P311 mediated adipogenesis, adipocyte plasticity and metabolic regulation

P311 介导的脂肪生成、脂肪细胞可塑性和代谢调节

• 批准号: 10334071
• 负责人: Kameswara Rao Badri
• 金额: $ 35.5万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10334071
• 关键词: Ablation; Adipocytes; Adipose tissue; Affect; Age; Apoptosis; Autophagocytosis; Binding; Biochemical; Biological Assay; Biology; Body mass index; Brown Fat; CRISPR/Cas technology; Carrier Proteins; Cell physiology; Cellular biology; Chronic Disease; Clinical; Cues; Development; Diabetes Mellitus; Disease; Epidemic; Equilibrium; Equipment; Event; Fatty acid glycerol esters; Functional disorder; Funding; GLUT 4 protein; Generations; Genetic; Glucose; Glucose Transporter; Goals; Health; Heart Diseases; Heterogeneity; Homeostasis; Hyperglycemia; Hyperglycemic Mice; Hyperplasia; Hypertension; Hypertrophy; Immunoassay; Infiltration; Insulin Resistance; Kinetics; Knock-out; Knockout Mice; Link; Lipids; Lipolysis; Location; Malignant Neoplasms; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic dysfunction; Metabolism; Methods; Molecular; Molecular Biology; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PPAR gamma; Pathology; Peroxisome Proliferator-Activated Receptors; Phenotype; Play; Population; Primary Cell Cultures; Principal Investigator; Proteins; Regulation; Reporter; Research; Risk; Role; Skeletal Muscle; Technology; Testing; Therapeutic; Tissue Expansion; Transgenic Animals; Vascular Smooth Muscle; Work; adipocyte biology; adipocyte differentiation; age group; base; blood glucose regulation; conditional knockout; digital; exhaust; fasting glucose; glucose transport; glycemic control; imaging modality; improved; innovation; lipid biosynthesis; macrophage; man; nano-string; novel; novel strategies; obesity treatment; precursor cell; stable isotope; subcutaneous; uncoupling protein 1

Summary One third of the US population is clinically obese, a condition which increases the risk for chronic diseases like type 2 diabetes mellitus (DM), heart disease and cancers. Adipocyte dysfunction (AD) is cardinal feature of metabolic dysregulation and increases the risk for developing insulin resistance (IR), DM, and hypertension. Along with adipocyte hypertrophy, macrophage infiltration of white adipose tissue (WAT) is associated with the pathophysiology of obesity, AD and IR, albeit the underlying molecular mechanisms are uncharacterized. We were first to show the presence of P311 in WAT, brown adipose tissue (BAT) and beige adipose tissue. The WAT of P311 knockout (KO) mice has fewer resident macrophages and decreased cellular dynamics, including decreased autophagy and apoptosis. This is potentially leading to adipocyte hypertrophy that in turn causes hyperglycemia due to age- and genetic ablation-mediated P311 expression leading to overworked and exhausted adipocytes in P311 KOs or low P311 expressing adipocytes compared to wild types. As studies are limited, resident macrophages could alter adipocyte function early in adipose tissue development, a novel mechanism requiring exploration. We will also explore key adipocyte cellular processes of apoptosis and autophagy/lipophagy, which may affect adipocyte turnover in the WAT of P311 KO mice, leading to adipocyte hypertrophy and dysfunction, and thus metabolic deregulation. The proposed project will test the central hypothesis that age- and genetic ablation-mediated P311 levels play a key role in white, brown and beige adipocyte development, plasticity and function, as well as in metabolic regulation. Further, we will investigate the role of P311 in cellular processes (i.e., WAT browning and BAT whitening) and its effect on adipocyte function and glycemic control, as P311 KO mice are hyperglycemic. We will also evaluate the ability of P311 to modulate adipose biology and metabolic regulation through PPAR and UCP1 regulation; and myo1C binding to GLUT4. We will develop adipocyte-specific P311 KO conditional mice using novel CRISPR technology to evaluate the adipocyte-specific P311 roles. The current project will thereby establish P311 as a new player in adipocyte biology and metabolic regulation. Our experimental strategy will incorporate transgenic animals using classic cell biology, molecular biology, biochemical, immunoassays and imaging methods studies. Our findings will enhance the understanding of P311 mediated fat cell development and function and fat mass expansion. Our ongoing studies indicate that P311 potentially regulates metabolism through adipocyte dynamics, function and plasticity (a novel approach to targeting metabolic disorders through browning of WAT); regulating resident and infiltrating macrophages; and controlling adipocyte cellular processes. These studies are new and do not overlap with existing funding.

总结 三分之一的美国人患有临床肥胖症，这种情况会增加患慢性疾病的风险， 2型糖尿病（DM）、心脏病和癌症。脂肪细胞功能障碍（AD）是肥胖的主要特征。 代谢失调并增加发生胰岛素抵抗（IR）、DM和高血压的风险。 沿着脂肪细胞肥大，白色脂肪组织（WAT）的巨噬细胞浸润与 肥胖、AD和IR的病理生理学，尽管潜在的分子机制尚未表征。我们 首先显示P311存在于WAT、棕色脂肪组织（BAT）和米色脂肪组织中。的 P311敲除（KO）小鼠的WAT具有较少的常驻巨噬细胞和降低的细胞动力学， 包括减少自噬和凋亡。这可能导致脂肪细胞肥大， 由于年龄和遗传消融介导的P311表达导致过度劳累， 与野生型相比，P311科斯耗尽的脂肪细胞或低P311表达的脂肪细胞。由于研究 有限的，常驻巨噬细胞可以改变脂肪组织发育早期的脂肪细胞功能，一种新的 需要探索的机制。我们还将探讨关键的脂肪细胞凋亡过程， 自噬/脂肪吞噬，这可能会影响P311 KO小鼠WAT中的脂肪细胞周转，导致脂肪细胞 肥大和功能障碍，从而代谢失调。 该项目将测试年龄和遗传消融介导的P311水平发挥作用的中心假设。 在白色、棕色和米色脂肪细胞发育、可塑性和功能以及代谢中起关键作用。 调控此外，我们将研究P311在细胞过程中的作用（即，WAT布朗宁和BAT 美白）及其对脂肪细胞功能和血糖控制的作用，因为P311 KO小鼠是高血糖的。我们 还将评估P311通过PPAR γ调节脂肪生物学和代谢调节的能力， UCP 1调节;和myo 1C结合GLUT 4。我们将开发脂肪细胞特异性P311 KO条件小鼠 使用新的CRISPR技术来评估脂肪细胞特异性P311的作用。本项目将 建立P311作为脂肪细胞生物学和代谢调节中的新参与者。我们的实验策略将 使用经典的细胞生物学、分子生物学、生物化学、免疫测定和 成像方法研究。我们的发现将加深对P311介导的脂肪细胞发育的理解。 以及功能和脂肪量的扩张。我们正在进行的研究表明，P311可能调节代谢 通过脂肪细胞的动力学，功能和可塑性（一种新的方法，以针对代谢紊乱， WAT的布朗宁）;调节驻留和浸润的巨噬细胞;以及控制脂肪细胞细胞 流程.这些研究是新的，与现有的资金不重叠。