JPST000096-1 Beige adipocyte phosphoproteomics [Reanalysis: JPST000096]

Catecholamines promote lipolysis both in brown and white adipocytes, whereas the same stimuli preferentially activate thermogenesis in brown adipocytes. Molecular mechanisms for the adipose-selective activation of thermogenesis remain poorly understood. Here, we employed quantitative phosphoproteomics to map global and temporal phosphorylation profiles in brown, beige, and white adipocytes under β3-adrenenoceptor activation and identified kinases responsible for the adipose-selective phosphorylation profiles. We found that casein kinase2 (CK2) activity is preferentially higher in white adipocytes than brown/beige adipocytes. Genetic or pharmacological blockade of CK2 in white adipocytes activates the thermogenic program in response to cAMP stimuli. Such activation is largely through reduced CK2-mediated phosphorylation of class I HDACs. Notably, inhibition of CK2 promotes beige adipocyte biogenesis and leads to an increase in whole-body energy expenditure and ameliorates diet-induced obesity and insulin resistance. These results indicate that CK2 is a plausible target to rewire the β3-adrenenoceptor signaling cascade that promotes thermogenesis in adipocytes. [Original project description]

儿茶酚胺（Catecholamines）可同时促进棕色脂肪细胞（brown adipocytes）与白色脂肪细胞（white adipocytes）的脂解过程，而该类刺激却优先激活棕色脂肪细胞的产热（thermogenesis）程序。目前，脂肪组织选择性产热激活的分子机制仍未被充分阐明。本研究采用定量磷酸化蛋白质组学（quantitative phosphoproteomics），绘制了β3肾上腺素能受体（β3-adrenenoceptor）激活条件下棕色、米色脂肪细胞（beige adipocytes）与白色脂肪细胞的全局及动态磷酸化谱，并鉴定出介导脂肪组织选择性磷酸化特征的激酶。研究发现，酪蛋白激酶2（casein kinase 2, CK2）在白色脂肪细胞中的活性显著高于棕色/米色脂肪细胞。在白色脂肪细胞中对CK2进行遗传或药理学阻断，可使其在环磷酸腺苷（cAMP）刺激下激活产热程序，该过程主要通过降低CK2介导的I类组蛋白去乙酰化酶（class I HDACs）磷酸化水平实现。值得注意的是，抑制CK2可促进米色脂肪细胞生成，提升整体机体能量消耗，并改善饮食诱导的肥胖与胰岛素抵抗。上述结果表明，CK2是重塑脂肪细胞产热相关β3肾上腺素能受体信号级联反应的潜在靶点。[原始项目描述]