Wong G William, Krawczyk Sarah A, Kitidis-Mitrokostas Claire, Revett Tracy, Gimeno Ruth, Lodish Harvey F
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Biochem J. 2008 Dec 1;416(2):161-77. doi: 10.1042/BJ20081240.
The insulin-sensitizing hormone, adiponectin, belongs to the expanding C1q/TNF (tumour necrosis factor) family of proteins. We recently identified a family of adiponectin paralogues designated as CTRP (C1q/TNF-related protein) 1-7, and in the present study describe CTRP10. In the present study, we show that CTRP1, CTRP2, CTRP3, CTRP5 and CTRP7 transcripts are expressed predominantly by adipose tissue. In contrast, placenta and eye expressed the highest levels of CTRP6 and CTRP10 transcripts respectively. Expression levels of CTRP1, CTRP2, CTRP3, CTRP6 and CTRP7 transcripts are up-regulated in 8-week-old obese (ob/ob) mice relative to lean controls. Treatment of mice with a PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) agonist, rosiglitazone, increased the expression of CTRP1 and decreased CTRP6 transcript levels. All CTRPs are secreted glycoproteins when expressed in mammalian cells. CTRP1, CTRP2, CTRP3, CTRP5 and CTRP6 circulate in the blood and are potential endocrine hormones; their serum levels vary according to the sex and genetic background of mice. Importantly, serum levels of CTRP1 and CTRP6 are increased in adiponectin-null mice. Like adiponectin, all secreted CTRP proteins form trimers as their basic structural units. CTRP3, CTRP5, CTRP6 and CTRP10 trimers are further assembled into higher-order oligomeric complexes via disulfide bonding mediated by their N-terminal cysteine residues. Besides forming homo-oligomers, CTRP1/CTRP6, CTRP2/CTRP7 and adiponectin/CTRP2 are secreted as heterotrimers, thus providing a mechanism to potentially generate functionally distinct ligands. Functional characterization of one such family member, CTRP1, showed that it specifically activates Akt and p44/42-MAPK (mitogen-activated protein kinase) signalling pathways in differentiated mouse myotubes. Moreover, injection of recombinant CTRP1 into mice significantly reduced their serum glucose levels. Thus at least CTRP1 may be considered a novel adipokine. In summary, these molecular, biochemical and functional data provide an important framework to further address the physiological functions and mechanisms of the action of this family of secreted glycoproteins in normal and disease states.
胰岛素增敏激素脂联素属于不断扩展的C1q/TNF(肿瘤坏死因子)蛋白家族。我们最近鉴定出一个脂联素旁系同源物家族,命名为C1q/TNF相关蛋白(CTRP)1 - 7,并在本研究中描述了CTRP10。在本研究中,我们发现CTRP1、CTRP2、CTRP3、CTRP5和CTRP7转录本主要由脂肪组织表达。相比之下,胎盘和眼睛分别表达最高水平的CTRP6和CTRP10转录本。与瘦对照相比,8周龄肥胖(ob/ob)小鼠中CTRP1、CTRP2、CTRP3、CTRP6和CTRP7转录本的表达水平上调。用PPAR-γ(过氧化物酶体增殖物激活受体-γ)激动剂罗格列酮处理小鼠,可增加CTRP1的表达并降低CTRP6转录本水平。所有CTRP在哺乳动物细胞中表达时都是分泌型糖蛋白。CTRP1、CTRP2、CTRP3、CTRP5和CTRP6在血液中循环,是潜在的内分泌激素;它们的血清水平因小鼠的性别和遗传背景而异。重要的是,脂联素缺失小鼠中CTRP1和CTRP6的血清水平升高。与脂联素一样,所有分泌的CTRP蛋白都以三聚体作为其基本结构单元。CTRP3、CTRP5、CTRP6和CTRP10三聚体通过其N端半胱氨酸残基介导的二硫键进一步组装成高阶寡聚复合物。除了形成同型寡聚体,CTRP1/CTRP6、CTRP2/CTRP7和脂联素/CTRP2还以异源三聚体形式分泌,从而提供了一种潜在产生功能不同配体的机制。对其中一个家族成员CTRP1的功能表征表明,它在分化的小鼠肌管中特异性激活Akt和p44/42-MAPK(丝裂原活化蛋白激酶)信号通路。此外,向小鼠注射重组CTRP1可显著降低其血糖水平。因此,至少CTRP1可被视为一种新型脂肪因子。总之,这些分子、生化和功能数据为进一步研究该分泌型糖蛋白家族在正常和疾病状态下的生理功能及作用机制提供了重要框架。