New Engl J Med:减肥药研发获重大突破,三家制药巨头同时发现有效治疗肥胖的作用靶点

2017-08-30 刘盼盼、王新凯 奇点网

肥胖是一个全球性的健康问题,会导致包括2型糖尿病、心血管疾病、骨关节炎和癌症等疾病。据统计全球共有19亿人被列为超重,其中有6亿肥胖患者。肥胖已经对人类社会医疗保健造成了重大负担。

肥胖是一个全球性的健康问题,会导致包括2型糖尿病、心血管疾病、骨关节炎和癌症等疾病。据统计全球共有19亿人被列为超重,其中有6亿肥胖患者。肥胖已经对人类社会医疗保健造成了重大负担[1]。

然而,目前的药理学治疗只实现了相当适度(5-8%)的体重减轻[2]。 因此,减肥药,仍然是未能满足的巨大医疗需求。开发可以安全而有效地减轻体重的新型治疗剂不仅意义重大,而且利润可观。


科学家们最早在晚期前列腺癌患者中观察到,患者体重减轻与血清中GDF15水平升高相关,由此提出了GDF15与体重调节之间的联系[3]。在动物模型中科学家们发现,GDF15的过度表达会导致出现体瘦、摄食量减少以及代谢指数改善等现象[4]。这也让GDF15成为治疗肥胖和2型糖尿病的潜在希望。

但是之前有研究证明GDF15还涉及多种生物学功能,包括癌症恶病质(恶性肿瘤晚期患者出现的机体严重消瘦、贫血、厌食和全身衰弱的表现)、肾脏和心脏衰竭、动脉粥样硬化以及代谢异常等[5]。

由于GDF15这种牵一发而动全身的复杂作用,再加上一直以来科学家们对于GDF15介导体重减轻的信号传导和作用机制,包括相关受体,都知之甚少。这也就导致了利用GDF15治疗肥胖的潜在价值,也就一直没有取得大的突破。

就在今天,《自然医学》同时刊登了来自诺和诺德(NVO)、礼来(LLY)、强生(JNJ)三家制药巨头研究人员的三篇独立文章,明确指出GFRAL是GDF15的高亲和力受体,在减少摄食和降低体重机制中发挥着核心作用。试验过程中研究人员敲低GFRAL表达或阻断GFRAL与GDF15相互作用,会导致进食增多和体重增加,以及葡萄糖耐量异常[6-8]。


丹麦诺和诺德公司、礼来制药和美国强生公司

这是科学家们首次确定GDF15调节体重的核心机制和关键受体,为肥胖和Ⅱ型糖尿病的治疗提供了绝佳的靶点。也就是说,靶向增强GDF15-GFRAL信号通路介导的摄食抑制,可以有效治疗饮食导致的肥胖。NVO相关人员表示,靶向GFRAL的药物有望在两到三年内进入诊所。

JNJ研究与发展实验室的研究人员,首先尝试通过皮下注射GDF15观察对动物模型体重的影响。结果发现,在给予饮食导致肥胖的小鼠皮下注射GDF15六小时后,食物摄取量开始减少,6天后观察到食物摄取量和体重均小于对照组。


因饮食引起肥胖的小鼠在给药后体重变化

为了进一步观察GDF15在更高等动物中的作用,研究人员又向猕猴皮下注射人GDF15血清蛋白重组体(HSA-GDF15),2周后发现猕猴摄食减少,4周后对照组猕猴体重上升,而实验组猕猴体重下降。另外研究还表明,注射GDF15剂量相对越高,猕猴食物摄取和体重减少越明显。

临床监测还显示,接受治疗的动物均没有出现不适的迹象,这也更加强调了GDF15治疗肥胖症的潜力。

GDF15究竟是怎样发挥抑制摄食和减少体重的作用?为了寻找GDF15抑制能量摄取的胞内受体,三个研究团队分别下了不少功夫。

JNJ研究人员利用细胞芯片技术测试了4493个膜蛋白,找到了其中5个可能与GDF15结合的“嫌疑对象”,然后利用荧光激活细胞分选系统逐一测试,发现只有表达GFRAL的细胞可以与GDF15特异性结合。

