Paternally inherited gsα mutation impairs adipogenesis and potentiates a lean phenotype in vivo.
Paternally inherited gsα mutation impairs adipogenesis and potentiates a lean phenotype in vivo.
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DOI：
10.1002/stem.1109
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发表时间：
2012-07
期刊：
影响因子：
5.2
通讯作者：
Shore, Eileen M.
中科院分区：
文献类型：
--
作者：
Liu, Jan-jan;Russell, Elizabeth;Zhang, Deyu;Kaplan, Frederick S.;Pignolo, Robert J.;Shore, Eileen M.
关键词：
父系遗传的GNAS基因失活突变与一种罕见的致残性遗传疾病进行性骨发育异常有关，其中异位骨化发生在皮肤外软组织（如皮肤、皮下脂肪和骨骼肌）内。这种异位骨形成被假设是由间充质祖细胞分化失调引起的，其影响双能成骨-成脂谱系细胞命运转换。有趣的是，具有父系遗传的GNAS失活突变的患者都是瘦的。使用Gsα特异性外显子1破坏的小鼠模型，我们检查了Gnas的杂合失活是否影响来自皮下脂肪组织（脂肪垫）的间充质前体细胞的成脂分化。我们发现父系遗传的Gsα失活（Gsα+/p−）损害脂肪源性基质细胞（ASC）的成脂分化。ASC中Gsα+/p−突变也降低了脂肪形成因子CCAAT增强子结合蛋白（C/EBP）β、C/EBPα、过氧化物酶体增殖物激活受体γ和脂肪细胞蛋白2的表达。受损的脂肪细胞分化被腺苷酸环化酶激活剂forskolin拯救，并提供证据表明Gsα-cAMP信号在该过程的早期阶段是必需的。支持Gnas在体内脂肪形成中的作用，来自Gsα+/p−小鼠的多种类型脂肪组织的脂肪组织重量和脂肪形成基因的表达显著降低。有趣的是，父系遗传的Gsα突变对脂肪形成的抑制也增强了成骨因子、msh同源框2、runt相关转录因子2和骨钙素的表达。这些数据支持以下假设：Gsα在调节软组织中脂肪和骨决定之间的平衡中起关键作用，这一发现对各种骨生成和脂肪生成疾病具有重要意义。
Paternally inherited inactivating mutations of the GNAS gene have been associated with a rare and disabling genetic disorder, progressive osseous heteroplasia, in which heterotopic ossification occurs within extraskeletal soft tissues, such as skin, subcutaneous fat, and skeletal muscle. This ectopic bone formation is hypothesized to be caused by dysregulated mesenchymal progenitor cell differentiation that affects a bipotential osteogenic-adipogenic lineage cell fate switch. Interestingly, patients with paternally inherited inactivating mutations of GNAS are uniformly lean. Using a mouse model of Gsα-specific exon 1 disruption, we examined whether heterozygous inactivation of Gnas affects adipogenic differentiation of mesenchymal precursor cells from subcutaneous adipose tissues (fat pad). We found that paternally inherited Gsα inactivation (Gsα+/p−) impairs adipogenic differentiation of adipose-derived stromal cells (ASCs). The Gsα+/p− mutation in ASCs also decreased expression of the adipogenic factors CCAAT-enhancer-binding protein (C/EBP)β, C/EBPα, peroxisome proliferator-activated receptor gamma, and adipocyte protein 2. Impaired adipocyte differentiation was rescued by an adenylyl cyclase activator, forskolin, and provided evidence that Gsα-cAMP signals are necessary in early stages of this process. Supporting a role for Gnas in adipogenesis in vivo, fat tissue weight and expression of adipogenic genes from multiple types of adipose tissues from Gsα+/p− mice were significantly decreased. Interestingly, the inhibition of adipogenesis by paternally inherited Gsα mutation also enhances expression of the osteogenic factors, msh homeobox 2, runt-related transcription factor 2, and osteocalcin. These data support the hypothesis that Gsα plays a critical role in regulating the balance between fat and bone determination in soft tissues, a finding that has important implications for a wide variety of disorders of osteogenesis and adipogenesis.
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DOI：
10.1073/pnas.0408268102
发表时间：
2005-05-17
影响因子：
11.1
作者：
Chen, M;Gavrilova, O;Weinstein, LS
通讯作者：
Weinstein, LS
影响因子：
2
作者：
Adegbite, N. S.;Xu, M.;Kaplan, F. S.;Shore, E. M.;Pignolo, R. J.
通讯作者：
Pignolo, R. J.
影响因子：
158.5
作者：
Shore, EM;Ahn, J;Kaplan, FS
通讯作者：
Kaplan, FS
影响因子：
82.9
作者：
Sabatakos, G;Sims, NA;Baron, R
通讯作者：
Baron, R
影响因子：
6.2
作者：
Pignolo, Robert J.;Kassem, Moustapha
通讯作者：
Kassem, Moustapha