CTRP9, a novel adipose tissue-secreted glycoprotein

描述（由申请人提供）：本提案的目标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（统称为脂肪因子）通过控制外周组织的葡萄糖和脂质利用，在调节全身胰岛素敏感性中发挥重要作用。一种被广泛研究的脂肪因子是脂联素，它是一种众所周知的胰岛素增敏剂，可以促进肌肉中的脂肪酸氧化，抑制肝脏中的糖异生。然而，脂联素缺失小鼠表现出可变且相对轻微的代谢功能障碍，表明存在代偿机制。我们最近发现了一个由十个脂联素类似物组成的新家族，命名为C1q/ tnf相关蛋白(CTRP)-1至10。CTRP9是脂联素最接近的类似物，由脂肪组织表达，并以多聚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异源三聚体。在肥胖（ob/ob）小鼠中，腺病毒介导的CTRP9过表达导致血糖水平适度但显著降低。由于脂肪量减少，循环CTRP9升高的转基因（Tg）小鼠明显更瘦。当用高脂肪饮食挑战时，CTRP9 Tg小鼠对体重增加具有抵抗力，空腹血糖和胰岛素水平显着降低，脂质谱更好，并且在葡萄糖耐量测试中表现出显着改善。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)哪些特定的代谢过程（如葡萄糖摄取和脂肪酸氧化）受CTRP9调控；3)体外和体内CTRP9调控葡萄糖和脂肪酸利用的机制是什么；4)在应答性细胞类型中，哪些代谢信号通路（如Akt和/或AMPK）被CTRP9激活；5) CTRP9调节小鼠体重、肥胖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的遗传模型（如瘦素缺乏的ob/ob小鼠）中，CTRP9是否有可能在恢复胰岛素敏感性和使葡萄糖和脂质谱正常化方面具有治疗潜力？总之，这些研究将提供关于脂肪因子，特别是CTRP9如何连接多个组织以协调系统能量平衡的基本见解。这些研究可能会为肥胖和糖尿病的治疗提供新的途径。

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.