The Role of Adipocyte Uridine Biosynthesis in Obesity and Diabetes Progression

脂肪细胞尿苷生物合成在肥胖和糖尿病进展中的作用

基本信息

批准号：
10683228
负责人：
Yingfeng Deng
金额：
$ 44万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10683228
关键词：
Acute Adipocytes Adipose tissue Agonist Anabolism Attenuated Beta Cell Cell Line Cells Characteristics Chronic Circulation Couples Data Development Diabetes Mellitus Enzymes Epidemic Etiology Fasting Functional disorder High Fat Diet Homeostasis Human Hyperinsulinism Impairment In Vitro Insulin Insulin Resistance Insulin Signaling Pathway Intake Islet Cell Leptin Link Liver Mammals Mediating Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nucleosides Nutrient Obese Mice Obesity Organ Osmosis Pathologic Pathway interactions Plasma Play Post-Translational Protein Processing Prediabetes syndrome Production Proteins Pump Regulation Risk Factors Role Scientist Structure of beta Cell of islet Testing Transducers Uridine XBP1 gene adipokines antagonist combat comorbidity design diet-induced obesity dietary driving force endoplasmic reticulum stress experimental study feeding gain of function glucose uptake glycemic control in vivo evaluation insight insulin secretagogues insulin secretion insulin sensitivity islet lipid biosynthesis loss of function mouse model novel novel therapeutic intervention partial response response therapeutically effective

项目摘要

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.

项目摘要脂肪细胞通过分泌一系列的分泌在全身能量体内稳态中起关键作用脂肪因子。最近的研究表明，脂肪细胞合成并释放尿苷，最丰富循环核外侧，在细胞中具有大量功能。但是，脂肪细胞尿苷的意义肥胖和糖尿病进展的产生仍然未知。从历史上看，肝脏被认为是尿苷合成和血浆供应的主要器官。最近的研究表明，脂肪细胞对于禁食状态下的血浆尿苷供应至关重要，而ER应力可能可能刺激脂肪细胞中的尿苷合成。与脂肪组织的大规模扩张和慢性ER应力，肥胖是一种需要增加脂肪组织尿苷供应的疾病。的确，然而，发现循环尿苷水平升高，但是，脂肪细胞的贡献和对胰岛素抵抗的意义仍然难以捉摸。这里的初步结果表明，为了响应高脂肪饮食喂养，小鼠增加了尿苷浓度在脂肪组织中的循环和尿苷的生物合成能力，但在肝脏中不可能。先前的研究表明，尿苷对血糖控制有双重作用。尿苷的短暂增加供应对血糖控制有益，而尿苷水平的慢性升高是有害的。初步数据在这里表明尿苷是一种潜在的胰岛素促分子。值得注意的是，尿苷诱导的过度分泌胰岛素关键取决于瘦素。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。鉴于胰岛素是成生成和脂肪形成的驱动力，尿苷的增加可促进胰岛素和全身性高胰岛素血症的过度分泌。因此，肥胖通过尿苷介导的胰岛素过度分泌成为“自我维持”。即使急性高程尿苷通过胰岛素分泌促进葡萄糖摄取，尿苷供应的连续增加可能通过干扰细胞胰岛素信号通路通过O-GLCNAC蛋白来减少胰岛素反应修改。因此，尿苷的慢性升高可能导致与并发胰岛素的高胰岛素血症抗性，肥胖相关前糖尿病的关键特征。根据以前的发现和当前的初步数据，脂肪细胞的尿苷供应增加为假设可以促进肥胖和糖尿病进展。功能丧失的鼠标模型都获得已经生成测试1）脂肪细胞对肥胖症循环尿苷供应的贡献，2）肥胖症高胰岛素血症中的尿苷。将进行离体和体外实验以证实体内测试。阐明脂肪细胞对尿苷供应的重要性以及尿苷与肥胖症中的高胰岛素血症将阐明胰岛素抵抗的病因，并为新颖，更多的方式铺平 2型糖尿病的有效治疗设计。