Henver S Brunetta, Anna S Jung, Fernando Valdivieso-Rivera, Stepheny C de Campos Zani, Joel Guerra, Vanessa O Furino, Annelise Francisco, Marcelo Berçot, Pedro M Moraes-Vieira, Susanne Keipert, Martin Jastroch, Laurent O Martinez, Carlos H Sponton, Roger F Castilho, Marcelo A Mori, Alexander Bartelt
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引用次数: 0
Abstract
While mechanisms controlling uncoupling protein-1 (UCP1) in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis, it remains unclear whether F1Fo-ATP synthase function is also regulated in brown adipose tissue (BAT). Here, we show that inhibitory factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In vivo, IF1 levels are diminished in BAT of cold-adapted mice compared to controls. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential (MMP) through ATP hydrolysis (the so-called "reverse mode" of ATP synthase) is increased in brown fat. In cultured brown adipocytes, IF1 overexpression results in an inability of mitochondria to sustain the MMP upon adrenergic stimulation, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus-mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in BAT. Taken together, our work identifies downregulation of IF1 upon cold as a critical event for the facilitation of the reverse mode of ATP synthase as well as to enable energetic adaptation of BAT to effectively support non-shivering thermogenesis.
虽然控制产热脂肪细胞中解偶联蛋白-1(UCP1)的机制在非颤抖性产热中起着关键作用,但棕色脂肪组织(BAT)中的 F1Fo-ATP 合酶功能是否也受到调控仍不清楚。在这里,我们发现抑制因子 1(IF1,由 Atp5if1 编码)是 ATP 合酶水解活性的抑制剂,是棕色脂肪细胞能量代谢的关键负调控因子。与对照组相比,冷适应小鼠体内 BAT 中的 IF1 水平降低。此外,棕色脂肪中的 ATP 合成酶通过 ATP 水解产生线粒体膜电位(MMP)的能力(即所谓的 ATP 合成酶 "反向模式")也有所增加。在培养的棕色脂肪细胞中,IF1 过表达会导致线粒体在肾上腺素能刺激下无法维持 MMP,从而导致棕色脂肪细胞出现类似静止的表型。在小鼠体内,腺相关病毒介导的 IF1 在 BAT 中的过表达抑制了肾上腺素能刺激下的产热,并降低了 BAT 的线粒体呼吸。综上所述,我们的研究发现,IF1 在寒冷时的下调是促进 ATP 合成酶反向模式的关键事件,也是使 BAT 进行能量适应以有效支持非颤抖性产热的关键事件。
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