Role of STAT3 in Brown Adipose Tissue Development

STAT3 在棕色脂肪组织发育中的作用

• 批准号: 9761538
• 负责人: Marc Cantwell
• 金额: $ 3.68万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-16 至 2020-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761538
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agents; Adult; Affect; American; Animals; Attention; Binding; Body Weight decreased; Brown Fat; Bypass; Calories; Cell Differentiation process; Cell Nucleus; Cell physiology; Cells; ChIP-seq; Complex; DNA; Data; Deposition; Development; Diabetes Mellitus; Disease; Expenditure; Family; Fatty Acids; Fatty acid glycerol esters; Future; Gene Expression; Gene Targeting; Genes; Growth Factor; Human; In Vitro; Individual; Infant; Intake; Knock-out; Knowledge; Lead; Lipids; Location; Mammals; Measures; Mediating; Metabolism; Methods; Mitochondria; Mitochondrial Matrix; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxides; Pathway interactions; Patients; Physiology; Play; Production; Productivity; Protein Tyrosine Kinase; Protons; Quality Indicator; Quality of life; Regulation; Reporting; Respiration; Rest; Rodent; Role; Skeletal Muscle; Stat3 protein; Stem cells; Testing; Therapeutic; Tissue Differentiation; Tissues; Treatment Cost; Tyrosine; Tyrosine Phosphorylation; United States; Weight; adipocyte differentiation; blood glucose regulation; combat; cytokine; diet and exercise; experimental study; glucose tolerance; improved; in vitro Model; in vivo; inhibitor/antagonist; interest; knock-down; novel strategies; oxidized lipid; programs; promoter; response; subcutaneous; theories; transcription factor; uncoupling protein 1; volunteer

Project Summary Rates of Obesity and Type II Diabetes (T2D) remain high in the United States. The consequences of these rates can be measured in dollars, including treatment costs and lost productivity, and in lower indicators of quality of life. Despite the general knowledge that decreased calorie intake and increased calorie expenditure can lead to weight loss and better glucose tolerance, Americans have not made a significant dent in the rates of these diseases through sustained dieting and exercise. Clearly, new treatments are needed to help combat these diseases. One new approach that has received a lot of attention is to increase a type of fat called brown fat, also known as thermogenic adipose tissue. In mammals there are two types of adipose tissue: brown fat and white fat. Brown fat oxidizes fatty acids as heat energy. White fat stores lipids for future use. Previously, our lab has shown that the JAK/STAT pathway is required for proper differentiation of brown adipose tissue in- vitro, specifically Tyk2-STAT3 signaling. This proposed study focuses on the STAT3 aspect of brown fat differentiation. There is almost nothing known about the targets STAT3 regulates during differentiation of brown fat, however, in the preliminary data we show that inhibiting STAT3 significantly reduces expression of brown fat-selective genes while moderately affecting expression of genes common to brown- and white- fat. The in-vivo consequences from loss of STAT3 in brown fat are unknown, and no role of STAT3 in the development of human thermogenic fat has been reported. We hypothesize that STAT3 plays a major role in the terminal differentiation of brown fat by directly regulating brown fat-selective genes. The aims of this study are to determine: 1) The gene targets regulated by STAT3 by performing ChIPseq on murine brown preadipocytes in-vitro, 2) the disturbances to whole animal metabolism due to loss of STAT3 in thermogenic fat, and 3) the role of STAT3 in the differentiation of human thermogenic fat, specifically if STAT3 regulates similar genes that we will identify in rodent tissue. The answers to these questions will increase our understanding the differentiation mechanism of thermogenic adipose tissue, which would be the first step to realizing a therapeutic approach.

项目摘要 肥胖和II型糖尿病（T2 D）的发病率在美国仍然很高。这些后果 费率可以用美元衡量，包括治疗费用和生产力损失， 生活质量尽管人们普遍认为减少卡路里摄入和增加卡路里消耗 可以导致体重减轻和更好的葡萄糖耐量，美国人还没有取得显着的凹痕率 通过持续的节食和锻炼来预防这些疾病。显然，需要新的治疗方法来帮助对抗 这些疾病。一种新的方法受到了很多关注，那就是增加一种叫做棕色的脂肪 脂肪，也称为产热脂肪组织。在哺乳动物中有两种类型的脂肪组织：棕色脂肪 和白色脂肪。棕色脂肪氧化脂肪酸作为热能。白色脂肪储存脂质以备将来使用。在此之前， 我们的实验室已经表明JAK/STAT途径是棕色脂肪组织正常分化所必需的， 体外，特别是Tyk 2-STAT 3信号传导。这项研究的重点是棕色脂肪的STAT 3方面， 分化关于STAT 3在细胞分化过程中调节的靶点几乎一无所知。 然而，在初步数据中，我们表明抑制STAT 3显著降低了 棕色脂肪选择性基因，同时适度影响棕色脂肪和白色脂肪共有基因的表达。 褐色脂肪中STAT 3缺失的体内后果尚不清楚，并且STAT 3在细胞凋亡中没有作用。 已经报道了人类产热脂肪的发展。我们假设STAT 3在细胞凋亡中起主要作用。 通过直接调控棕色脂肪选择基因实现棕色脂肪的终末分化。本研究的目的 目的：1）通过ChIPseq对小鼠棕色细胞进行STAT 3调控， 2）由于产热前脂肪细胞中STAT 3的丢失而对整个动物代谢的干扰， 3）STAT 3在人产热脂肪分化中的作用，特别是如果STAT 3调节 我们将在啮齿类动物组织中发现类似的基因。这些问题的答案将增加我们的 了解产热脂肪组织的分化机制，这将是第一步， 实现治疗方法。