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

项目3：孕烷X受体在饮食引起的肥胖和代谢综合征中的作用

• 批准号: 9750533
• 负责人: Maxwell Afari Gyamfi
• 金额: $ 32.76万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9750533
• 关键词: Adipose tissue; Affect; African American; Age; Alleles; Attenuated; Beta Cell; Bioinformatics; Biological Assay; Blood; Cardiovascular Diseases; Caucasians; Characteristics; Chemicals; Chronic Disease; Complex; Data; Development; Diabetes Mellitus; Diet; Disease; Epidemic; Exhibits; Female; Frequencies; Gender; Gene Frequency; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genetic Transcription; Genome; Genomic DNA; Genotype; Glucokinase; Glucose; Glucose Intolerance; Goals; Gonadal Steroid Hormones; High Fat Diet; Homeostasis; Human; Hyperglycemia; Hypertension; Impairment; Ingestion; Insulin Resistance; Intestines; Kansas; Knock-out; Knockout Mice; Link; Lipids; Liver; Matched Group; Measures; Medical center; Metabolic; Metabolic syndrome; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Not Hispanic or Latino; Nuclear Receptors; Obesity; Pathway interactions; Patients; Phenotype; Plasma; Pregnenolone; Prevention strategy; Proteins; RNA; Receptor Gene; Regulation; Regulator Genes; Research; Resistance; Risk; Rodent; Role; Sampling; Serum; Sex Differences; Signal Transduction; Signal Transduction Pathway; Single Nucleotide Polymorphism; Soleus Muscle; Tissue Banks; Tissue Sample; Tissues; Transgenic Organisms; Universities; Variant; Weight Gain; Wild Type Mouse; Woman; Xenobiotics; adipokines; adiponectin; base; cardiovascular health; clinically relevant; deep sequencing; diagnostic biomarker; ethnic difference; experimental study; fasting glucose; feeding; genetic variant; glucose metabolism; health disparity; hormone metabolism; humanized mouse; impaired glucose tolerance; insight; insulin sensitivity; lipid metabolism; liver biopsy; male; men; mouse model; novel; novel diagnostics; obesity development; obesity risk; obesity treatment; pregnane X receptor; racial difference; racial disparity; receptor expression; sex; targeted treatment; therapeutic target; transcriptome; treatment strategy

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.

抽象的 主要由肥胖引起的代谢综合征是一种全球流行病，会增加以下风险： 多种慢性疾病，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)。脂联素（一种由脂联素分泌的蛋白质）血浆水平低 脂肪组织与肥胖 AA 中 T2D 的发展有关。虽然，最初 作为一种异生核受体，对于防御有毒物质很重要， 孕烷 X 受体 (PXR) 似乎与脂质和葡萄糖代谢有关，有助于 代谢综合征流行。我们发现 PXR 对 HFD 引起的肥胖和 高血糖具有性别和物种依赖性。然而，连接 PXR 的具体机制 这些疾病的发生尚不清楚。因此，我们的长期目标是确定种族和性别 脂质相关疾病（例如肥胖和 T2D）的特定目标，这些疾病不成比例地 威胁 AA 的心血管健康，制定新的预防和治疗策略。 我们提案的目标是：1）研究 PXR 多态性是否更重要 AA 中常见的因素与已知的肥胖风险增加有关，并且 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 后肥胖加剧或 T2D 喂养。在令人信服的初步数据的指导下，我们的中心假设是 PXR 缺乏会导致脂联素信号受损，从而导致胰岛素抵抗和 葡萄糖不耐受具有更为突出的种族和性别差异。我们将利用人类 血液和肝组织样本以及 3 个具有不同 PXR 活性的小鼠遗传模型（野生 型、PXR 敲除小鼠和 PXR 人源化小鼠），以及分子和细胞研究。目的 图1研究了人类PXR基因及其多态性对AA肥胖风险的影响。 目标 2 确定有助于抵抗 HFD 的遗传和代谢因素 诱导 Pxr 缺失小鼠肥胖。目标 3 探讨肥胖与肥胖之间的关系 具有不同 PXR 活性的小鼠的糖尿病和低脂联素血症。我们的研究是新颖的 使用临床相关的 PXR 人源化 (hPXR) 小鼠来表征 PXR。这项研究对于提供关于相似性和差异性的宝贵见解具有重要意义。 小鼠 PXR 与 PXR 之间的表型表达和信号转导通路 人类 PXR 基因在不同情况下促进肥胖和 T2D 的发展 性别。我们的研究应该为可实现的途径提供突破性进展 旨在治疗 AA 中的肥胖和代谢综合征。