总体目标是确定 解释对超重的代谢反应变异性的特定遗传机制 并评估针对这些机制的药物的治疗潜力。这项研究包括三项 互补策略：首先，我们将对选定的候选基因进行大范围、多种族的排序 每个参与者都经历了广泛代谢的人群(达拉斯心脏研究) 对表型进行表征，并将表型与选定的基因类型联系起来。我们的重点是两组基因： 1)编码循环蛋白的基因，这些循环蛋白在大脑、肝脏、脂肪组织之间传递代谢信号， 和肠道(代谢物)，以及2)编码选定转录调控分子的基因 对代谢信号(“细胞代谢调节器”)作出反应。这些研究中包括的基因是 在项目1-3中机械地审问。第二，我们将使用全基因组方法作为公正的 发现有助于个体间遗传的新基因和序列变异的方法 对肥胖的代谢反应的差异。第三，我们将在项目4中与调查人员合作 &5，并对小鼠和人类的葡萄糖和脂肪代谢进行详细研究，以阐明 遗传变异对肥胖不良代谢后果易感性的机制基础。 这一雄心勃勃的跨学科计划利用了我们在配对仔细表型方面的既定优势 对人类进行全面的基因分析以发现新的基因和序列 导致新陈代谢特征的变异。此外，我们还建立了提供访问权限的协作 到大规模、预期的人群研究，在这些研究中，遗传序列变异的影响可以严格地 已验证。这些协作，再加上我们项目合作者的互补专业知识 1-5极大地扩展了我们研究的科学范围，并增加了我们寻找新疗法的潜力 预防和治疗肥胖的不良代谢后果的目标和方法。

The prevalence of obesity is burgeoning in the United States. As a result, obesity-related metabolic disorders that confer increased CVD risk, including diabetes, dyslipidemia, and hypertension are reaching epidemic proportions. Susceptibility to the adverse metabolic consequences of obesity varies widely in the population: modest increases in adiposity lead to severe metabolic decompensation in some individuals, whereas others maintain a normal metabolic profile despite severe obesity. The overall goal of this project is to identify specific genetic mechanisms that account for the variability of metabolic responses to excess body weight and to evaluate the therapeutic potential of agents that target these mechanisms. The study includes three complementary strategies: First, we will sequence selected candidate genes in a large, multi-ethnic population (The Dallas Heart Study) in which each participant has undergone extensive metabolic characterization and relate the phenotypes to selected genotypes. Our focus will be on two groups of genes: 1) genes encoding circulating proteins that carry metabolic signals between the brain, liver, adipose tissue, and intestine ('metabokines'), and 2) genes encoding selected transcriptional regulatory molecules than respond to metabolic signals ('cellular metabolic regulators'). Included in these studies are genes being mechanistically interrogated in Projects 1-3. Second, we will use genome-wide methods as unbiased approaches toward the discovery of new genes and sequence variants that contribute to inter-individual differences in the metabolic responses to obesity. Third, we will collaborate with investigators in Projects 4 & 5 and perform detailed studies of glucose and lipid metabolism in both mice and humans to elucidate the mechanistic basis for genetic variation in susceptibility to the adverse metabolic consequences of obesity. This ambitious, interdisciplinary program leverages our established strengths in pairing careful phenotypic characterization with comprehensive genetic analyses in humans to discover new genes and sequence variations contributing to metabolic traits. In addition we have established collaborations that provide access to large, prospective population studies in which the effects of genetic sequence variants can be rigorously validated. These collaborations, together with the complementary expertise of our collaborators in Projects 1-5 greatly expand the scientific scope of our studies and increases our potential to identify new therapeutic targets and approaches to prevent and treat the adverse metabolic consequences of obesity.