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，通过分泌一系列的 脂肪因子最近的研究表明，脂肪细胞合成和释放尿苷， 在细胞中具有过多功能的循环核苷。然而，脂肪细胞尿苷 在肥胖和糖尿病进展中的产生仍然是未知的。 历史上，肝脏被认为是尿苷合成和血浆供应的主要器官。最近 研究表明，脂肪细胞在禁食状态下对血浆尿苷供应至关重要，并且ER应激是有效的。 刺激脂肪细胞尿苷合成。与脂肪组织的大量扩张有关， 在慢性ER应激中，肥胖是一种需要增加来自脂肪组织的尿苷供应的病症。的确， 在肥胖小鼠中发现循环尿苷水平升高，然而，脂肪细胞和 胰岛素抵抗的重要性仍然是难以捉摸的。 这里的初步结果表明，作为对高脂肪饮食喂养的反应，小鼠增加了 尿苷在循环中的浓度和尿苷在脂肪组织中的生物合成能力，而不是在肝脏中。 以往的研究表明，尿苷对血糖控制具有双重作用。尿苷的短暂增加 尿苷供应有利于血糖控制，而尿苷水平的慢性升高是有害的。初步数据 表明尿苷是一种有效促胰岛素分泌剂。值得注意的是，尿苷诱导的 胰岛素严重依赖于瘦素。在缺乏瘦素的情况下，尿苷从激动剂转化为抑制剂。 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， 尿苷增加促进胰岛素分泌过多和全身性高胰岛素血症。因此，肥胖症 通过尿苷介导的胰岛素分泌过多而变得"自我维持"。即使急性升高， 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通路，降低胰岛素反应 改性因此，尿苷的慢性升高可能导致高胰岛素血症， 抵抗力，肥胖相关的前驱糖尿病的一个关键特征。 根据以前的发现和目前的初步数据，增加尿苷供应的脂肪细胞是 假设它会促进肥胖和糖尿病的发展。功能获得和功能丧失小鼠模型 已经产生了测试1）脂肪细胞的贡献，循环尿苷供应肥胖，2）的作用， 尿苷在肥胖高胰岛素血症中的作用。将进行离体和体外实验以证实 体内试验。阐明脂肪细胞对尿苷供应的重要性以及尿苷与脂肪细胞增殖的相关性。 肥胖症中的高胰岛素血症将揭示胰岛素抵抗的病因，并为新的、更广泛的研究铺平道路。 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.