The Role of Adipocyte Uridine Biosynthesis in Obesity and Diabetes Progression

点击翻译按钮获取中文摘要

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.