Regulation of beige adipogenesis

米色脂肪生成的调节

• 批准号: 10188374
• 负责人: Alexandra Reissmann Yesian
• 金额: $ 3.19万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188374
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agonists; Adult; Age; Agonist; Animals; Anti-Inflammatory Agents; Cell Line; Cells; Clone Cells; Core Facility; Data; Development; Energy Metabolism; Event; Faculty; Fatty Acids; Fellowship; Funding; Genetic Transcription; Glucose; Goals; Homeostasis; IL-13Ralpha1; IL13RA1 gene; Immune system; Impairment; Inflammation; Interleukin-13; Interleukin-4; Investigation; Knock-out; Knockout Mice; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; PPAR gamma; Platelet-Derived Growth Factor alpha Receptor; Play; Population; Process; Public Health Schools; Publishing; Regulation; Reporting; Research; Role; STAT6 gene; Signal Transduction; Source; Stimulus; Thermogenesis; Tissues; Training; Work; adipocyte biology; cytokine; glucose uptake; in vitro Model; insulin sensitivity; knock-down; lipid biosynthesis; macrophage; mature animal; medical schools; metabolic abnormality assessment; mouse model; obesity treatment; overexpression; postnatal development; programs; recruit; response; stem cells; subcutaneous; symposium; targeted treatment; transcriptome sequencing

PROJECT SUMMARY The immune system promotes adipose tissue homeostasis through a tightly orchestrated network of pro- and anti-inflammatory signaling events. The Th2 cytokines interleukin-13 (IL-13) and IL-4 temper inflammation and promote insulin sensitivity through the alternative activation of resident macrophages. IL-13 and IL-4 have also been reported to regulate the development and activation of thermogenic beige adipocytes through canonical and non-canonical mechanisms that have not been fully elucidated. Upon activation, beige adipocytes rapidly take up glucose and fatty acids to fuel heat production, making them a potential target for the treatment of obesity and type 2 diabetes. Data from our lab and others indicate that in mice, Th2 cytokines directly act on adipocyte progenitor cells to promote the development of beige cells, a cell population that rapidly dissipates after 4 weeks of age. The source of beige cells in adult animals remains an unanswered question. The molecular mechanism through which Th2 cytokines induce beige adipogenesis is also unclear. Preliminary data indicate that activation of this program in early post-natal development appears to be crucial for the establishment of an inducible pool of beige adipocytes that persists into adulthood. We hypothesize IL-13-IL-13Ra signaling plays a key role in this process. The current research plan will utilize two conditional Il13ra1 knockout models to define the roles of IL- 13 in preadipocytes and mature adipocytes, respectively. In vitro models, including primary preadipocytes and immortalized inguinal preadipocyte cell lines from wild-type and Il13ra1-/- mice will be used to investigate the mechanism by which the IL-13Ra1/STAT6/PPARg signaling axis promotes beige adipogenesis. Investigation of these regulatory mechanisms in preadipocytes will clarify existing discrepancies, characterize unexplored mediators of thermogenesis, and may inform the development of more targeted therapies for obesity and type 2 diabetes. The proposed research will be conducted within the Department of Molecular Metabolism at the Harvard T.H. Chan School of Public Health. The department specializes in the study of metabolism and is equipped with both the facilities and expertise to facilitate the successful completion of this work. Harvard Medical School core facilities and faculty with expertise in adipocyte biology will serve as a further source of support for this work. The goal of the fellowship training is to publish the research findings and present results at a scientific conference by the end of the funding period.

项目摘要 免疫系统通过紧密精心策划的Pro和Pro和 抗炎信号事件。 Th2细胞因子白介素13（IL-13）和IL-4炎症和 通过替代居民巨噬细胞的替代激活来促进胰岛素敏感性。 IL-13和IL-4也有 据报道，通过规范来调节热米色脂肪细胞的发育和激活 以及尚未完全阐明的非典型机制。激活后，米色脂肪细胞迅速 吸收葡萄糖和脂肪酸来促进热量产生，使其成为治疗肥胖症的潜在目标 和2型糖尿病。来自我们实验室和其他人的数据表明，在小鼠中，Th2细胞因子直接作用于脂肪细胞 祖细胞促进米色细胞的发展，米色细胞的发展，该细胞群在4周后迅速消失 年龄。成年动物中米色细胞的来源仍然是一个未解决的问题。分子机制 Th2细胞因子诱导米色脂肪形成也尚不清楚。初步数据表明激活 该计划的早期产后发展似乎对于建立诱导池至关重要 长成年的米色脂肪细胞。我们假设IL-13-IL-13RA信号传导在此起着关键作用 过程。当前的研究计划将利用两个条件IL13RA1敲除模型来定义IL-的作用 13分别在前膜细胞和成熟的脂肪细胞中。体外模型，包括主要的前脂肪细胞和 来自野生型和IL13RA1-/ - 小鼠的永生腹股沟前细胞细胞系将用于研究 IL-13RA1/STAT6/PPARG信号轴促进米色脂肪形成的机制。调查 预粒细胞中的这些调节机制将阐明现有的差异，这是未开发的 热生成的介体，可以告知肥胖和2型靶向疗法的发展 糖尿病。拟议的研究将在分子代谢部内进行 哈佛T.H.陈公共卫生学院。该部门专门研究代谢，是 配备了设施和专业知识，以促进这项工作的成功完成。哈佛医疗 学校核心设施和具有脂肪细胞生物学专业知识的教师将成为对 这项工作。奖学金培训的目的是发表研究结果，并在科学上提出结果 在资金期结束时会议。