Hatting Maximilian, Rines Amy K, Luo Chi, Tabata Mitsuhisa, Sharabi Kfir, Hall Jessica A, Verdeguer Francisco, Trautwein Christian, Puigserver Pere
Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; RWTH Aachen University, Aachen 52074, Germany.
Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Cell Metab. 2017 Feb 7;25(2):428-437. doi: 10.1016/j.cmet.2016.12.007. Epub 2017 Jan 12.
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 diet 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 the 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.
一种有前景的治疗肥胖的方法是增加棕色脂肪组织(BAT)中饮食诱导的产热,但这一过程的调节机制仍不清楚。在这里,我们发现类CDC激酶2(CLK2)在BAT中表达,并在重新进食后上调。脂肪组织中缺乏CLK2的小鼠在高脂饮食间歇性禁食期间表现出肥胖加剧和能量消耗减少。此外,CLK2缺陷型BAT中的组织氧消耗和UCP1蛋白水平降低。由于CREB去磷酸化增强,缺乏CLK2的BAT细胞中UCP1的转录激活因子CREB的磷酸化显著降低。从机制上讲,通过抑制靶向CREB的磷酸酶PP2A可以挽救CREB的去磷酸化。我们的结果表明,CLK2通过增加CREB依赖的UCP1表达,是BAT中饮食诱导产热的调节成分。