2. Academic Validation
  3. NK2R control of energy expenditure and feeding to treat metabolic diseases

NK2R control of energy expenditure and feeding to treat metabolic diseases

  • Nature. 2024 Nov;635(8040):987-1000. doi: 10.1038/s41586-024-08207-0.
Frederike Sass # 1 2,  Tao Ma # 1,  Jeppe H Ekberg 1 3,  Melissa Kirigiti 4,  Mario G Ureña 1,  Lucile Dollet 1,  Jenny M Brown 1 5,  Astrid L Basse 1,  Warren T Yacawych 6 7,  Hayley B Burm 1,  Mette K Andersen 1,  Thomas S Nielsen 1,  Abigail J Tomlinson 6,  Oksana Dmytiyeva 1,  Dan P Christensen 1 3,  Lindsay Bader 4,  Camilla T Vo 1 8,  Yaxu Wang 2 9,  Dylan M Rausch 1,  Cecilie K Kristensen 1,  María Gestal-Mato 1,  Wietse In Het Panhuis 10,  Kim A Sjøberg 1,  Stace Kernodle 11,  Jacob E Petersen 1,  Artem Pavlovskyi 1,  Manbir Sandhu 2 9,  Ida Moltke 12,  Marit E Jørgensen 13 14 15,  Anders Albrechtsen 12,  Niels Grarup 1,  M Madan Babu 2 9,  Patrick C N Rensen 10,  Sander Kooijman 10,  Randy J Seeley 11,  Anna Worthmann 16,  Joerg Heeren 16,  Tune H Pers 1 5,  Torben Hansen 1,  Magnus B F Gustafsson 3 17,  Mads Tang-Christensen 3 18,  Tuomas O Kilpeläinen 1 5,  Martin G Myers Jr 6 7,  Paul Kievit 4,  Thue W Schwartz 1 3,  Jakob B Hansen 19 20,  Zachary Gerhart-Hines 21 22 23
Affiliations

Affiliations

  • 1 Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
  • 2 Center for Adipocyte Signaling (ADIPOSIGN), University of Southern Denmark, Odense, Denmark.
  • 3 Embark Laboratories, Copenhagen, Denmark.
  • 4 Division of Metabolic Health and Disease, Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, USA.
  • 5 The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 6 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • 7 Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
  • 8 Neuroscience Academy Denmark, Copenhagen, Denmark.
  • 9 Center of Excellence for Data Driven Discovery, Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN, USA.
  • 10 Department of Medicine, Division of Endocrinology and Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
  • 11 Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
  • 12 Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
  • 13 Clinical Research, Copenhagen University Hospital - Steno Diabetes Center Copenhagen, Herlev, Denmark.
  • 14 Centre for Public Health in Greenland, National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.
  • 15 Steno Diabetes Center Greenland, Nuuk, Greenland.
  • 16 Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 17 Chemical Process Research and Development, Chemical Process Research & DevelopmentLEO Pharma, Ballerup, Denmark.
  • 18 School of Biomedical Sciences Faculty of Medicine, Nursing and Health Sciences Monash University, Melbourne, Victoria, Australia.
  • 19 Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. jbh@embarklaboratories.com.
  • 20 Embark Laboratories, Copenhagen, Denmark. jbh@embarklaboratories.com.
  • 21 Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. zpg@sund.ku.dk.
  • 22 Center for Adipocyte Signaling (ADIPOSIGN), University of Southern Denmark, Odense, Denmark. zpg@sund.ku.dk.
  • 23 Embark Laboratories, Copenhagen, Denmark. zpg@sund.ku.dk.
  • # Contributed equally.
PMID: 39537932 DOI: 10.1038/s41586-024-08207-0
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.

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