Role of PIK3R1 in Adipose Tissue Insulin Resistance and Inflammation in Obesity

PIK3R1 在脂肪组织胰岛素抵抗和肥胖炎症中的作用

• 批准号: 9214385
• 负责人: Carrie E McCurdy
• 金额: $ 30.8万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-17 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9214385
• 关键词: Acute; Adaptor Signaling Protein; Address; Adenovirus Vector; Adipocytes; Adipose tissue; Animals; Biological Assay; Caloric Restriction; Cardiovascular Diseases; Cell Proliferation; Cells; Chemotaxis; Chronic; Clinical; Co-Immunoprecipitations; Coronary heart disease; Cytokine Activation; Cytokine Receptors; Data; Deacetylase; Defect; Development; Disease Progression; Dominant-Negative Mutation; Genes; Growth; Health; High Fat Diet; Human; Hypertension; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Knowledge; Lead; Link; Lipolysis; Measures; Mediating; Metabolic; Metabolic Diseases; Microscopy; Molecular; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nutrient; Obese Mice; Obesity; Palmitates; Pathway interactions; Phenotype; Phosphotransferases; Physiology; Play; Population; Production; Public Health; Regulation; Research; Resources; Risk; Role; Secondary to; Signal Pathway; Signal Transduction; Skeletal Muscle; Stat3 protein; Stimulus; System; TLR4 gene; Techniques; Testing; Thinking; Transgenic Mice; United States; Up-Regulation; Wild Type Mouse; anticancer research; base; chemokine; cytokine; design; feeding; improved; in vitro testing; in vivo; inhibitor/antagonist; insulin sensitivity; knock-down; macrophage; metabolic abnormality assessment; monocyte; mouse model; novel therapeutics; nutrient metabolism; overexpression; prevent; research study; response; transcription factor; uptake

DESCRIPTION (provided by applicant): Obesity and its associated metabolic diseases are one of the greatest public health challenges in the United States. Insulin resistance is a primary contributor to this increase in metabolic disease with obesity and is proposed to arise secondary to an inflammatory response caused by infiltration of adipose tissue (AT) with macrophages and increased pro-inflammatory cytokine production. Surprisingly, however, the cellular signals within AT that initiate and propagate the inflammatory phenotype in response to nutrient excess are largely unknown, highlighting a significant gap in knowledge. Phosphoinosital 3-kinase (PI3K) regulates key insulin, cytokine, and growth signaling pathways, and is thus a strong candidate for linking cellular insulin resistance with the inflammatory response. We recently found a 2-4-fold increase in the PI3K p55α and p50α regulatory subunits in parallel with reduced insulin sensitivity in adipocytes from high-fat diet (HFD)-induced obese mice. Blocking HFD-induced increase in p55α and p50α through global heterozygous deletion of Pik3r1, the gene that encodes the regulatory subunits, reduced AT macrophage infiltration and significantly improved adipocyte, skeletal muscle and systemic insulin sensitivity in obese mice. Studies by our group have identify sirtuin 1 (SIRT1) and signal transducer and activator of transcription 3 (STAT3) as key regulators of p50α and p55α expression and subsequent PI3K activity in muscle with nutrient restriction, highlighting a potential universal link between insulin sensitiviy and cellular energy status. We hypothesize that nutrient excess increases adipocyte p55α and p50α abundance to, 1) inhibit insulin-stimulated PI3K signaling, further suppressing nutrient uptake and, 2) promote PI3K-mediate NFκB activation, thereby stimulating cytokine production and macrophage recruitment. In contrast to the current paradigm, we predict that insulin resistance itself, through PI3K signaling promotes the inflammatory response, rather than inflammation causing insulin resistance. To address this hypothesis, we will use an integrative approach that combines whole animal physiology with cell and molecular techniques. Specifically, AIM1 will use transgenic mouse models with adipocyte-specific knockdown or over-expression of p55α and p50α to investigate whether increased adipocyte p55α and p50α abundance is necessary and sufficient to stimulate macrophage recruitment after acute or chronic HFD feeding. In AIM2, we will test in vitro whether increased adipocyte p55α and p50α alters cytokine secretion through up-regulation of NFκB signaling to promote macrophage chemotaxis and/or inhibition of insulin suppression of lipolysis. In AIM3, we will use transgenic mouse models to determine in vivo if the HFD-induced increase in AT p55α and p50α is downstream of a SIRT1-STAT3 axis. Considering the integral role of PI3K in metabolic disease and cancer research, these studies will provide unique new resources for PI3K research, will broaden our understanding of PI3K regulation and will facilitate the development of more focused approaches for targeting PI3K, which has the potential to treat metabolic, and ultimately impact human health.

