Research Resource: Roles for Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) in Systems Metabolism
Research Resource: Roles for Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CaMKK2) in Systems Metabolism
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DOI：
10.1210/me.2016-1021
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发表时间：
2016-05-01
影响因子：
--
通讯作者：
York, Brian
中科院分区：
文献类型：
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作者：
Marcelo, Kathrina L.;Ribar, Thomas;York, Brian
许多流行病学研究表明，钙（Ca2+）信号是肥胖的一个主要因素，导致系统代谢异常。有点矛盾的是，肥胖与循环Ca2+水平降低相关，导致内质网细胞内Ca2+储存释放增加。这些发现表明，与肥胖状态相关的胰岛素抵抗与典型Ca2+信号通路的激活有关。从机制上讲，增加的细胞内Ca2+结合钙调蛋白（CaM）来激活一组Ca2+/CaM依赖性蛋白激酶。在本研究资源中，我们探索Ca2+/CaM依赖性蛋白激酶激酶2 （CaMKK2）作为Ca2+/CaM作用的代谢效应物的代谢功能和意义。我们揭示了CaMKK2对控制胰岛素从胰腺β细胞释放的重要性，同时影响胰岛素反应组织的敏感性。为了更好地了解CaMKK2缺失对代谢的影响，我们在CaMKK2缺失的小鼠中对葡萄糖、脂肪酸和氨基酸代谢的关键代谢副产物进行了有针对性的代谢组学分析。我们对CaMKK2（-/-）小鼠及其野生型幼崽在饮食应激（低脂饮食、正常饮食、高脂饮食和禁食）条件下分离的3种胰岛素敏感组织（肝脏、骨骼肌、血浆）中的氨基酸和酰基肉碱进行了定量分析，从而揭示了CaMKK2独特的代谢功能。我们的研究结果强调了CaMKK2作为胰岛素作用的分子变阻器，并强调了Ca2+/CaM/CaMKK2在调节全身代谢中的重要性。这些发现表明，CaMKK2可能是对抗胰岛素信号紊乱相关合并症的一个有吸引力的治疗靶点。
A number of epidemiological studies have implicated calcium (Ca2+) signaling as a major factor in obesity that contributes to aberrant systems metabolism. Somewhat paradoxically, obesity correlates with decreased circulating Ca2+ levels, leading to increased release of intracellular Ca2+ stores from the endoplasmic reticulum. These findings suggest that insulin resistance associated with the obese state is linked to activation of canonical Ca2+ signaling pathways. Mechanistically, increased intracellular Ca2+ binds calmodulin (CaM) to activate a set of Ca2+/CaM-dependent protein kinases. In this research resource, we explore the metabolic functions and implications of Ca2+/CaM-dependent protein kinase kinase 2 (CaMKK2) as a metabolic effector of Ca2+/CaM action. We reveal the importance of CaMKK2 for gating insulin release from pancreatic beta-cells while concomitantly influencing the sensitivity of insulin-responsive tissues. To provide a better understanding of the metabolic impact of CaMKK2 loss, we performed targeted metabolomic analyses of key metabolic byproducts of glucose, fatty acid, and amino acid metabolism in mice null for CaMKK2. We quantified amino acids and acyl carnitines in 3 insulin-sensitive tissues (liver, skeletal muscle, plasma) isolated from CaMKK2(-/-) mice and their wild-type littermates under conditions of dietary stress (low-fat diet, normal chow, high-fat diet, and fasting), thereby unveiling unique metabolic functions of CaMKK2. Our findings highlight CaMKK2 as a molecular rheostat for insulin action and emphasize the importance of Ca2+/CaM/CaMKK2 in regulation of whole-body metabolism. These findings reveal that CaMKK2 may be an attractive therapeutic target for combatting comorbidities associated with perturbed insulin signaling.