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: 8630010
• 负责人: Carrie E McCurdy
• 金额: $ 31.93万
• 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/8630010
• 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; Complement Factor B; Coronary heart disease; Cytokine Activation; Cytokine Receptors; Data; Deacetylase; Defect; Development; Diet; Disease Progression; Dominant-Negative Mutation; Fatty acid glycerol esters; Genes; Growth; Health; 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; TNFRSF5 gene; Techniques; Testing; Thinking; Transgenic Mice; United States; Up-Regulation; Wild Type Mouse; anticancer research; base; chemokine; cytokine; design; feeding; human MPP1 protein; improved; in vitro testing; in vivo; inhibitor/antagonist; insulin sensitivity; macrophage; metabolic abnormality assessment; monocyte; mouse model; novel therapeutics; nutrient metabolism; overexpression; prevent; public health relevance; research study; response; toll-like receptor 4; transcription factor; uptake

PROJECT SUMMARY 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 p55¿ and p50¿ regulatory subunits in parallel with reduced insulin sensitivity in adipocytes from high-fat diet (HFD)-induced obese mice. Blocking HFD-induced increase in p55¿ and p50¿ 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 p50¿ and p55¿ expression and subsequent PI3K activity in muscle with nutrient restriction, highlighting a potential universal link between insulin sensitivity and cellular energy status. We hypothesize that nutrient excess increases adipocyte p55¿ and p50¿ abundance to, 1) inhibit insulin-stimulated PI3K signaling, further suppressing nutrient uptake and, 2) promote PI3K-mediate NF¿B 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 p55¿ and p50¿ to investigate whether increased adipocyte p55¿ and p50¿ 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 p55¿ and p50¿ alters cytokine secretion through up-regulation of NF¿B 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 p55¿ and p50¿ 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.

项目摘要 肥胖及其相关的代谢疾病是美国最大的公共卫生挑战之一。 States.胰岛素抵抗是肥胖症代谢疾病增加的主要原因， 建议继发于脂肪组织（AT）浸润引起的炎症反应， 巨噬细胞和增加的促炎细胞因子产生。然而，令人惊讶的是， 在AT内，响应于营养过剩而引发和传播炎性表型的AT主要是 未知，突出了知识的巨大差距。磷酸肌醇3-激酶（PI 3 K）调节关键胰岛素， 细胞因子和生长信号通路，因此是连接细胞胰岛素抵抗的强有力的候选者。 与炎症反应有关我们最近发现PI 3 K p55 <$and p50 <$调控因子增加了2-4倍。 在高脂饮食（HFD）诱导的肥胖小鼠的脂肪细胞中，胰岛素亚基的表达与胰岛素敏感性的降低平行。 通过Pik 3r 1基因的全杂合缺失阻断HFD诱导的p55和p50增加， 编码调节亚单位，减少AT巨噬细胞浸润和显着改善脂肪细胞， 肥胖小鼠骨骼肌和全身胰岛素敏感性。我们小组的研究已经鉴定出sirtuin 1 SIRT 1和STAT 3作为p50和p55的关键调节因子 表达和随后的PI 3 K活性在肌肉营养限制，突出了潜在的普遍性 胰岛素敏感性和细胞能量状态之间的联系。我们假设营养过剩会增加 脂肪细胞p55 <$and p50 <$丰度，1）抑制胰岛素刺激的PI 3 K信号传导，进一步抑制 营养摄取，2）促进PI 3 K介导的NF B活化，从而刺激细胞因子产生， 巨噬细胞募集与目前的模式相反，我们预测胰岛素抵抗本身，通过 PI 3 K信号传导促进炎症反应，而不是炎症引起胰岛素抵抗。到 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生物学相结合， 和分子技术。具体而言，AIM 1将使用具有脂肪细胞特异性的转基因小鼠模型。 敲低或过表达p55 <$和p50 <$，以研究是否增加脂肪细胞p55 <$和p50 <$ 在急性或慢性HFD后，充足的量是刺激巨噬细胞募集的必要和充分的 喂食在AIM 2中，我们将在体外测试脂肪细胞p55和p50的增加是否会改变细胞因子的分泌。 通过上调NF B信号以促进巨噬细胞趋化性和/或抑制胰岛素 抑制脂肪分解。在AIM 3中，我们将使用转基因小鼠模型来体内确定HFD诱导的HFD是否在体内表达。 AT p55 <$和p50 <$的增加位于SIRT 1-STAT 3轴的下游。考虑到PI 3 K在 代谢疾病和癌症研究，这些研究将为PI 3 K研究提供独特的新资源， 将扩大我们对PI 3 K调节的理解，并将促进更集中的 靶向PI 3 K的方法，它有可能治疗代谢，并最终影响人类健康。