CTRP9, a novel adipose tissue-secreted glycoprotein

描述(由申请人提供)：本提案的目的是了解新型脂肪因子CTRP9调节全身能量平衡的作用和机制。脂肪组织分泌因子(总称脂肪因子)通过控制外周组织中的糖和脂的利用，在调节全身胰岛素敏感性方面发挥重要作用。一种被广泛研究的脂肪因子是脂联素，众所周知，它是一种胰岛素敏感剂，可以促进肌肉中的脂肪酸氧化，抑制肝脏中的糖异生。然而，脂联素缺失的小鼠表现出可变的和相对轻微的代谢功能障碍，这表明存在代偿机制。我们最近发现了一个新的10个脂联素类似物家族，命名为C1q/肿瘤坏死因子相关蛋白(CTRP)-1到10。CTRP9是脂联素最接近的类似物，由脂肪组织表达，以多聚体糖蛋白的形式在血浆中循环。CTRP9与脂联素形成同源低聚物和杂三聚体。腺病毒介导的CTRP9在肥胖(ob/ob)小鼠中的过度表达导致血糖水平轻微但显著下降。由于脂肪质量减少，循环CTRP9升高的转基因(TG)小鼠明显瘦了。当受到高脂饮食的挑战时，CTRP9TG小鼠对体重增加具有抵抗力，具有显著较低的空腹血糖和胰岛素水平，更好的血脂状况，并在糖耐量测试中表现出显著改善。这些体内表型与CTRP9在体外抑制糖异生和促进脂肪酸氧化的能力相关。我们的数据支持CTRP9通过控制组织中葡萄糖和脂肪酸的利用来调节体重和肥胖的假设。为了了解CTRP9发挥其有益代谢功能的机制，我们旨在解决以下问题：1)CTRP9的靶组织是什么；2)CTRP9调控哪些特定的代谢过程(如葡萄糖摄取和脂肪酸氧化)；3)CTRP9在体外和体内控制葡萄糖和脂肪酸利用的机制是什么；4)在反应细胞类型中，CTRP9激活了哪些代谢信号通路(如Akt和/或AMPK)；5)CTRP9调节小鼠体重、脂肪和胰岛素敏感性的机制是什么；6)在饮食诱导的肥胖小鼠模型和肥胖遗传模型(如瘦素缺乏的ob/ob小鼠)中，CTRP9是否有可能恢复胰岛素敏感性并使血糖和血脂正常？总之，这些研究将为脂肪因子，特别是CTRP9如何连接多个组织以协调全身能量平衡提供基本的见解。这些研究可能会为肥胖和糖尿病的治疗提供新的途径。 公共卫生相关性：近年来，肥胖症和密切相关的疾病(如糖尿病和心血管疾病)的发病率急剧上升。对控制全身营养利用和能量平衡的分子、细胞和生理机制的基本了解将为治疗肥胖症和糖尿病提供新的途径。

DESCRIPTION (provided by applicant): The goal of this proposal is to understand the role of and mechanism by which the novel adipokine, CTRP9, regulates whole body energy balance. Adipose tissue-secreted factors (collectively termed adipokines) play important roles in regulating systemic insulin sensitivity by controlling glucose and lipid utilization in the peripheral tissues. One widely studied adipokine is adiponectin, well-known for being an insulin-sensitizer that promotes fatty acid oxidation in muscles and suppresses gluconeogenesis in liver. However, adiponectin-null mice display variable and relatively mild metabolic dysfunctions, suggesting the existence of compensatory mechanisms. We have recently discovered a novel family of ten adiponectin paralogs, designated as C1q/TNF-related protein (CTRP)-1 to 10. CTRP9, the closest paralog of adiponectin, is expressed by adipose tissue and circulates in plasma as a multimeric glycoprotein. CTRP9 forms homo-oligomers as well as heterotrimers with adiponectin. Adenovirus-mediated over-expression of CTRP9 in obese (ob/ob) mice leads to a modest but significant decrease in blood glucose levels. Transgenic (Tg) mice with elevated circulating CTRP9 are significantly leaner due to reduced fat mass. When challenged with a high-fat diet, CTRP9 Tg mice are resistant to body weight gain, have significantly lower fasting glucose and insulin levels, better lipid profiles, and exhibit marked improvements in glucose tolerance tests. These in vivo phenotypes correlate with the ability of CTRP9 to suppress gluconeogenesis and promote fatty acid oxidation in vitro. Our data support the hypothesis that CTRP9 regulates body weight and adiposity by controlling glucose and fatty acid utilization in tissues. To understand the mechanism by which CTRP9 exerts its beneficial metabolic function, we aim to address the following questions: 1) what are the target tissues of CTRP9; 2) what specific metabolic processes (e.g., glucose uptake and fatty acid oxidation) are regulated by CTRP9; 3) what is the mechanism by which CTRP9 controls glucose and fatty acid utilization in vitro and in vivo; 4) what metabolic signaling pathways (e.g., Akt and/or AMPK) are activated by CTRP9 in responsive cell types; 5) what is the mechanism by which CTRP9 regulates body weight, adiposity, and insulin sensitivity in mice; and, 6) is there a possible therapeutic potential of CTRP9 in restoring insulin sensitivity and normalizing glucose and lipid profiles in a diet-induced obesity mouse model and a genetic model of obesity (as in leptin-deficient ob/ob mice)? Together, these studies will provide fundamental insights into how adipokines in general, and CTRP9 in particular, connect multiple tissues to coordinate systemic energy balance. These studies will likely provide new avenues for the treatment of obesity and diabetes. PUBLIC HEALTH RELEVANCE: The incidence of obesity and closely-linked diseases (e.g. diabetes and cardiovascular disease) has risen dramatically in recent years. A basic understanding of the molecular, cellular, and physiological mechanisms involved in controlling whole body nutrient utilization and energy balance will provide new avenues to treat obesity and diabetes.