Bax inhibitor-1 deficiency leads to obesity by increasing Ca2+-dependent insulin secretion
Bax inhibitor-1 deficiency leads to obesity by increasing Ca2+-dependent insulin secretion
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Bax抑制剂-1缺乏通过增加Ca2依赖性胰岛素分泌导致肥胖
DOI：
10.1007/s00109-020-01914-x
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Axel Methner
中科院分区：
文献类型：
--
作者：
Koenraad Philippaert;Michael Roden;Dmitrij Lisak;Diones Bueno;Tomas Jelenik;Konstantin Radyushkin;Teresa Schacht;Marion Mesuere;Verena Wüllner;Ann-Kathrin Herrmann;Jan Baumbart;Rudi Vennekens;Axel Methner
摘要 跨膜 BAX 抑制剂基序包含 6 (TMBIM6)，也称为 Bax 抑制剂-1，是一种参与内质网 (ER) 功能的进化保守蛋白。 TMBIM6 是一种 ER Ca2+ 泄漏通道，其缺陷会因抑制 ER 应激传感器 IRE1α 而增强对 ER 应激的敏感性。之前的研究表明，TMBIM6 过表达可改善葡萄糖代谢，TMBIM6 敲除小鼠会出现肥胖。我们在这里检查了肥胖表型背后的代谢变化，并对 TMBIM6 敲除小鼠进行间接量热法和稳定同位素稀释的正常血糖-高胰岛素测试，以测量组织特异性胰岛素敏感性。这表明产热、食物摄入、活动或肝脏和外周胰岛素敏感性没有变化。然而，通过高血糖钳夹试验和肝脂肪变性评估，TMBIM6 敲除小鼠体内葡萄糖刺激的胰岛素分泌更高。这与分离的胰腺 β 细胞中葡萄糖介导的 Ca2+ 调节的深刻变化以及 IRE1α 水平的增加相一致，但 IRE1α 的下游效应（如胰腺中 Xbp1mRNA 剪接增加或 Ire1 依赖性胰岛素 mRNA 衰减）没有差异。因此，我们得出结论，缺乏 TMBIM6 不会影响胰岛素敏感性，但会导致高胰岛素血症，这可以解释体重增加的原因。 TMBIM6介导的代谢改变主要是由于其在ER中作为Ca2+释放通道的作用引起的。关键信息TMBIM6−/−导致肥胖和肝脂肪变性。TMBIM6−/−小鼠的食物摄入和能量消耗没有变化。TMBIM6−/−小鼠的胰岛素抵抗没有变化。胰岛素分泌增加引起 改变β细胞中的钙动态。
AbstractTransmembrane BAX inhibitor motif containing 6 (TMBIM6), also known as Bax inhibitor-1, is an evolutionarily conserved protein involved in endoplasmic reticulum (ER) function. TMBIM6 is an ER Ca2+leak channel and its deficiency enhances susceptibility to ER stress due to inhibition of the ER stress sensor IRE1α. It was previously shown that TMBIM6 overexpression improves glucose metabolism and that TMBIM6 knockout mice develop obesity. We here examined the metabolic alterations underlying the obese phenotype and subjected TMBIM6 knockout mice to indirect calorimetry and euglycemic-hyperinsulinemic tests with stable isotope dilution to gauge tissue-specific insulin sensitivity. This demonstrated no changes in heat production, food intake, activity or hepatic and peripheral insulin sensitivity. TMBIM6 knockout mice, however, featured a higher glucose-stimulated insulin secretion in vivo as assessed by the hyperglycemic clamp test and hepatic steatosis. This coincided with profound changes in glucose-mediated Ca2+regulation in isolated pancreatic β cells and increased levels of IRE1α levels but no differences in downstream effects of IRE1α like increasedXbp1mRNA splicing or Ire1-dependent decay of insulin mRNA in the pancreas. We therefore conclude that lack of TMBIM6 does not affect insulin sensitivity but leads to hyperinsulinemia, which serves to explain the weight gain. TMBIM6-mediated metabolic alterations are mainly caused by its role as a Ca2+release channel in the ER.Key messagesTMBIM6−/−leads to obesity and hepatic steatosis.Food intake and energy expenditure are not changed in TMBIM6−/−mice.No changes in insulin resistance in TMBIM6−/−mice.Increased insulin secretion caused by altered calcium dynamics in β cells.
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影响因子：
16
作者：
Chae, HJ;Kim, HR;Reed, JC
通讯作者：
Reed, JC
影响因子：
12.4
作者：
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作者：
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