Project 3: Role of pregnane X receptor in diet-induced obesity and metabolic syndrome

摘要 主要由肥胖驱动的代谢综合征是一种全球性流行病，它增加了患 几种慢性病，包括2型糖尿病(T2D)。T2D在男性和女性中都很常见 所有年龄段的非裔美国人(AA)。低水平的血浆脂联素，一种由 脂肪组织参与了肥胖型腹主动脉硬化患者T2D的发生。虽然，最初 作为一种对防御有毒物质非常重要的异源核受体， 孕烷X受体(PXR)似乎与脂和糖代谢有关，有助于 代谢综合征的流行。我们发现，PXR对高脂饮食诱导的肥胖和 高血糖与性别和物种有关。然而，连接PXR的具体机制 对这些疾病的致病作用仍不清楚。因此，我们的长期目标是确定种族和性别- 不成比例的脂相关疾病的特定目标(如肥胖和T2D) 威胁腹主动脉系统的心血管健康，开发新的预防和治疗策略。 我们建议的目标是：1)调查PXR基因的多态，更多 AA中常见的与已知的肥胖风险增加有关，2)了解 PXR基因和/或其变体调节脂质的潜在分子机制， 葡萄糖和性激素代谢，导致HFD肥胖或T2D增加 喂食。在令人信服的初步数据的指导下，我们的中心假设是PXR 缺乏导致脂联素信号受损，导致胰岛素抵抗和 葡萄糖不耐受的种族和性别差异更突出。我们将使用人类 PXR活性不同的小鼠的血液和肝组织样本及3种遗传模型(野生型 类型、PXR基因敲除和PXR人源化的小鼠)，以及分子和细胞研究。目标 1研究人类PXR基因及其多态性对AAS肥胖风险的影响。 目的2确定导致对HFD的抗性的遗传和代谢因素 诱导PXR基因缺失小鼠肥胖。目标3探索肥胖导致的 具有不同PXR活性的小鼠糖尿病和低脂联素血症。我们的研究在以下方面是新颖的 利用临床相关的PXR人源化(HPXR)小鼠研究PXR的功能和调节 PXR.本研究具有重要的现实意义，有助于我们更深入地了解 小鼠PXR和PXR的表型表达及信号转导途径 人类PXR基因在肥胖和T2D发病中的不同作用 性别。我们的研究应该提供突破性的进展， 主要用于治疗AAS中的肥胖和代谢综合征。

Abstract Metabolic syndrome, driven mainly by obesity is a global epidemic that increases the risk of several chronic diseases including type 2 diabetes (T2D). T2D is prevalent in male and female African Americans (AAs) of all ages. Low plasma levels of adiponectin, a protein secreted by adipose tissue are implicated in the development of T2D in obese AAs. Although, initially characterized as a xenobiotic nuclear receptor important for defense against toxic agents, the pregnane X receptor (PXR) appears to be linked to lipid and glucose metabolism contributing to the metabolic syndrome epidemic. We find that the impact of PXR on HFD-induced obesity and hyperglycemia is sex- and species-dependent. However, the specific mechanisms linking PXR to these diseases remain unclear. Thus, our long term goal is to identify ethnic- and sex- specific targets for lipid-associated diseases (such as obesity and T2D) that disproportionately threaten cardiovascular health in AAs, to develop novel prevention and treatment strategies. The objectives of our proposal are: 1) to investigate whether PXR polymorphisms, more common in AAs are associated with known increases in obesity risk and 2) to understand the underlying molecular mechanisms by which the PXR gene and/or its variants regulate lipid, glucose, and sex hormone metabolism, leading to either enhanced obesity or T2D upon HFD feeding. Guided by compelling preliminary data, our central hypothesis is that PXR deficiency results in impaired adiponectin signaling leading to insulin resistance and glucose intolerance with more prominent race and sex differences. We will use human blood and liver tissue samples and 3 genetic models of mice with differential PXR activity (wild type, PXR-knockout, and PXR-humanized mice), along with molecular and cellular studies. Aim 1 investigates the effect of the human PXR gene and its polymorphisms on obesity risk in AAs. Aim 2 determines the genetic and metabolic factors that contribute to resistance to HFD- induced obesity in Pxr-null mice. Aim 3 explores the relationship between obesity-induced diabetes and hypoadiponectinemia in mice with different PXR activity. Our studies are novel in using clinically relevant PXR-humanized (hPXR) mice to characterize function and regulation of PXR. This study is significant in providing valuable insights in similarities and differences in phenotypic expression and signal transduction pathways between the mouse PXR and the human PXR gene in contributing to the development of obesity and T2D in the different genders. Our studies should provide ground-breaking advances into pathways that can be targeted for the treatment of obesity and metabolic syndrome in AAs.