TMEM16B determines cholecystokinin sensitivity of intestinal vagal afferents of nodose neurons.
TMEM16B determines cholecystokinin sensitivity of intestinal vagal afferents of nodose neurons.
复制标题
DOI：
10.1172/jci.insight.122058
复制
发表时间：
2019-03
期刊：
影响因子：
8
通讯作者：
Runping Wang;Yongjun Lu;M. Cicha;Madhu V Singh;C. Benson;C. Madden;M. Chapleau;F. Abboud
中科院分区：
文献类型：
--
作者：
Runping Wang;Yongjun Lu;M. Cicha;Madhu V Singh;C. Benson;C. Madden;M. Chapleau;F. Abboud
几十年来，胆囊收缩素（CCK）的饱腹感和代谢作用已被认为是肥胖症的潜在治疗靶点。我们发现了一种潜在的新型 Ca2+ 激活氯 (Cl-) 电流 (CaCC)，它是由 CCK 在结状神经元的肠道迷走神经传入中诱导的。 CaCC 亚基 Anoctamin 2 (Ano2/TMEM16B) 是该电流的主要贡献者。它的表达降低，高脂饮食 (HFD) 的肥胖小鼠中 CCK 当前活性也降低。感觉神经元通道杂合子 KO 中 TMEM16B 表达减少会导致肥胖表型，肠结节神经元中 CCK 敏感性丧失、CCK 诱导的饱腹感丧失和代谢变化，包括能量消耗减少。对能量消耗的影响得到了大鼠证据的进一步支持，表明 CCK 增强了棕色脂肪组织中的交感神经活动和生热作用，而这些影响可通过 HFD 和迷走神经切断术消除。我们的研究结果表明，Ano2/TMEM16B 是结节神经元迷走神经传入中的 Ca2+ 激活的氯离子通道，也是 CCK 诱导的饱腹感、体重控制和能量消耗的主要决定因素，使其成为肥胖症的潜在治疗靶点。
The satiety effects and metabolic actions of cholecystokinin (CCK) have been recognized as potential therapeutic targets in obesity for decades. We identified a potentially novel Ca2+-activated chloride (Cl-) current (CaCC) that is induced by CCK in intestinal vagal afferents of nodose neurons. The CaCC subunit Anoctamin 2 (Ano2/TMEM16B) is the dominant contributor to this current. Its expression is reduced, as is CCK current activity in obese mice on a high-fat diet (HFD). Reduced expression of TMEM16B in the heterozygote KO of the channel in sensory neurons results in an obese phenotype with a loss of CCK sensitivity in intestinal nodose neurons, a loss of CCK-induced satiety, and metabolic changes, including decreased energy expenditure. The effect on energy expenditure is further supported by evidence in rats showing that CCK enhances sympathetic nerve activity and thermogenesis in brown adipose tissue, and these effects are abrogated by a HFD and vagotomy. Our findings reveal that Ano2/TMEM16B is a Ca2+-activated chloride channel in vagal afferents of nodose neurons and a major determinant of CCK-induced satiety, body weight control, and energy expenditure, making it a potential therapeutic target in obesity.