Elevated UCP1 levels are sufficient to improve glucose uptake in human white adipocytes
Elevated UCP1 levels are sufficient to improve glucose uptake in human white adipocytes
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DOI：
10.1016/j.redox.2019.101286
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发表时间：
2019-09-01
期刊：
影响因子：
11.4
通讯作者：
Fischer-Posovszky, P.
中科院分区：
文献类型：
--
作者：
Tews, D.;Pula, T.;Fischer-Posovszky, P.
棕色脂肪组织（BAT）被认为通过参与葡萄糖稳态的调节而有益于代谢健康。使葡萄糖摄取超过正常水平的褐变因素尚不清楚，但 UCP1 敲除小鼠的葡萄糖摄取不受影响。在这里，我们在人类白色脂肪细胞中证明，仅通过提高 UCP1 蛋白水平即可改善基础/静息葡萄糖摄取。通过稳定敲除和过表达 UCP1 生成人类白色辛普森-戈拉比-贝梅尔综合征 (SGBS) 脂肪细胞，我们发现过表达 UCP1 的脂肪细胞可显着提高 40% 的葡萄糖摄取。从机制上讲，这是由较高的糖酵解通量引起的，表现为耗氧量、细胞外酸化和乳酸分泌率增加。葡萄糖处理的改善与白色到棕色的转变相当，这是通过首次直接比较体外分化的小鼠棕色脂肪细胞与白色脂肪细胞来判断的。尽管SGBS细胞中的脂肪形成、代谢和线粒体基因表达没有显着改变，但GLUT1的药理抑制完全消除了UCP1+和对照细胞之间的差异，从而揭示了GLUT1介导的摄取作为许可的看门人。总的来说，我们的数据表明，提高 UCP1 水平足以改善人类白色脂肪细胞作为葡萄糖汇的作用，而不会产生不利的细胞效应，因此不需要肾上腺素能控制的复杂褐变网络，这通常会阻碍转化工作。
Brown adipose tissue (BAT) has been considered beneficial for metabolic health by participating in the regulation of glucose homoeostasis. The browning factors that improve glucose uptake beyond normal levels are still unknown but glucose uptake is not affected in UCP1 knockout mice. Here, we demonstrate in human white adipocytes that basal/resting glucose uptake is improved by solely elevating UCP1 protein levels. Generating human white Simpson-Golabi-Behmel syndrome (SGBS) adipocytes with a stable knockout and overexpression of UCP1, we discovered that UCP1 overexpressing adipocytes significantly improve glucose uptake by 40%. Mechanistically, this is caused by higher glycolytic flux, seen as increased oxygen consumption, extracellular acidification and lactate secretion rates. The improvements in glucose handling are comparable to white-to-brown transitions, as judged by, for the first time, directly comparing in vitro differentiated mouse brown vs white adipocytes. Although no adipogenic, metabolic and mitochondrial gene expressions were significantly altered in SGBS cells, pharmacological inhibition of GLUT1 completely abrogated differences between UCP1 + and control cells, thereby uncovering GLUT1-mediated uptake as permissive gatekeeper. Collectively, our data demonstrate that elevating UCP1 levels is sufficient to improve human white adipocytes as a glucose sink without adverse cellular effects, thus not requiring the adrenergic controlled, complex network of browning which usually hampers translational efforts.