Helmholtz Diabetes Center, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Research Unit Analytical Pathology, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
Cell Metab. 2015 Nov 3;22(5):838-50. doi: 10.1016/j.cmet.2015.08.022. Epub 2015 Sep 24.
Canonical protein phosphatase 3/calcineurin signaling is central to numerous physiological processes. Here we provide evidence that calcineurin plays a pivotal role in controlling systemic energy and body weight homeostasis. Knockdown of calcineurin in Drosophila melanogaster led to a decrease in body weight and energy stores, and increased energy expenditure. In mice, global deficiency of catalytic subunit Ppp3cb, and tissue-specific ablation of regulatory subunit Ppp3r1 from skeletal muscle, but not adipose tissue or liver, led to protection from high-fat-diet-induced obesity and comorbid sequelæ. Ser637 hyperphosphorylation of dynamin-related protein 1 (Drp1) in skeletal muscle of calcineurin-deficient mice was associated with mitochondrial elongation into power-cable-shaped filaments and increased mitochondrial respiration, but also with attenuated exercise performance. Our data suggest that calcineurin acts as highly conserved pivot for the adaptive metabolic responses to environmental changes such as high-fat, high-sugar diets or exercise.
规范的蛋白磷酸酶 3/钙调神经磷酸酶信号通路是许多生理过程的核心。在这里，我们提供了证据表明钙调神经磷酸酶在控制全身能量和体重平衡方面起着关键作用。在黑腹果蝇中敲低钙调神经磷酸酶会导致体重和能量储存减少，而能量消耗增加。在小鼠中，钙调神经磷酸酶的催化亚基 Ppp3cb 的全局缺失，以及骨骼肌中调节亚基 Ppp3r1 的组织特异性缺失，但不是脂肪组织或肝脏，可防止高脂肪饮食引起的肥胖和并发后遗症。钙调神经磷酸酶缺失小鼠骨骼肌中动力相关蛋白 1（Drp1）的 Ser637 过度磷酸化与线粒体延伸成动力电缆状纤维和增加线粒体呼吸有关，但也与运动表现减弱有关。我们的数据表明，钙调神经磷酸酶作为一种高度保守的支点，在适应代谢反应中发挥作用，以应对环境变化，如高脂肪、高糖饮食或运动。
