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: 9977716
• 负责人: Maxwell Afari Gyamfi
• 金额: $ 30.05万
• 依托单位: NORTH CAROLINA CENTRAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977716
• 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 代谢综合征主要由肥胖驱动是一种全球流行病，可增加 几种慢性疾病，包括2型糖尿病（T2D）。 T2D在男性和女性中很普遍 各个年龄段的非裔美国人（AAS）。低血浆脂联素水平，该蛋白质由 脂肪组织与肥胖AAS中T2D的发展有关。虽然，最初 以对防御有毒药物很重要的异生核受体的特征 怀孕X受体（PXR）似乎与脂质和葡萄糖代谢有关 代谢综合征流行。我们发现PXR对HFD诱导的肥胖症的影响 高血糖是性别和物种依赖性的。但是，连接pxr的特定机制 这些疾病仍然不清楚。因此，我们的长期目标是确定种族和性别 - 脂质相关疾病的特定靶标（例如肥胖和T2D） 威胁AAS中的心血管健康，以制定新颖的预防和治疗策略。 我们提案的目标是：1）调查PXR多态性是否更多 AAS中常见与肥胖风险的已知增加有关，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的肥胖或T2D增强 进食。通过引人注目的初步数据指导，我们的中心假设是PXR 缺乏导致脂联素信号传导受损，导致胰岛素抵抗和 葡萄糖不耐症，种族和性别差异更大。我们将使用人类 血液和肝组织样品以及具有差异PXR活性的小鼠的3种遗传模型（野生 类型，PXR敲除和PXR人性化的小鼠），以及分子和细胞研究。目的 1研究了人类PXR基因及其多态性对AAS肥胖风险的影响。 AIM 2确定有助于HFD-的遗传和代谢因子 PXR无效小鼠诱导肥胖。 AIM 3探索肥胖引起的关系 具有不同PXR活性的小鼠中的糖尿病和低载脂蛋白血症。我们的研究是新颖的 使用临床相关的PXR人性化（HPXR）小鼠来表征功能和调节 pxr。这项研究对于提供相似性和差异的有价值的见解很重要 小鼠PXR与小鼠PXR之间的表型表达和信号转导途径 人类PXR基因在不同 性别。我们的研究应该为可以成为的途径提供突破性的进步 针对AAS中肥胖和代谢综合征的治疗。