论文标题：Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes

期刊：

作者：Christoffer Clemmensen, Sigrid Jall, Maximilian Kleinert, Carmelo Quarta, Tim Gruber, Josefine Reber, Stephan Sachs, Katrin Fischer, Annette Feuchtinger, Angelos Karlas, Stephanie E. Simonds, Gerald Grandl, Daniela Loher, Eva Sanchez-Quant, Susanne Keipert, Martin Jastroch, Susanna M. Hofmann, Emmani B. M. Nascimento, Patrick Schrauwen, Vasilis Ntziachristos, Michael A. Cowley, Brian Finan, Timo D. Müller, Matthias H. Tschop

发表时间：2018/10/23

数字识别码： 10.1038/s41467-018-06769-y

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根据《自然-通讯》发表的一项研究Coordinated targeting of cold and nicotinic receptors synergistically improves obesity and type 2 diabetes，使用药物同时针对尼古丁（又名烟碱）和冷暴露信号传导通路，被证明可以降低小鼠体重并改善小鼠的代谢健康。化合物冰素（icilin）和二甲基苯基哌嗪会刺激食欲抑制通路和产热促进通路，从而调节全身能量平衡以促进肥胖小鼠减重。

图1：化合物冰素（icilin）和二甲基苯基哌嗪（DMPP）联合治疗增加了交感神经系统相关的棕色脂肪组织（BAT）产热。图源：Clemmensen等

肥胖是代谢疾病（例如糖尿病）的风险因素，对健康构成重大威胁。吸烟和冷暴露是人体能量代谢的环境调节因子，分别抑制食欲，增加能量消耗。目前，人们正在寻求通过药物方式增加产热，希望可以借此模拟冷暴露，增加能量消耗，从而促进减重。然而，同时带来的食物摄入的增加可能会抵消这些影响。

德国亥姆霍兹慕尼黑研究中心-德国环境健康研究中心的Matthias Tschöp及其同事采用一种联合疗法，即同时使用烟碱型乙酰胆碱受体α3β4和瞬态电压感受器阳离子通道M8（TRPM8），TRPM8可在低温下被小分子疗法激活。作者发现，这种疗法降低了肥胖小鼠的体重并纠正了葡萄糖耐受不良。

图2：烟碱受体激动剂DMPP降低了饮食诱导的肥胖小鼠的体重并改善了其葡萄糖耐量图源：Clemmensen等

作者指出，以上研究结果为治疗肥胖开辟了一条潜在的新途径，而且这种治疗不会产生与香烟烟雾相关的负面健康后果。不过，还需要开展进一步的研究，以确定这些发现是否可以转化至人类身上。

摘要：Pharmacological stimulation of brown adipose tissue (BAT) thermogenesis to increase energy expenditure is progressively being pursued as a viable anti-obesity strategy. Here, we report that pharmacological activation of the cold receptor transient receptor potential cation channel subfamily M member 8 (TRPM8) with agonist icilin mimics the metabolic benefits of cold exposure. In diet-induced obese (DIO) mice, treatment with icilin enhances energy expenditure, and decreases body weight, without affecting food intake. To further potentiate the thermogenic action profile of icilin and add complementary anorexigenic mechanisms, we set out to identify pharmacological partners next to icilin. To that end, we specifically targeted nicotinic acetylcholine receptor (nAChR) subtype alpha3beta4 (α3β4), which we had recognized as a potential regulator of energy homeostasis and glucose metabolism. Combinatorial targeting of TRPM8 and nAChR α3β4 by icilin and dimethylphenylpiperazinium (DMPP) orchestrates synergistic anorexic and thermogenic pathways to reverse diet-induced obesity, dyslipidemia, and glucose intolerance in DIO mice.

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