NK2R control of energy expenditure and feeding to treat metabolic diseases
成果类型：
Article
署名作者：
Sass, Frederike; Ma, Tao; Ekberg, Jeppe H.; Kirigiti, Melissa; Urena, 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, Maria; Panhuis, Wietse In Het; Sjoberg, Kim A.; Kernodle, Stace; Petersen, Jacob E.; Pavlovskyi, Artem; Sandhu, Manbir; Moltke, Ida; Jorgensen, 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; Kilpelainen, Tuomas O.; Myers Jr, Martin G.; Kievit, Paul; Schwartz, Thue W.; Hansen, Jakob B.; Gerhart-Hines, Zachary
署名单位：
University of Copenhagen; University of Southern Denmark; Oregon Health & Science University; Oregon National Primate Research Center; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; St Jude Children's Research Hospital; Leiden University - Excl LUMC; Leiden University; Leiden University Medical Center (LUMC); Leiden University; Leiden University Medical Center (LUMC); Leiden University - Excl LUMC; University of Michigan System; University of Michigan; University of Copenhagen; Steno Diabetes Center; University of Copenhagen; Copenhagen University Hospital; University of Southern Denmark; University of Hamburg; University Medical Center Hamburg-Eppendorf; Monash University
刊物名称：
Nature
ISSN/ISSBN：
0028-5760
DOI：
10.1038/s41586-024-08207-0
发表日期：
2024-11-28
关键词：
substance-p
glucagon
receptor
obesity
weight
DISCOVERY
polymorphisms
association
mechanisms
overweight
摘要：
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 effects2-4, 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. In mouse and nonhuman primate models, treatment with selective, long-acting neurokinin 2 receptor agonists aids weight loss by suppressing appetite and increasing energy expenditure, as well as by increasing insulin sensitivity.