NK2R control of energy expenditure and feeding to treat metabolic diseases

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<sup>1</sup>. Yet current pharmacological approaches require conjugation of multiple receptor agonists to achieve both effects<sup>2-4</sup>, 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<sup>5,6</sup>. 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.

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Journal
Nature
Published
2024-11-13
DOI
https://doi.org/10.1038/s41586-024-08207-0
Citations
37
Primary Topic
Pancreatic function and diabetes
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article
Field-Weighted Citation Impact
20.05
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article

NK2R control of energy expenditure and feeding to treat metabolic diseases

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Nature
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NK2R control of energy expenditure and feeding to treat metabolic diseases

Manbir Sandhu, Dylan M. Rausch, Anders Albrechtsen, Paul Kievit, Jöerg Heeren, Melissa A. Kirigiti, Mads Tang‐Christensen, Lindsay Bader, Lucile Dollet, Thue Walter Schwartz, Thomas S. Nielsen, Martin Grosvenor Myers, Kim A. Sjøberg, Jacob E. Petersen, Sander Kooijman, Astrid Linde Basse, Warren T. Yacawych, Patrick C.N. Rensen, Mario García‐Ureña, Stace Kernodle, Mette K. Andersen, Marit E. Jørgensen, Tao Ma, Frederike Sass, Cong Phat Vo, Ida Moltke, Magnus Gustafsson, Tuomas O. Kilpeläinen, Jeppe H. Ekberg, Christian Haag Kristensen, Niels Grarup, Randy J. Seeley, Anna Worthmann, Tune H. Pers, Jenny M. Brown, Zachary Gerhart‐Hines, Abigail J. Tomlinson, Yaxu Wang, Dan Ploug Christensen, Hayley Burm, Wietse In het Panhuis, Jakob Bondo Hansen, Torben Hansen, M. Madan Babu, Artem Pavlovskyi, Oksana Dmytiyeva, María Gestal-Mato
article en
37 citations

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 diabetes<sup>1</sup>. Yet current pharmacological approaches require conjugation of multiple receptor agonists to achieve both effects<sup>2-4</sup>, 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<sup>5,6</sup>. 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.

NatureVol. 635(8040)
Oregon National Primate Research Center (US), Broad Institute (US), University of Copenhagen (DK), St. Jude Children's Research Hospital (US), Steno Diabetes Centers (DK), Universität Hamburg (DE), Oregon Health & Science University (US), Ilisimatusarfik (GL), University of Southern Denmark (DK), University of Michigan (US), Leiden University Medical Center (NL), Copenhagen Business Academy (DK), Novo Nordisk Foundation (DK), Copenhagen University Hospital (DK), Foundation Center (US), Novo Nordisk (United States) (US), University Medical Center Hamburg-Eppendorf (DE), Monash Health (AU), Keskuslaboratorio (FI), Leo Pharma (Denmark) (DK), Monash University (AU)
Openalex Percentile: Top 0%
Pancreatic function and diabetes
20.05
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