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NK2R control of energy expenditure and feeding to treat metabolic diseases

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Title: NK2R control of energy expenditure and feeding to treat metabolic diseases
Authors: Frederike Sass, Tao Ma, Jeppe H. Ekberg, Melissa Kirigiti, Mario G. Ureña, Lucile Dollet, Jenny M. Brown, Astrid L. Basse, Warren T. Yacawych, Hayley B. Burm, Mette K. Andersen, Thomas S. Nielsen, Abigail J. Tomlinson, Oksana Dmytiyeva, Dan P. Christensen, Lindsay Bader, Camilla T. Vo, Yaxu Wang, Dylan M. Rausch, Cecilie K. Kristensen, María Gestal-Mato, Wietse In het Panhuis, Kim A. Sjøberg, Stace Kernodle, Jacob E. Petersen, Artem Pavlovskyi, Manbir Sandhu, Ida Moltke, Marit E. Jørgensen, Anders Albrechtsen, Niels Grarup, M. Madan Babu, Patrick C. N. Rensen, Sander Kooijman, Randy J. Seeley, Anna Worthmann, Joerg Heeren, Tune H. Pers, Torben Hansen, Magnus B. F. Gustafsson, Mads Tang-Christensen, Tuomas O. Kilpeläinen, Martin G. Myers, Paul Kievit, Thue W. Schwartz, Jakob B. Hansen, Zachary Gerhart-Hines
Source: Nature
Sass, F, Ma, T, Ekberg, J H, Kirigiti, M, Ureña, M G, Dollet, L, Brown, J M, Basse, A L, Yacawych, W T, Burm, H B, Andersen, M K, Nielsen, T S, Tomlinson, A J, Dmytiyeva, O, Christensen, D P, Bader, L, Vo, C T, Wang, Y, Rausch, D M, Kristensen, C K, Gestal-Mato, M, In het Panhuis, W, Sjøberg, K A, Kernodle, S, Petersen, J E, Pavlovskyi, A, Sandhu, M, Moltke, I, Jørgensen, M E, Albrechtsen, A, Grarup, N, Babu, M M, Rensen, P C N, Kooijman, S, Seeley, R J, Worthmann, A, Heeren, J, Pers, T H, Hansen, T, Gustafsson, M B F, Tang-Christensen, M, Kilpeläinen, T O, Myers, M G, Kievit, P, Schwartz, T W, Hansen, J B & Gerhart-Hines, Z 2024, ' NK2R control of energy expenditure and feeding to treat metabolic diseases ', Nature, vol. 635, no. 8040, pp. 987–1000 . https://doi.org/10.1038/s41586-024-08207-0
Publisher Information: Springer Science and Business Media LLC, 2024.
Publication Year: 2024
Subject Terms: Homeostasis/drug effects, Male, Blood Glucose, Leptin, 0301 basic medicine, Type 2/metabolism, Obesity/drug therapy, Weight Loss/drug effects, Appetite/drug effects, Appetite, Cholesterol/blood, Inbred C57BL, Article, Energy Metabolism/drug effects, Mice, 03 medical and health sciences, Blood Glucose/drug effects, Metabolic Diseases, Hyperinsulinism, Receptors, Diabetes Mellitus, Animals, Humans, Homeostasis, Feeding Behavior/drug effects, Obesity, Metabolic Diseases/blood, 0303 health sciences, Animal, Hyperinsulinism/drug therapy, Leptin/metabolism, Feeding Behavior, Neurokinin-2/agonists, Mice, Inbred C57BL, Triglycerides/blood, Disease Models, Animal, Cholesterol, Diabetes Mellitus, Type 2, Disease Models, Macaca, Female, Insulin Resistance, Energy Metabolism, Signal Transduction
Description: 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.
Document Type: Article
Other literature type
File Description: application/pdf
Language: English
ISSN: 1476-4687
0028-0836
DOI: 10.1038/s41586-024-08207-0
Access URL: https://pubmed.ncbi.nlm.nih.gov/39537932
https://hdl.handle.net/1887/4212412
https://curis.ku.dk/ws/files/413695577/s41586_024_08207_0.pdf
https://portal.findresearcher.sdu.dk/da/publications/33727b6a-62ea-41f9-b018-01d898a9c71a
https://doi.org/10.1038/s41586-024-08207-0
Rights: CC BY NC ND
CC BY
Accession Number: edsair.doi.dedup.....d1a1ceb8eda5d7187a9c43c3cbe34762
Database: OpenAIRE
Description
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 effects2-4, 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.
ISSN:14764687
00280836
DOI:10.1038/s41586-024-08207-0