Adipose Tissue CLK2 Promotes Energy Expenditure during High-Fat Diet Intermittent Fasting.
Adipose Tissue CLK2 Promotes Energy Expenditure during High-Fat Diet Intermittent Fasting.
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DOI：
10.1016/j.cmet.2016.12.007
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发表时间：
2017-02-07
期刊：
影响因子：
29
通讯作者：
Puigserver P
中科院分区：
文献类型：
--
作者：
Hatting M;Rines AK;Luo C;Tabata M;Sharabi K;Hall JA;Verdeguer F;Trautwein C;Puigserver P
治疗肥胖的一种有希望的方法是增加饮食诱导的棕色脂肪组织（BAT）产热，但这一过程的调控仍不清楚。在这里，我们发现CDC样激酶2（CLK2）在BAT中表达，并在再喂养时上调。在脂肪组织中缺乏CLK2的小鼠在高脂肪间歇性禁食期间表现出加重的肥胖和降低的能量消耗。此外，组织耗氧量和蛋白质水平的UCP1降低在CLK2缺陷BAT。CREB的磷酸化，UCP1的转录激活因子，在BAT细胞缺乏CLK2由于增强CREB去磷酸化显着减少。从机制上讲，CREB去磷酸化是通过抑制PP2A（一种靶向CREB的磷酸酶）来拯救的。我们的研究结果表明，CLK2是通过增加CREB依赖的UCP1表达的饮食诱导的BAT产热的调节成分。
A promising approach to treating obesity is to increase diet-induced thermogenesis in brown adipose tissue (BAT), but the regulation of this process remains unclear. Here, we find that CDC-like kinase 2 (CLK2) is expressed in BAT and upregulated upon refeeding. Mice lacking CLK2 in adipose tissue exhibit exacerbated obesity and decreased energy expenditure during high fat intermittent fasting. Additionally, tissue oxygen consumption and protein levels of UCP1 are reduced in CLK2-deficient BAT. Phosphorylation of CREB, a transcriptional activator of UCP1, is markedly decreased in BAT cells lacking CLK2 due to enhanced CREB dephosphorylation. Mechanistically, CREB dephosphorylation is rescued by inhibition of PP2A, a phosphatase that targets CREB. Our results suggest that CLK2 is a regulatory component of diet-induced thermogenesis in BAT through increased CREB-dependent expression of UCP1.