NK2R control of energy expenditure and feeding to treat metabolic diseases

• Published in: Nature (London) 2024-11, Vol.635 (8040), p.987-1000
• Main Authors: Sass, Frederike, Ma, Tao, Ekberg, Jeppe H., Kirigiti, Melissa, Ureña, 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, María, In het Panhuis, Wietse, Sjøberg, Kim A., Kernodle, Stace, Petersen, Jacob E., Pavlovskyi, Artem, Sandhu, Manbir, Moltke, Ida, Jørgensen, 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, Kilpeläinen, Tuomas O., Myers, Martin G., Kievit, Paul, Schwartz, Thue W., Hansen, Jakob B., Gerhart-Hines, Zachary
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 14/32; 14/63; 38/43; 38/91; 631/154/436/2387; 631/443/319/1557; 64; 64/110; 64/60; 692/163/2743/137/773; 692/163/2743/393; 692/699/317; 96/35; Animals; Appetite - drug effects; Blood Glucose - drug effects; Cholesterol - blood; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Disease Models, Animal; Energy Metabolism - drug effects; Feeding Behavior - drug effects; Female; Homeostasis - drug effects; Humanities and Social Sciences; Humans; Hyperinsulinism - drug therapy; Hyperinsulinism - metabolism; Insulin Resistance; Leptin - metabolism; Macaca; Male; Metabolic Diseases - blood; Metabolic Diseases - drug therapy; Metabolic Diseases - metabolism; Mice; Mice, Inbred C57BL; multidisciplinary; Obesity - drug therapy; Obesity - metabolism; Receptors, Neurokinin-2 - agonists; Receptors, Neurokinin-2 - metabolism; Science; Science (multidisciplinary); Signal Transduction; Triglycerides - blood; Weight Loss - drug effects
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-024-08207-0

The combination of decreasing food intake and increasing energy expenditure represents a powerful strategy for counteracting cardiometabolic diseases such as obesity and type 2 diabetes 1 . Yet current pharmacological approaches require conjugation of multiple receptor agonists to achieve both effects 2 – 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 specificity 5 , 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.