CTRP9, a novel adipose tissue-secreted glycoprotein

CTRP9，一种新型脂肪组织分泌糖蛋白

• 批准号: 8107483
• 负责人: Guang William Wong
• 金额: $ 34.01万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8107483
• 关键词: Address; Adenoviruses; Adipocytes; Adipose tissue; Blood Glucose; Body Weight; Cardiovascular Diseases; Complement 1q; Data; Development; Diabetes Mellitus; Diet; Disease; Exhibits; Family; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Genetic Models; Gluconeogenesis; Glucose; Glucose tolerance test; Glycoproteins; Goals; Hepatocyte; Homo; In Vitro; Incidence; Insulin; Insulin Resistance; Knockout Mice; Lead; Leptin; Link; Lipids; Liver; Mediating; Metabolic; Metabolism; Modeling; Molecular; Mus; Muscle; Muscle Cells; Muscle Fibers; Nutrient; Obesity; Peripheral; Phenotype; Physiological; Plasma; Play; Primary carcinoma of the liver cells; Proteins; Recombinants; Resistance; Role; Serum; Signal Pathway; TNF gene; Therapeutic; Tissues; Transgenic Mice; Weight Gain; adipokines; adiponectin; blood glucose regulation; cell type; energy balance; fasting glucose; fatty acid oxidation; glucose uptake; in vivo; insight; insulin sensitivity; insulin sensitizing drugs; mouse model; novel; obesity treatment; paralogous gene; public health relevance; research study; response

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.

描述（由申请人提供）：本提案的目的是了解新型脂肪因子CTRP 9调节全身能量平衡的作用和机制。脂肪组织分泌的因子（统称为脂肪因子）通过控制外周组织中的葡萄糖和脂质利用而在调节全身胰岛素敏感性中起重要作用。脂联素是一种被广泛研究的脂肪因子，它是一种胰岛素增敏剂，可促进肌肉中脂肪酸的氧化，抑制肝脏中脂肪的生成。然而，脂联素基因敲除小鼠表现出不同的和相对轻微的代谢功能障碍，提示存在代偿机制。我们最近发现了一个新家族的10个脂联素旁系同源物，命名为C1 q/TNF相关蛋白（CTRP）-1至10。CTRP 9是脂联素的最接近的蛋白，由脂肪组织表达，并作为多聚体糖蛋白在血浆中循环。CTRP 9与脂联素形成同源寡聚体以及异源三聚体。腺病毒介导的CTRP 9在肥胖（ob/ob）小鼠中的过表达导致血糖水平适度但显著的降低。具有升高的循环CTRP 9的转基因（Tg）小鼠由于减少的脂肪量而显著更瘦。当用高脂肪饮食挑战时，CTRP 9 Tg小鼠抵抗体重增加，具有显著更低的空腹葡萄糖和胰岛素水平，更好的脂质谱，并且在葡萄糖耐量试验中表现出显著改善。这些体内表型与CTRP 9在体外抑制脂肪生成和促进脂肪酸氧化的能力相关。我们的数据支持CTRP 9通过控制组织中的葡萄糖和脂肪酸利用来调节体重和肥胖的假设。为了理解CTRP 9发挥其有益代谢功能的机制，我们旨在解决以下问题：1）CTRP 9的靶组织是什么; 2）什么特定的代谢过程（例如，葡萄糖摄取和脂肪酸氧化）受CTRP 9调节; 3）CTRP 9在体外和体内控制葡萄糖和脂肪酸利用的机制是什么; 4）什么代谢信号传导途径（例如，Akt和/或AMPK）在应答细胞类型中被CTRP 9激活; 5）CTRP 9调节小鼠体重、肥胖和胰岛素敏感性的机制是什么;以及，6）在饮食诱导的肥胖小鼠模型和肥胖的遗传模型（如瘦素缺陷型ob/ob小鼠）中，CTRP 9在恢复胰岛素敏感性和使葡萄糖和脂质谱正常化方面是否存在可能的治疗潜力？总之，这些研究将为脂肪因子，特别是CTRP 9如何连接多个组织以协调全身能量平衡提供基本见解。这些研究可能会为肥胖和糖尿病的治疗提供新的途径。 公共卫生关系：近年来，肥胖症和密切相关疾病（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理解将为治疗肥胖和糖尿病提供新的途径。