Alternative Gnas gene products have opposite effects on glucose and lipid metabolism
Alternative Gnas gene products have opposite effects on glucose and lipid metabolism
复制标题
DOI：
10.1073/pnas.0408268102
复制
发表时间：
2005-05-17
影响因子：
11.1
通讯作者：
Weinstein, LS
中科院分区：
文献类型：
--
作者：
Chen, M;Gavrilova, O;Weinstein, LS
Gnas是一种具有多种基因产物的印记基因，其由不同的第一外显子选择性剪接到共同的第二外显子上而产生。这些产物包括刺激性G蛋白α-亚基（G（s）α），受体刺激cAMP产生所需的G蛋白;特大G（s）α（XL α s），父本表达的G（s α）同种型;和神经内分泌特异性蛋白（NESP 55），母本表达的嗜铬粒蛋白样蛋白。G（s）alpha经历组织特异性印记，在某些组织中主要从母体等位基因表达。在母亲（E2（m-/+））或父亲（E2（+/p-））等位基因上的外显子2的杂合突变导致对能量代谢的相反影响。E2（m-/+）小鼠肥胖且代谢低下，而E2（+/p-）小鼠消瘦且代谢亢进。我们现在研究了G（s）alpha缺陷的影响，而不破坏其他Gnas基因产物，删除G（s）alpha外显子1（El）。E1（+/p-）小鼠缺乏E2（+/p-）表型，并出现肥胖和胰岛素抵抗。E2（+/p-）表现型是由XL α s缺乏引起的，而E1（+/p-）小鼠中父系特异性G（s）α表达的缺失导致相反的代谢表型。因此，替代的Gnas基因产物对葡萄糖和脂质代谢具有相反的作用。与E2（m-/+）小鼠一样，E1（m-/+）小鼠具有s.c.出生时水肿，可能是由于母体G（s）α表达丧失所致。然而，E1（m-/+）小鼠在其他方面与E2（m-/+）小鼠不同，这增加了存在其他母体特异性基因产物的可能性。相对于E1（+/p-）小鼠，E1（m-/+）小鼠具有更严重的肥胖和胰岛素抵抗以及更低的代谢率。E1（m-/+）和E1（+/p-）小鼠之间的差异可能是由于对G（s）α在正常印迹的组织中表达的差异影响。
Gnas is an imprinted gene with multiple gene products resulting from alternative splicing of different first exons onto a common exon 2. These products include stimulatory G protein alpha-subunit (G(s)alpha), the G protein required for receptor-stimulated cAMP production; extralarge G(s)alpha (XL alpha s), a paternally expressed G(s alpha) isoform; and neuroendocrine-specific protein (NESP55), a maternally expressed chromogranin-like protein. G(s)alpha undergoes tissue-specific imprinting, being expressed primarily from the maternal allele in certain tissues. Heterozygous mutation of exon 2 on the maternal (E2(m-/+)) or paternal (E2(+/p-)) allele results in opposite effects on energy metabolism. E2(m-/+) mice are obese and hypometabolic, whereas E2(+/p-) mice are lean and hypermetabolic. We now studied the effects of G(s)alpha deficiency without disrupting other Gnas gene products by deleting G(s)alpha exon 1 (El). E1(+/p-) mice lacked the E2(+/p-) phenotype and developed obesity and insulin resistance. The lean, hypermetabolic, and insulin-sensitive E2(+/p-) phenotype appears to result from XL alpha s deficiency, whereas loss of paternal-specific G(s)alpha expression in E1(+/p-) mice leads to an opposite metabolic phenotype. Thus, alternative Gnas gene products have opposing effects on glucose and lipid metabolism. Like E2(m-/+) mice, E1(m-/+) mice had s.c. edema at birth, presumably due to loss of maternal G(s)alpha expression. However, E1(m-/+) mice differed from E2(m-/+) mice in other respects, raising the possibility for the presence of other maternal-specific gene products. E1(m-/+) mice had more severe obesity and insulin resistance and lower metabolic rate relative to E1(+/p-) mice. Differences between E1(m-/+) and E1(+/p-) mice presumably result from differential effects on G(s)alpha expression in tissues where G(s)alpha is normally imprinted.