The Role of PPAR Gamma in Fat-Resident Regulatory T Cells and Glucose Homeostasis

PPAR Gamma 在脂肪驻留调节性 T 细胞和血糖稳态中的作用

• 批准号: 8457922
• 负责人: Sagar Pradeep Bapat
• 金额: $ 3.81万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2015-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457922
• 关键词: 2,4-thiazolidinedione; Adipocytes; Adipose tissue; Agonist; Alleles; Antidiabetic Drugs; Cell Therapy; Cells; ChIP-seq; Chronic; Clinical; Data Set; Dendritic Cells; Diet; Employee Strikes; Epidemic; Fatty acid glycerol esters; Gene Expression Profile; Genes; Heart Diseases; Immune system; Immunosuppressive Agents; In Vitro; Inflammation; Insulin; Insulin Resistance; Interleukin-4; Intervention; Janus kinase 3; Kidney Diseases; Link; Maintenance; Maps; Measures; Mediating; Mediator of activation protein; Metabolic stress; Metabolic syndrome; Metabolism; Microarray Analysis; Molecular; Molecular Profiling; Morbidity - disease rate; Mus; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obese Mice; Obesity; PPAR gamma; Pathogenesis; Patients; Performance; Pharmaceutical Preparations; Physiological; Play; Population; Protein Tyrosine Kinase; Publishing; Regulation; Regulatory T-Lymphocyte; Research; Rest; Retinal Diseases; Role; STAT6 Transcription Factor; Signal Pathway; Signal Transduction; Spleen; T-Lymphocyte Subsets; Technology; Testing; Therapeutic; Thiazolidinediones; Transcriptional Regulation; Vascular Diseases; Visceral; blood glucose regulation; cell type; cytokine; diabetic; fasting glucose; feeding; glucose tolerance; insight; insulin tolerance; interest; lipid biosynthesis; loss of function; lymph nodes; macrophage; member; mortality; mouse model; novel; premature; prevent; receptor; research study

DESCRIPTION (provided by applicant): Insulin resistance and type-2 diabetes often accompany obesity and have been linked to obesity by the low- grade chronic inflammation of adipose tissue that occurs in the obese state. Recently, cells of the adaptive immune system have been shown to be involved in the regulation of adipose tissue inflammation. Specifically, regulatory T cells (Tregs), a subset of T lymphocytes with an immunosuppressive function, are enriched in adipose tissue of lean, but not obese, mice. These fat-resident Tregs (fTregs) may have a role in suppressing inflammation and preventing insulin resistance in the visceral fat. Their abundance in the visceral fat of mice inversely correlates with the level of inflammation in the visceral fat as well as insulin resistance. A recent study showed that fTregs have a different gene expression signature compared to Tregs isolated from the spleen or lymph nodes in mice. In particular, one of the genes specifically upregulated in fTregs is peroxisome proliferator-activated receptor gamma (PPAR!), a key regulator of adipogenesis and organismal metabolism. In addition, preliminary studies have shown that when PPAR! is specifically deleted in Tregs in mice, Tregs are no longer enriched in the visceral fat. It is thus hypothesized that th fat-specific adaptation of fTregs is dependent upon the expression and transcriptional activity of PPAR! in these cells. This proposal seeks to characterize the key molecular mechanisms involved in the upstream induction of PPAR!"and its downstream transcriptional targets in fTregs. Furthermore, the necessity of PPAR!"in fTregs for the therapeutic mechanism of action of thiazolidinediones (TZDs), an important anti-diabetic class of drugs that are PPAR!"agonists, will be investigated using a mouse model generated in our lab. First, it is hypothesized that the unique expression of PPAR! in fTregs is due to a distinct adipokine/cytokine milieu within visceral adipose tissue. The upstream signaling pathways involved in PPAR! induction in fTregs will be dissected using in vitro loss-of-function experiments. Second, it is hypothesized that, once expressed, PPAR! acts in a unique way to reshape the transcriptional signature of fTregs and to enable fTreg-specific function, including maintenance of Treg enrichment in visceral fat and potentially protection against insulin resistance. Thus, ChIP-Seq and microarray expression technologies will be used to map the PPAR! cistrome in fTregs and identify key PPAR! downstream targets that could potentially mediate fTreg function. Third, it is hypothesized that expression of PPAR! in fTregs is critical for TZDs to exert their full therapeutic, insulin-sensitizing potential in mice under metabolic stress. Mice with a Treg-specific PPAR! deletion will be generated and fed high fat diet with or without TZD. The ability of TZDs to protect against progression of insulin resistance and metabolic syndrome in these mice will be compared to their wild-type counterparts. Taken together, these studies will systematically characterize the role of PPAR! in fTregs and illuminate the role of fTregs in the pathogenesis of obesity-related type-2 diabetes. PUBLIC HEALTH RELEVANCE: Obesity-related type-2 diabetes is a growing global epidemic with clinical interventions that are insufficient to prevent premature morbidity and mortality arising from the common debilitating sequelae of type-2 diabetes including retinopathy, neuropathy, vascular disease, heart disease, and kidney disease. Our research seeks to characterize, on a molecular level, a newly discovered population of cells, fat-resident regulatory T cells, that could possibly play a role in protection against insulin resistance and type-2 diabetes. This research could lay the groundwork for a novel cell-based therapy for patients suffering from obesity-related type-2 diabetes.

