Fibroblast Growth Factor and Energy Metabolism

成纤维细胞生长因子和能量代谢

• 批准号: 10220487
• 负责人: Yu-Hua Tseng
• 金额: $ 60.69万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-03 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10220487
• 关键词: Adipocytes; Adipose tissue; Automobile Driving; Blood Vessels; Brown Fat; Calories; Cell Differentiation process; Cell Fraction; Cell Proliferation; Cell Separation; Chromatin; Chromatin Remodeling Factor; Complex; DNA Methylation; Data; Diabetes Mellitus; Disease; Endocrine; Endothelial Cells; Endothelium; Energy Metabolism; Epidemic; Epigenetic Process; FGF9 gene; FGFR3 gene; Fatty acid glycerol esters; Fibroblast Growth Factor; Gene Expression; Genes; Genetic Transcription; Goals; Grant; Growth Factor; Health; In Vitro; Knockout Mice; Knowledge; Ligands; Lipids; Mammals; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Mitochondria; Modeling; Mus; Nanotechnology; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Pathology; Pathway interactions; Physiological; Play; Protein Engineering; Proteins; Regulation; Research; Rodent; Role; Scheme; Signal Transduction; Stimulus; System; Therapeutic; Thermogenesis; United States; Vascular Endothelial Cell; Vascularization; adipokines; angiogenesis; autocrine; base; combat; comorbidity; epigenetic regulation; fibroblast growth factor 6; fibroblast growth factor 9; glucose tolerance; histone modification; improved; in vivo; innovation; insulin sensitivity; intercellular communication; lipid biosynthesis; loss of function; mouse model; nanoparticle; neovascularization; novel; novel therapeutics; obesity prevention; precursor cell; progenitor; programs; receptor; recruit; response; single-cell RNA sequencing; stem cells; success; uncoupling protein 1

Project Summary/Abstract Obesity is growing at epidemic rates worldwide and leads to a broad spectrum of other disorders, which collectively form metabolic syndrome. Central to these pathologies is the adipose tissue. In mammals, there are two functionally distinct types of fat: white adipose tissue, which stores excess calories, and brown and its related beige adipose tissue, which dissipates energy for thermogenesis. Numerous studies in rodents have demonstrated that increasing the amount or activity of brown or beige fat holds excellent therapeutic potential for obesity-related metabolic diseases. Adipose tissue undergoes dramatic remodeling in response to environmental challenges. Cold exposure is an effective way to increase brown fat mass and activity. as well as to induce browning of white adipose tissue. While it has long been postulated that growth factors produced by the adipose niche play a critical role in the remodeling of brown and white fat upon cold challenge, the identity of such factors have remained mostly unidentified. Recently, we discovered that fibroblast growth factor (FGF) 9 is a cold-induced adipokine and can induce UCP1 expression independent of brown adipogenesis. In addition to adipose progenitors, FGF9 also stimulates thermogenic program in mature adipocytes. Importantly, expression of FGF receptor 3 (FGFR3), the receptor that mediates FGF9’s effects, is also induced by cold in both the stromal vascular fraction (SVF) cells and adipocytes, suggesting that FGF9 functions as an autocrine/endocrine factor within the adipose niche. Using single-cell RNA sequencing of the adipose SVF, we identify FGFR3’s abundant expression in the vascular endothelial cells. Based on these exciting findings, we hypothesize that FGF9, produced by adipocytes, functions as a niche factor to promote brown and white adipose tissue remodeling and modulate thermogenic program in mature adipocytes, in response to cold challenge. The primary goals of this grant are to 1) determine the role of FGF9 in regulation of thermogenic program in mature adipocytes and delineate the underlying transcriptional and epigenetic mechani, 2) determine the role of FGF9-induced angiogenesis in adipose remodeling, and 3) use both gain- and loss-of-function mouse models and nanotechnology to define the in vivo role of the FGF9-FGFR3 axis in energy metabolism and explore the potential of targeting this pathway to develop new therapies to treat obesity and its many related co-morbidities. Completion of the proposed studies will lead to a new understanding of adipose remodeling and could provide potential therapeutic approaches for obesity, type 2 diabetes, and other related metabolic diseases.

项目概要/摘要 肥胖症在世界范围内呈流行趋势，并导致一系列其他疾病， 它们共同形成代谢综合征。这些病理学的核心是脂肪组织。在哺乳动物中， 脂肪有两种功能不同的类型：白色脂肪组织，储存多余的热量；棕色脂肪组织 及其相关的米色脂肪组织，其消耗生热能量。对啮齿动物的大量研究 已经证明，增加棕色或米色脂肪的数量或活性具有极好的治疗作用 与肥胖相关的代谢疾病的可能性。脂肪组织响应而经历戏剧性的重塑 应对环境挑战。冷暴露是增加棕色脂肪质量和活性的有效方法。作为 以及诱导白色脂肪组织褐变。虽然长期以来人们一直认为生长因子 脂肪生态位产生的脂肪在寒冷时棕色和白色脂肪的重塑中发挥着关键作用 挑战，这些因素的身份大多仍未确定。最近，我们发现 成纤维细胞生长因子 (FGF) 9 是一种冷诱导的脂肪因子，可独立诱导 UCP1 表达 棕色脂肪生成。除了脂肪祖细胞外，FGF9 还刺激成熟细胞的生热程序 脂肪细胞。重要的是，FGF 受体 3 (FGFR3)（介导 FGF9 作用的受体）的表达是 基质血管成分 (SVF) 细胞和脂肪细胞中的冷也会诱导 FGF9 作为脂肪生态位内的自分泌/内分泌因子。使用单细胞 RNA 测序 在脂肪 SVF 中，我们发现 FGFR3 在血管内皮细胞中大量表达。基于这些 令人兴奋的发现，我们假设脂肪细胞产生的 FGF9 作为利基因子发挥作用，促进 棕色和白色脂肪组织重塑并调节成熟脂肪细胞的产热程序 应对寒冷的挑战。这笔赠款的主要目标是 1) 确定 FGF9 在监管中的作用 成熟脂肪细胞中的产热程序并描述潜在的转录和表观遗传 机制，2) 确定 FGF9 诱导的血管生成在脂肪重塑中的作用，3) 使用增益- 和功能丧失小鼠模型和纳米技术来定义 FGF9-FGFR3 轴在体内的作用 能量代谢并探索针对该途径开发新疗法的潜力 肥胖及其许多相关的并发症。完成拟议的研究将产生新的 了解脂肪重塑并可为 2 型肥胖提供潜在的治疗方法 糖尿病和其他相关代谢性疾病。