p62 Links β-adrenergic input to mitochondrial function and thermogenesis
p62 Links β-adrenergic input to mitochondrial function and thermogenesis
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DOI：
10.1172/jci64209
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发表时间：
2013-01-01
影响因子：
15.9
通讯作者：
Tschoep, Matthias H.
中科院分区：
文献类型：
--
作者：
Mueller, Timo D.;Lee, Sang Jun;Tschoep, Matthias H.
支架蛋白p62（隔离体1; SQSTM 1）是细胞的代谢、免疫和增殖过程之间的新兴关键分子联系。在这里，我们报告，脂肪细胞特异性，但不是中枢神经系统，肝脏，肌肉，或骨髓特异性p62缺陷小鼠肥胖，并表现出降低的代谢率所造成的受损nonshriving产热。我们的研究结果表明，p62通过控制棕色脂肪组织（BAT）中的线粒体功能来调节能量代谢。因此，脂肪细胞特异性p62缺陷导致线粒体功能受损，导致BAT对β-肾上腺素能刺激无反应。p62的消融导致p38靶点的活化降低，影响控制线粒体功能的信号分子，如ATF 2、CREB、PGC 1 α、DIO 2、NRF 1、CYTC、COX 2、ATP 5 β和UCP 1。在HIB 1B和BAT原代细胞中的p62消融表明，p62以细胞自主方式控制产热，与棕色脂肪细胞的发育或分化无关。总之，我们的数据确定p62作为线粒体功能和棕色脂肪产热的一种新的调节剂。
The scaffold protein p62 (sequestosome 1; SQSTM1) is an emerging key molecular link among the metabolic, immune, and proliferative processes of the cell. Here, we report that adipocyte-specific, but not CNS-, liver-, muscle-, or myeloid-specific p62-deficient mice are obese and exhibit a decreased metabolic rate caused by impaired nonshivering thermogenesis. Our results show that p62 regulates energy metabolism via control of mitochondrial function in brown adipose tissue (BAT). Accordingly, adipocyte-specific p62 deficiency led to impaired mitochondrial function, causing BAT to become unresponsive to beta-adrenergic stimuli. Ablation of p62 leads to decreased activation of p38 targets, affecting signaling molecules that control mitochondrial function, such as ATF2, CREB, PGC1 alpha, DIO2, NRF1, CYTC, COX2, ATP5 beta, and UCP1.p62 ablation in HIB1B and BAT primary cells demonstrated that p62 controls thermogenesis in a cell-autonomous manner, independently of brown adipocyte development or differentiation. Together, our data identify p62 as a novel regulator of mitochondrial function and brown fat thermogenesis.