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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature |
| Vol/bind | 635 |
| Udgave nummer | 8040 |
| Sider (fra-til) | 987–1000 |
| Antal sider | 37 |
| ISSN | 0028-0836 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:The authors thank the members of the Gerhart-Hines laboratory for discussions; L. Thisted and G. Hansen for in vivo pharmacological studies; U. Roostalu and T. Topilko for iDISCO whole-brain imaging; L. Steuernagel, C. A. Bauder and J. C. Br\u00FCning for assistance with snRNA-seq of the DVC; K. Kristiansen for providing the Ucp1 -knockout mice; C. Kukat and M. Germer for fluorescence-activated cell sorting of nuclei for single-nuclei sequencing experiments; and the Cologne Center for Genomics for library preparation and sequencing. We acknowledge the Rodent Metabolic Phenotyping Platform at the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) for technical and computational expertise and support. M.M.B. and M.S. received support from the American Lebanese Syrian Associated Charities. This project was supported by the Novo Nordisk Foundation (NNF21SA0072102 and NNF22OC0074128 to TOK; International Postdoctoral Fellowship NNF20OC0060969 to L.D.; NNF18OC0033444 to the Center for Adipocyte Signaling for F.S., M.S., M.M.B. and Z.G.-H.). This project has received funding from the European Research Council (ERC) under the European Union\u2019s Horizon 2020 Research and Innovation Programme (Starting Grant aCROBAT agreement no. 639382 to Z.G.-H. and Proof-of-concept Grant GET-UP BAT agreement no. 768783 to Z.G.-H., Consolidator Grant HEAT-UP agreement no. 101088636 to Z.G.-H.). A.W. was supported by the M\u00FChlbauer-foundation, and A.W. and J.H. received support from the Deutsche Forschungsgesellschaft (450149205-TRR333/1 and 335447717-SFB1328). R.J.S. was supported by the National Institutes of Health/National Institutes of Diabetes and Digestive and Kidney Diseases (P30DK089503, R01DK133140). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research centre at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF18CC0034900 and NNF23SA0084103). Figs. 1b,g,n, 2a,e,l,u, 3m,w, 4a,m and 5a and Extended Data Figs. 1a, 3u and 4f were created with BioRender.com.
Funding Information:
The authors thank the members of the Gerhart-Hines laboratory for discussions; L. Thisted and G. Hansen for in vivo pharmacological studies; U. Roostalu and T. Topilko for iDISCO whole-brain imaging; L. Steuernagel, C. A. Bauder and J. C. Br\u00FCning for assistance with snRNA-seq of the DVC; K. Kristiansen for providing the Ucp1-knockout mice; C. Kukat and M. Germer for fluorescence-activated cell sorting of nuclei for single-nuclei sequencing experiments; and the Cologne Center for Genomics for library preparation and sequencing. We acknowledge the Rodent Metabolic Phenotyping Platform at the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) for technical and computational expertise and support. M.M.B. and M.S. received support from the American Lebanese Syrian Associated Charities. This project was supported by the Novo Nordisk Foundation (NNF21SA0072102 and NNF22OC0074128 to TOK; International Postdoctoral Fellowship NNF20OC0060969 to L.D.; NNF18OC0033444 to the Center for Adipocyte Signaling for F.S., M.S., M.M.B. and Z.G.-H.). This project has received funding from the European Research Council (ERC) under the European Union\u2019s Horizon 2020 Research and Innovation Programme (Starting Grant aCROBAT agreement no. 639382 to Z.G.-H. and Proof-of-concept Grant GET-UP BAT agreement no. 768783 to Z.G.-H., Consolidator Grant HEAT-UP agreement no. 101088636 to Z.G.-H.). A.W. was supported by the M\u00FChlbauer-foundation, and A.W. and J.H. received support from the Deutsche Forschungsgesellschaft (450149205-TRR333/1 and 335447717-SFB1328). R.J.S. was supported by the National Institutes of Health/National Institutes of Diabetes and Digestive and Kidney Diseases (P30DK089503, R01DK133140). The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent research centre at the University of Copenhagen, partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF18CC0034900 and NNF23SA0084103). Figs. , , , and and Extended Data Figs. , and were created with BioRender.com.
Publisher Copyright:
© The Author(s) 2024.