NK2R control of energy expenditure and feeding to treat metabolic diseases

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 () and Zachary Gerhart-Hines ()
Additional contact information
Frederike Sass: University of Copenhagen
Tao Ma: University of Copenhagen
Jeppe H. Ekberg: University of Copenhagen
Melissa Kirigiti: Oregon Health & Science University
Mario G. Ureña: University of Copenhagen
Lucile Dollet: University of Copenhagen
Jenny M. Brown: University of Copenhagen
Astrid L. Basse: University of Copenhagen
Warren T. Yacawych: University of Michigan
Hayley B. Burm: University of Copenhagen
Mette K. Andersen: University of Copenhagen
Thomas S. Nielsen: University of Copenhagen
Abigail J. Tomlinson: University of Michigan
Oksana Dmytiyeva: University of Copenhagen
Dan P. Christensen: University of Copenhagen
Lindsay Bader: Oregon Health & Science University
Camilla T. Vo: University of Copenhagen
Yaxu Wang: University of Southern Denmark
Dylan M. Rausch: University of Copenhagen
Cecilie K. Kristensen: University of Copenhagen
María Gestal-Mato: University of Copenhagen
Wietse In het Panhuis: Leiden University Medical Center
Kim A. Sjøberg: University of Copenhagen
Stace Kernodle: University of Michigan
Jacob E. Petersen: University of Copenhagen
Artem Pavlovskyi: University of Copenhagen
Manbir Sandhu: University of Southern Denmark
Ida Moltke: University of Copenhagen
Marit E. Jørgensen: Copenhagen University Hospital - Steno Diabetes Center Copenhagen
Anders Albrechtsen: University of Copenhagen
Niels Grarup: University of Copenhagen
M. Madan Babu: University of Southern Denmark
Patrick C. N. Rensen: Leiden University Medical Center
Sander Kooijman: Leiden University Medical Center
Randy J. Seeley: University of Michigan
Anna Worthmann: University Medical Center Hamburg-Eppendorf
Joerg Heeren: University Medical Center Hamburg-Eppendorf
Tune H. Pers: University of Copenhagen
Torben Hansen: University of Copenhagen
Magnus B. F. Gustafsson: Embark Laboratories
Mads Tang-Christensen: Embark Laboratories
Tuomas O. Kilpeläinen: University of Copenhagen
Martin G. Myers: University of Michigan
Paul Kievit: Oregon Health & Science University
Thue W. Schwartz: University of Copenhagen
Jakob B. Hansen: University of Copenhagen
Zachary Gerhart-Hines: University of Copenhagen

Nature, 2024, vol. 635, issue 8040, 987-1000

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-08207-0

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