Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A
Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A
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DOI：
10.1038/382622a0
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发表时间：
1996-08-15
期刊：
影响因子：
64.8
通讯作者：
McKnight, GS
中科院分区：
文献类型：
--
作者：
Cummings, DE;Brandon, EP;McKnight, GS
CYCLIC AMP是协调调节细胞代谢的重要第二信使，其作用由camp依赖性蛋白激酶（PKA）介导，PKA由两个调节亚基(R)和两个催化亚基(C)组装而成。在小鼠中，有四个R基因（编码RI α， RI β， RII α和RII β）和两个C基因（编码C α和C β），以组织特异性模式表达(1)。RII β亚型在棕色和白色脂肪组织和大脑中丰富，在其他地方表达有限。为了阐明其功能，我们产生了RII β敲除小鼠。在这里，我们报告突变体看起来很健康，但在正常食物摄入的情况下，白色脂肪组织明显减少，它们受到保护，不会发展为饮食引起的肥胖和脂肪肝，突变的棕色脂肪组织显示出RI α的代补性增加，它几乎完全取代了失去的RII β，产生了一个异构体开关。来自突变体脂肪组织的全酶比野生型酶更强烈地结合cAMP，更容易被激活，这导致解偶联蛋白的诱导和代谢率和体温的升高，导致瘦表型。我们的研究结果证明了RII β全酶在调节能量平衡和肥胖方面的作用。
CYCLIC AMP is an important second messenger in the coordinated regulation of cellular metabolism, Its effects are mediated by cAMP-dependent protein kinase (PKA), which is assembled from two regulatory (R) and two catalytic (C) subunits, In mice there are four R genes (encoding RI alpha, RI beta, RII alpha, and RII beta) and two C genes (encoding C alpha and C beta), expressed in tissue specific patterns(1). The RII beta isoform is abundant in brown and white adipose tissue and brain, with limited expression elsewhere. To elucidate its functions, we generated RII beta knockout mice, Here we report that mutants appear healthy but have markedly diminished white adipose tissue despite normal food intake, They are protected against developing diet-induced obesity and fatty livers, Mutant brown adipose tissue exhibits a compensatory increase in RI alpha, which almost entirely replaces lost RII beta, generating an isoform switch, The holoenzyme from mutant adipose tissue binds cAMP more avidly and is more easily activated than wild-type enzyme, This causes induction of uncoupling protein and elevations of metabolic rate and body temperature, contributing to the lean phenotype. Our results demonstrate a role for the RII beta holoenzyme in regulating energy balance and adiposity.