The Role of Adipocyte Uridine Biosynthesis in Obesity and Diabetes Progression

项目摘要 脂肪细胞在全身能量平衡中起关键作用，它通过分泌一系列 脂肪因子。最近的研究表明，脂肪细胞合成和释放尿苷是最丰富的 在细胞中具有多种功能的循环核苷。然而，脂肪细胞尿苷的意义 肥胖和糖尿病进展的结果仍不清楚。 历史上，肝脏被认为是尿苷合成和血浆供应的主要器官。近期 研究表明，脂肪细胞是禁食状态下血浆尿苷供应的关键，而内质网应激具有潜在的作用。 刺激脂肪细胞合成尿苷。与脂肪组织的大量扩张和 慢性内质网应激，肥胖是一种需要增加脂肪组织尿苷供应的情况。的确， 肥胖小鼠的循环尿苷水平升高，然而，脂肪细胞和 胰岛素抵抗的意义仍然难以捉摸。 初步结果表明，作为对高脂饮食喂养的反应，小鼠增加了 循环中尿苷的浓度和脂肪组织中尿苷的生物合成能力，但不是在肝脏中。 以往的研究表明，尿苷对血糖控制有双重作用。尿苷一过性升高 供应有益于血糖控制，而尿苷水平的慢性升高是有害的。初步数据 这表明尿苷是一种有效的胰岛素促分泌剂。值得注意的是，尿苷诱导的高分泌 胰岛素严重依赖瘦素。在没有瘦素的情况下，尿苷从激动剂转化为 胰岛素分泌的拮抗剂。鉴于胰岛素是脂肪生成和脂肪生成的驱动力， 尿苷的增加会促进胰岛素的高分泌和全身性高胰岛素血症。因此，肥胖 通过尿苷介导的胰岛素高分泌而变得“自我维持”。即使海平面急剧上升 尿苷通过胰岛素分泌促进葡萄糖摄取，尿苷供应的持续增加可能 通过O-GlcNAc蛋白干扰细胞胰岛素信号转导途径降低胰岛素反应 修改。因此，慢性尿苷升高可能导致高胰岛素血症并伴有胰岛素。 抵抗力，肥胖相关糖尿病前期的一个关键特征。 根据以前的发现和目前的初步数据，脂肪细胞增加的尿苷供应是 假设是为了促进肥胖和糖尿病的进展。功能增强型和失调型小鼠模型 用来测试1)脂肪细胞对肥胖症患者循环尿苷供应的贡献，2)作用 肥胖患者高胰岛素血症中尿苷的变化。将进行体外和体外实验，以证实 活体测试。阐明脂肪细胞对尿苷供应的意义及其与尿苷供应的相关性 肥胖症的高胰岛素血症将阐明胰岛素抵抗的病因，并为新的、更多的 针对2型糖尿病的有效治疗设计。

Project Summary Adipocytes play a critical role in whole body energy homeostasis through secretion of a spectrum of adipokines. Recent studies show that adipocytes synthesize and release uridine, the most abundant circulating nucleoside that has a plethora of functions in cells. However, the significance of adipocyte uridine production in obesity and diabetes progression remains unknown. Historically, liver is considered as the major organ for uridine synthesis and plasma supply. Recent studies show that adipocytes are critical for plasma uridine supply in fasted state, and ER stress potently stimulates uridine synthesis in adipocytes. Being associated with massive expansion of adipose tissue and chronic ER stress, obesity is a condition that warrants increased uridine supply from adipose tissue. Indeed, circulating uridine levels are found elevated in obese mice, however, the contribution of adipocytes and the significance to insulin resistance is still elusive. Preliminary results here show that in response to high fat diet feeding, the mice increase the concentration of uridine in circulation and the uridine biosynthetic capacity in adipose tissue, but not in liver. Previous studies indicate that uridine has a dual action on glycemic control. A transient increase in uridine supply is beneficial for glycemic control, while chronic elevation of uridine level is detrimental. Preliminary data here show that uridine is a potent insulin secretagogue. Remarkably, the uridine-induced hyper-secretion of insulin is critically dependent on leptin. In the absence of leptin, uridine is converted from an agonist to an antagonist in insulin secretion. Given that insulin is a driving force for adipogenesis and lipogenesis, the increase in uridine promotes hyper-secretion of insulin and systemic hyperinsulinemia. Thereby, obesity becomes “self-sustaining” through uridine-mediated insulin hyper-secretion. Even though acute elevation of uridine promotes glucose uptake through insulin secretion, a continuous increase of uridine supply may diminish insulin response by interfering with cellular insulin signaling pathway through O-GlcNAc protein modification. Therefore, chronic elevation in uridine may lead to hyperinsulinemia with concurrent insulin resistance, a key characteristic of obesity-associated prediabetes. Based on previous findings and the current preliminary data, increased uridine supply from adipocytes is hypothesized to promote obesity and diabetes progression. Both gain- and loss-of-function mouse models have been generated to test 1) the contribution of adipocytes to circulating uridine supply in obesity, 2) the role of uridine in hyperinsulinemia in obesity. Ex vivo and in vitro experiments will be performed to corroborate the in vivo tests. Elucidation of the significance of adipocytes to uridine supply and the relevance of uridine to hyperinsulinemia in obesity will shed light on the etiology of insulin resistance and pave a way for novel, more effective therapeutic design for type 2 diabetes.