Myonectin (CTRP15), a Novel Myokine That Links Skeletal Muscle to Systemic Lipid Homeostasis
Myonectin (CTRP15), a Novel Myokine That Links Skeletal Muscle to Systemic Lipid Homeostasis
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DOI：
10.1074/jbc.m111.336834
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发表时间：
2012-04-06
影响因子：
4.8
通讯作者：
Wong, G. William
中科院分区：
文献类型：
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作者：
Seldin, Marcus M.;Peterson, Jonathan M.;Wong, G. William
骨骼肌在全身葡萄糖和脂肪酸代谢中起重要作用。然而，肌肉还分泌细胞因子和生长因子（统称为肌因子），其可以潜在地以自分泌、旁分泌和/或内分泌方式起作用以调节代谢、炎症和其他过程。在这里，我们报告的鉴定和表征肌粘连蛋白，一种新的肌细胞因子属于C1 q/TNF相关蛋白（CTRP）家族。在分化的肌管中，肌粘连蛋白转录物被高度诱导，并且主要由骨骼肌表达。循环中的肌连结蛋白水平受代谢状态的严格调控;禁食抑制了其mRNA和血清水平，但再进食显著增加了其mRNA和血清水平。虽然在饮食诱导的肥胖状态下，肌连结蛋白的mRNA和循环水平降低，但自愿运动增加了其表达和循环水平。因此，肌连蛋白转录物被提高细胞cAMP或钙水平的化合物（毛喉素、肾上腺素、离子霉素）上调。在体外，分泌的肌连蛋白形成二硫键连接的寡聚体，当共表达时，与C1 q/TNF相关蛋白家族的其他成员形成异聚体复合物。在小鼠中，重组肌连蛋白给药降低了游离脂肪酸的循环水平，而不改变脂肪组织脂解。与此一致，肌粘连蛋白促进脂肪细胞和肝细胞培养的脂肪酸摄取，部分通过上调促进脂质摄取的基因（CD 36、FATP 1、Fabp 1和Fabp 4）的表达。总的来说，这些结果表明，肌粘连蛋白链接骨骼肌的脂质稳态在肝脏和脂肪组织中的能量状态的改变，揭示了一种新的肌粘连蛋白介导的代谢回路。
Skeletal muscle plays important roles in whole-body glucose and fatty acid metabolism. However, muscle also secretes cytokines and growth factors (collectively termed myokines) that can potentially act in an autocrine, a paracrine, and/or an endocrine manner to modulate metabolic, inflammatory, and other processes. Here, we report the identification and characterization of myonectin, a novel myokine belonging to the C1q/TNF-related protein (CTRP) family. Myonectin transcript was highly induced in differentiated myotubes and predominantly expressed by skeletal muscle. Circulating levels of myonectin were tightly regulated by the metabolic state; fasting suppressed, but refeeding dramatically increased, its mRNA and serum levels. Although mRNA and circulating levels of myonectin were reduced in a diet-induced obese state, voluntary exercise increased its expression and circulating levels. Accordingly, myonectin transcript was up-regulated by compounds (forskolin, epinephrine, ionomycin) that raise cellular cAMP or calcium levels. In vitro, secreted myonectin forms disulfide-linked oligomers, and when co-expressed, forms heteromeric complexes with other members of the C1q/TNF-related protein family. In mice, recombinant myonectin administration reduced circulating levels of free fatty acids without altering adipose tissue lipolysis. Consistent with this, myonectin promoted fatty acid uptake in cultured adipocytes and hepatocytes, in part by up-regulating the expression of genes (CD36, FATP1, Fabp1, and Fabp4) that promote lipid uptake. Collectively, these results suggest that myonectin links skeletal muscle to lipid homeostasis in liver and adipose tissue in response to alterations in energy state, revealing a novel myonectin-mediated metabolic circuit.