丹麦哥本哈根大学Zachary Gerhart-Hines等研究人员合作发现，NK2R对能量消耗和进食的调控可用于治疗代谢性疾病。2024年11月13日，《自然》杂志在线发表了这项成果。

研究人员展示了神经激肽2受体（NK2R）的激活足以在中枢抑制食欲，并在外周增加能量消耗。研究人员关注NK2R是因为其与肥胖和葡萄糖控制的遗传关联。然而，之前由于其内源性配体神经激肽A半衰期较短且缺乏受体特异性，NK2R信号的治疗性利用一直难以实现。因此，研究人员开发了选择性、长效的NK2R激动剂，具有在人体中每周一次给药的潜力。

在小鼠中，这些激动剂通过诱导能量消耗和非厌恶性的食欲抑制来引起体重减轻，绕过了典型的瘦素信号传导。此外，超胰岛素血症-正常血糖夹心实验表明，NK2R激动可以急性增强胰岛素敏感性。在糖尿病和肥胖的猕猴中，NK2R激活显著减少了体重、血糖、甘油三酯和胆固醇水平，并改善了胰岛素抵抗。这些发现揭示了一个单一的受体靶点，利用能量消耗和食欲抑制两种机制来改善能量稳态，并在不同物种中逆转心血管代谢功能障碍。

据介绍，减少食物摄入和增加能量消耗的结合是对抗心血管代谢疾病（如肥胖和2型糖尿病）的一种强有力策略。然而，当前的药物学方法需要结合多种受体激动剂才能实现这两种效果，并且迄今为止，还没有安全的能量消耗药物进入临床。

附：英文原文

Title: NK2R control of energy expenditure and feeding to treat metabolic diseases

Author: Sass, Frederike, Ma, Tao, Ekberg, Jeppe H., Kirigiti, Melissa, Urea, Mario G., Dollet, Lucile, Brown, Jenny M., Basse, Astrid L., Yacawych, Warren T., Burm, Hayley B., Andersen, Mette K., Nielsen, Thomas S., Tomlinson, Abigail J., Dmytiyeva, Oksana, Christensen, Dan P., Bader, Lindsay, Vo, Camilla T., Wang, Yaxu, Rausch, Dylan M., Kristensen, Cecilie K., Gestal-Mato, Mara, In het Panhuis, Wietse, Sjberg, Kim A., Kernodle, Stace, Petersen, Jacob E., Pavlovskyi, Artem, Sandhu, Manbir, Moltke, Ida, Jrgensen, Marit E., Albrechtsen, Anders, Grarup, Niels, Babu, M. Madan, Rensen, Patrick C. N., Kooijman, Sander, Seeley, Randy J., Worthmann, Anna, Heeren, Joerg, Pers, Tune H., Hansen, Torben, Gustafsson, Magnus B. F., Tang-Christensen, Mads, Kilpelinen, Tuomas O., Myers, Martin G., Kievit, Paul, Schwartz, Thue W., Hansen, Jakob B., Gerhart-Hines, Zachary

Issue&Volume: 2024-11-13

Abstract: The combination of decreasing food intake and increasing energy expenditure represents a powerful strategy for counteracting cardiometabolic diseases such as obesity and type 2 diabetes1. Yet current pharmacological approaches require conjugation of multiple receptor agonists to achieve both effects2,3,4, and so far, no safe energy-expending option has reached the clinic. Here we show that activation of neurokinin 2 receptor (NK2R) is sufficient to suppress appetite centrally and increase energy expenditure peripherally. We focused on NK2R after revealing its genetic links to obesity and glucose control. However, therapeutically exploiting NK2R signalling has previously been unattainable because its endogenous ligand, neurokinin A, is short-lived and lacks receptor specificity5,6. Therefore, we developed selective, long-acting NK2R agonists with potential for once-weekly administration in humans. In mice, these agonists elicit weight loss by inducing energy expenditure and non-aversive appetite suppression that circumvents canonical leptin signalling. Additionally, a hyperinsulinaemic–euglycaemic clamp reveals that NK2R agonism acutely enhances insulin sensitization. In diabetic, obese macaques, NK2R activation significantly decreases body weight, blood glucose, triglycerides and cholesterol, and ameliorates insulin resistance. These findings identify a single receptor target that leverages both energy-expending and appetite-suppressing programmes to improve energy homeostasis and reverse cardiometabolic dysfunction across species.

DOI: 10.1038/s41586-024-08207-0

Source: https://www.nature.com/articles/s41586-024-08207-0