Fibroblast Growth Factor and Energy Metabolism

项目总结/摘要 肥胖症在世界范围内以流行病的速度增长，并导致广泛的其他疾病， 共同形成代谢综合征。这些病理的中心是脂肪组织。在哺乳动物中， 有两种功能不同的脂肪：白色脂肪组织，储存多余的卡路里，和棕色脂肪组织。 及其相关的米色脂肪组织，其消耗能量用于产热。在啮齿类动物中进行的大量研究 已经证明，增加棕色或米色脂肪的量或活性具有良好的治疗效果， 肥胖相关代谢疾病的可能性。脂肪组织经历了戏剧性的重塑， 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的布朗宁。虽然长期以来人们一直认为生长因子 在棕色和白色脂肪在寒冷时的重塑中起着关键作用 然而，尽管存在挑战，但这些因素的身份仍然大多未得到确认。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，可以诱导UCP 1表达， 棕色脂肪形成除了脂肪祖细胞外，FGF 9还刺激成熟脂肪细胞中的产热程序。 脂肪细胞重要的是，FGF受体3（FGFR 3）的表达，介导FGF 9的作用， 在基质血管部分（SVF）细胞和脂肪细胞中也由冷诱导，这表明FGF 9 在脂肪生态位中起自分泌/内分泌因子的作用。使用单细胞RNA测序， 在脂肪SVF中，我们鉴定了FGFR 3在血管内皮细胞中的丰富表达。基于这些 令人兴奋的发现，我们假设FGF 9，由脂肪细胞产生，作为一个小生境因子，促进 棕色和白色脂肪组织重塑和调节成熟脂肪细胞中的产热程序， 应对寒冷的挑战。这项资助的主要目标是：1）确定FGF 9在调节中的作用 在成熟脂肪细胞的产热程序，并描绘了潜在的转录和表观遗传 机制，2）确定FGF 9诱导的血管生成在脂肪重塑中的作用，以及3）使用增益- 以及功能丧失小鼠模型和纳米技术，以确定FGF 9-FGFR 3轴在 能量代谢，并探索靶向这一途径的潜力，以开发新的治疗方法， 肥胖及其许多相关的并发症。完成拟议的研究将导致一个新的 了解脂肪重塑，并可能提供潜在的治疗方法肥胖，2型 糖尿病和其他相关的代谢疾病。

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.