Butyrylcholinesterase gene transfer in obese mice prevents postdieting body weight rebound by suppressing ghrelin signaling
Butyrylcholinesterase gene transfer in obese mice prevents postdieting body weight rebound by suppressing ghrelin signaling
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DOI：
10.1073/pnas.1706517114
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发表时间：
2017-10-10
影响因子：
11.1
通讯作者：
Brimijoin, Stephen
中科院分区：
文献类型：
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作者：
Chen, Vicky Ping;Gao, Yang;Brimijoin, Stephen
肥胖症的全球流行率正在以惊人的速度增长，但治疗选择仍然有限。尽管最初的成功，热量限制（CR）减肥往往失败，因为反弹体重增加。饮食后的饮食过量沿着下丘脑神经结构的改变似乎是这种不良结果的直接原因。作为对热量不足的反应，促进食欲的激素，酰基-胃饥饿素的循环水平急剧上升。我们假设适当调节酰基-生长激素释放肽及其受体的敏感性将有利地影响能量摄入并重新编程体重设定点。在这里，我们在饮食诱导的肥胖小鼠模型中应用了酰基胃促生长素水解酶丁酰胆碱酯酶（BChE）的病毒基因转移。我们的研究结果证实，BChE过表达降低循环酰基-ghrelin水平，抑制CR引起的ghrelin信号传导，并恢复中枢ghrelin敏感性。除了保持健康的体重，BChE治疗的小鼠有适度的饮食后食物摄入，并显示正常的葡萄糖稳态。自发活动和能量消耗没有显着差异治疗和未治疗的小鼠体重反弹后，表明BChE基因转移并没有改变能量消耗的长期。这些发现表明，BChE治疗与CR相结合可能是治疗人类肥胖和帮助终身体重管理的有效方法。
The worldwide prevalence of obesity is increasing at an alarming rate but treatment options remain limited. Despite initial success, weight loss by calorie restriction (CR) often fails because of rebound weight gain. Postdieting hyperphagia along with altered hypothalamic neuro-architecture appears to be one direct cause of this undesirable outcome. In response to calorie deficiency the circulating levels of the appetite-promoting hormone, acyl-ghrelin, rise sharply. We hypothesize that proper modulation of acyl-ghrelin and its receptor's sensitivity will favorably impact energy intake and reprogram the body weight set point. Here we applied viral gene transfer of the acylghrelin hydrolyzing enzyme, butyrylcholinesterase (BChE), in a mouse model of diet-induced obesity. Our results confirmed that BChE overexpression decreased circulating acyl-ghrelin levels, suppressed CR-provoked ghrelin signaling, and restored central ghrelin sensitivity. In addition to maintaining healthy body weights, BChE treated mice had modest postdieting food intake and showed normal glucose homeostasis. Spontaneous activity and energy expenditure did not differ significantly between treated and untreated mice after body weight rebound, suggesting that BChE gene transfer did not alter energy expenditure in the long term. These findings indicate that combining BChE treatment with CR could be an effective approach in treating human obesity and aiding lifelong weight management.