ESPEYB25 15. Editors' Choice Obesity (3 abstracts)
15.11. NK2R control of energy expenditure and feeding to treat metabolic diseases
Sass F , Ma T , Ekberg JH , Kirigiti M , Urena MG , Dollet L , Brown JM , Basse AL , Yacawych WT , Burm HB , Andersen MK , Nielsen TS , Tomlinson AJ , Dmytiyeva O , Christensen DP , Bader L , Vo CT , Wang Y , Rausch DM , Kristensen CK , Gestal-Mato M , In Het Panhuis W , Sjoberg KA , Kernodle S , Petersen JE , Pavlovskyi A , Sandhu M , Moltke I , Jorgensen ME , Albrechtsen A , Grarup N , Babu MM , Rensen PCN , Kooijman S , Seeley RJ , Worthmann A , Heeren J , Pers TH , Hansen T , Gustafsson MBF , Tang-Christensen M , Kilpelainen TO , Myers MG Jr. , Kievit P , Schwartz TW , Hansen JB & Gerhart-Hines Z
Nature 2024; 635:987-1000. PMID: 39537932 doi: 10.1038/s41586-024-08207-0
In Brief: The authors developed selective, long-acting agonists of the Gq-coupled neurokinin 2 receptor (NK2R) and used these in mouse and primate models. Activation of NK2R had dual effects on both suppressing appetite centrally and increasing energy expenditure peripherally.
Comment: The authors focussed on neurokinin 2 receptor (NK2R) gene (also known as tachykinin receptor 2 (TACR2)), because they first found robust genetic variant associations with HbA1c at this locus. They shifted their attention to obesity when they found associations between a NK2R expression-increasing allele and lower BMI.
Neurokinin A is the endogenous ligand for NK2R, but it has a short half-life and lacks receptor specificity. Therefore, the authors developed longer-acting peptide NK2R agonists (EB001/2), whose half-life was extended by covalently attaching the same 16-carbon fatty acid that prolongs the retention of liraglutide, and with potential for once-weekly administration in humans. In mice, these agonists elicited weight loss by inducing energy expenditure and non-aversive appetite suppression. In diabetic, obese macaques, NK2R activation reduced body weight, blood glucose, triglycerides and cholesterol, and improved insulin resistance.
Most currently available drugs to treat obesity act predominantly by reducing appetite and food intake, rather than increasing energy expenditure, which is the other half of the energy balance equation. Drugs that stimulate energy expenditure, such as thyroid hormone, amphetamines and mitochondrial uncouplers, had been used many decades ago as effective weight loss medications, but they all fell out of favour due to cardiovascular safety issues. Therefore, it is encouraging that NK2R agonists did not affect heart rate. They also spared lean mass and promoted insulin sensitization.
The authors comment that there is a high bar for new weight loss medication, as current and emerging treatments may typically already achieve 20% weight loss. Rather than being a potential new single agent therapy, they predict polyagonism strategies that add NK2R agonism to GLP-1 and GIP may provide the greatest therapeutic opportunity.
Volume 22
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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