LLY团队则是通过免疫沉淀技术,发现GDF15仅与标记GFRAL的细胞裂解物结合,且可紧密结合于高表达GFRAL的细胞。

NVO团队先是找到了可以表达跨膜蛋白细胞外域的2762个序列,然后通过次级免疫荧光及流式细胞仪技术进行观察,发现CDF15只与表达GFRAL的细胞结合。



在锁定GFRAL这个唯一的嫌疑之后,研究人员猜想,GFRAL或许是CDF15的依赖性受体,并在抑制摄食和降低体重过程中发挥关键作用。

为了验证猜想,三组研究人员分别尝试敲除小鼠GFRAL基因,在为小鼠注射GDF15后,三组结果均显示,所有小鼠均未出现摄食减少和体重减轻。


与野生型小鼠未注射GDF15(黑色实心圆点)、野生型小鼠注射GDF15(黑色实心方块)相比,敲除GFRAL基因(无论是否注射GDF15)都不能降低小鼠体重。

也就是说,缺乏了GFRAL后,CDF15减肥的神奇功能就失灵了。另外,LLY团队还通过单克隆抗体抑制GDF15与GFRAL的相互作用,得到了相同的结论。

在实验过程中研究人员注意到,GDF15基因32位点由色氨酸突变为丙氨酸过程中,与GFRAL的结合未受影响,但其介导的摄食抑制功能减弱。难道GDF15基因32位点的突变还影响了其它受体与GDF15的结合?进一步研究发现,GDF15与GFRAL的相互作用,还需要辅助受体RET的参与。

根据研究,GFRAL的表达在体内受到极大的限制,到目前为止研究人员确定GFRAL的表达仅限于小鼠、灵长类动物及人类的中枢神经系统,并且集中在脑后部及孤束核区域。由此看来,GDF15是在辅助受体RET的参与下与GFRAL细胞受体结合,构成了GDF15介导摄食抑制的完整信号通路,产生厌食作用从而导致体重降低。

这三项研究,均是首次揭示GDF15介导体重减轻的生理和细胞机制,并证明GFRAL的缺陷不利于GDF15介导的体重减轻、葡萄糖耐量和胰岛素敏感性改善。

研究人员表示,GFRAL作为GDF15受体的确定,将推动这一领域的工作进展,包括靶向增强该途径的方法。在小鼠及灵长类动物中对GDF15-GFRAL信号通路的发现,将很快应用于临床研究,以充分评估其治理肥胖的巨大潜力。

凭借三大制药巨头的实力,靶向GDF15-GFRAL信号通路的减肥药相信很快就会到来。

原始出处:


[2]Heymsfield S B, Wadden T A. Mechanisms, pathophysiology, and management of obesity[J]. New England Journal of Medicine, 2017, 376(3): 254-266.

[3]Brown D A, Moore J, Johnen H, et al. Serum macrophage inhibitory cytokine 1 in rheumatoid arthritis: a potential marker of erosive joint destruction[J]. Arthritis & Rheumatology, 2007, 56(3): 753-764.

[4]Chrysovergis K, Wang X, Kosak J, et al. NAG-1/GDF15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism[J]. International journal of obesity (2005), 2014, 38(12): 1555.

[5] Adela R, Banerjee S K. GDF-15 as a target and biomarker for diabetes and cardiovascular diseases: a translational prospective[J]. Journal of diabetes research, 2015, 2015.

[6]Shannon E Mullican,Xiefan Lin-Schmidt,Chen-Ni Chin,et al.GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates.doi:10.1038/nm.4392

[7]Paul J Emmerson,Feng Wang,Yong Du,et al.The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL.doi:10.1038/nm.4393

[8]Linda Yang,Chih-Chuan Chang,Zhe Sun,et al.GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand.doi:10.1038/nm.4394

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    2017-12-28 spoonycyy
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    2018-03-21 haouestc
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    2017-09-01 lqvr
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    2017-08-31 189****7206

    学习了谢谢分享

    0

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