描述（由申请人提供）：胰岛素抵抗和2型糖尿病通常伴随着肥胖，并且与肥胖有关，因为肥胖状态下脂肪组织发生低度慢性炎症。近年来，适应性免疫系统的细胞已被证明参与脂肪组织炎症的调节。具体来说，调节性T细胞（Tregs），一种具有免疫抑制功能的T淋巴细胞亚群，在瘦弱而非肥胖小鼠的脂肪组织中富集。这些脂肪常驻Tregs （fTregs）可能在抑制炎症和防止内脏脂肪的胰岛素抵抗中起作用。它们在小鼠内脏脂肪中的丰度与内脏脂肪中的炎症水平以及胰岛素抵抗呈负相关。最近的一项研究表明，与从小鼠脾脏或淋巴结分离的Tregs相比，fTregs具有不同的基因表达特征。特别是，在fTregs中特异性上调的基因之一是过氧化物酶体增殖物激活受体γ (PPAR!)，它是脂肪形成和机体代谢的关键调节因子。此外，初步研究表明，当PPAR！在小鼠中，Tregs在内脏脂肪中不再富集。因此，假设fTregs的脂肪特异性适应依赖于PPAR的表达和转录活性！在这些细胞中。本研究旨在描述PPAR上游诱导的关键分子机制。及其在fTregs中的下游转录靶点。此外，PPAR！“噻唑烷二酮（TZDs）是一种重要的抗糖尿病药物，是PPAR!”激动剂，在fTregs中的治疗作用机制将使用我们实验室生成的小鼠模型进行研究。首先，我们假设PPAR！在fTregs中是由于内脏脂肪组织内独特的脂肪因子/细胞因子环境。PPAR的上游信号通路ftreg的诱导将通过体外功能丧失实验进行解剖。其次，假设一旦表达，PPAR！以一种独特的方式重塑ftreg的转录特征，并使ftreg具有特异性功能，包括维持内脏脂肪中Treg的富集和潜在的胰岛素抵抗保护。因此，ChIP-Seq和微阵列表达技术将用于绘制PPAR！并识别关键的PPAR！可能介导fTreg功能的下游靶标。第三，我们假设PPAR！在代谢应激小鼠中，TZDs发挥其充分的治疗和胰岛素增敏潜力至关重要。具有treg特异性PPAR的小鼠！将产生缺失，并饲喂高脂饲料（含或不含TZD）。tzd的防御能力