Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat
Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat
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DOI：
10.1016/j.celrep.2022.110566
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发表时间：
2022-03-29
期刊：
影响因子：
8.8
通讯作者：
Takamura, Toshinari
中科院分区：
文献类型：
--
作者：
Oo, Swe Mar;Oo, Hein Ko;Takamura, Toshinari
在生理性冷暴露和去甲肾上腺素（NA）刺激下，活性氧（ROS）激活棕色脂肪组织（BAT）中的解偶联蛋白1（UCP 1）以增加产热。然而，活性氧的内源性调节剂在激活BAT和其在病理条件下的作用仍然不清楚。我们发现，血清硒蛋白P（SeP;由SELENOP编码）水平与人体BAT活性呈负相关。生理冷暴露下调BAT中的硒磷酸盐。Selenop基因敲除小鼠在冷暴露期间表现出更高的直肠温度和UCP 1亚磺酰化。SeP处理棕色脂肪细胞消除NA诱导的线粒体活性氧通过上调谷胱甘肽过氧化物酶4和受损的细胞产热。高脂肪/高蔗糖饮食升高血清SeP水平，并减少升高的NA诱导的BAT-Selenop KO小鼠产热。因此，SeP是诱导还原性应激的内在因素，其损害BAT中的产热，并且可能是肥胖和糖尿病的潜在治疗靶点。
Reactive oxygen species (ROS) activate uncoupler protein 1 (UCP1) in brown adipose tissue (BAT) under physiological cold exposure and noradrenaline (NA) stimulation to increase thermogenesis. However, the endogenous regulator of ROS in activated BAT and its role in pathological conditions remain unclear. We show that serum levels of selenoprotein P (SeP; encoded by SELENOP) negatively correlate with BAT activity in humans. Physiological cold exposure downregulates Selenop in BAT. Selenop knockout mice show higher rectal temperatures and UCP1 sulfenylation during cold exposure. SeP treatment to brown adipocytes eliminated the NA-induced mitochondrial ROS by upregulating glutathione peroxidase 4 and impaired cellular thermogenesis. A high-fat/high-sucrose diet elevates serum SeP levels and diminishes the elevated NA induced thermogenesis in BAT-Selenop KO mice. Therefore, SeP is the intrinsic factor inducing reductive stress that impairs thermogenesis in BAT and may be a potential therapeutic target for obesity and diabetes.