描述（由申请人提供）：肥胖及其相关代谢疾病是美国最大的公共卫生挑战之一。胰岛素抵抗是肥胖代谢性疾病增加的主要原因，并且被认为是继发于巨噬细胞浸润脂肪组织（AT）和促炎细胞因子产生增加引起的炎症反应。然而，令人惊讶的是，AT 内响应营养过剩而启动和传播炎症表型的细胞信号在很大程度上是未知的，这凸显了知识上的巨大差距。磷酸肌醇 3-激酶 (PI3K) 调节关键的胰岛素、细胞因子和生长信号通路，因此是将细胞胰岛素抵抗与炎症反应联系起来的有力候选者。我们最近发现，高脂饮食 (HFD) 诱导的肥胖小鼠的脂肪细胞中，PI3K p55α 和 p50α 调节亚基增加了 2-4 倍，同时胰岛素敏感性降低。通过编码调节亚基的基因 Pik3r1 的整体杂合缺失，阻断 HFD 诱导的 p55α 和 p50α 增加，减少 AT 巨噬细胞浸润，并显着改善肥胖小鼠的脂肪细胞、骨骼肌和全身胰岛素敏感性。我们小组的研究发现，sirtuin 1 (SIRT1) 和信号转导子和转录激活子 3 (STAT3) 是 p50α 和 p55α 表达以及随后的营养限制肌肉中 PI3K 活性的关键调节因子，强调了胰岛素敏感性和细胞能量状态之间潜在的普遍联系。我们假设营养过剩会增加脂肪细胞 p55α 和 p50α 丰度，从而：1) 抑制胰岛素刺激的 PI3K 信号传导，进一步抑制营养吸收，2) 促进 PI3K 介导的 NFκB 激活，从而刺激细胞因子的产生和巨噬细胞的招募。与当前的范例相反，我们预测胰岛素抵抗本身通过 PI3K 信号传导促进炎症反应，而不是炎症导致胰岛素抵抗。为了解决这个假设，我们将使用一种综合方法，将整个动物生理学与细胞和分子技术相结合。具体来说，AIM1将使用脂肪细胞特异性敲低或过度表达p55α和p50α的转基因小鼠模型来研究脂肪细胞p55α和p50α丰度的增加是否是必要且足以刺激急性或慢性HFD喂养后巨噬细胞的招募。在 AIM2 中，我们将在体外测试增加的脂肪细胞 p55α 和 p50α 是否通过上调 NFκB 信号传导来改变细胞因子分泌，从而促进巨噬细胞趋化性和/或抑制胰岛素抑制脂肪分解。在 AIM3 中，我们将使用转基因小鼠模型来体内确定 HFD 诱导的 AT p55α 和 p50α 增加是否位于 SIRT1-STAT3 轴的下游。考虑到 PI3K 在代谢疾病和癌症研究中的不可或缺的作用，这些研究将为 PI3K 研究提供独特的新资源，将拓宽我们对 PI3K 调控的理解，并将促进开发更有针对性的靶向 PI3K 的方法，该方法具有治疗代谢疾病并最终影响人类健康的潜力。