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Hass, D, ; Madsen, A.N.* ; da Silva Buttkus, P. ; Kjølbye, A.L.* ; Støy, S.* ; Nøhr-Meldgaard, J.* ; Sandahl, T.D.* ; Hrabě de Angelis, M. ; Jorgensen, R.* ; Rohm, M. ; van de Bunt, M.*

Lipidated Interleukin-22 reduces body weight and spares lean mass in mice by a novel gut acting mechanism additive to GLP-1 agonism. 

Mol. Ther. 34, 3568-3578 (2026)
DOI PMC
Open Access Gold as soon as Publ. Version/Full Text is submitted to ZB.
The prevalence of metabolic diseases, including obesity and type 2 diabetes, continues to rise. Although GLP-1 receptor agonists (GLP-1RAs) now provide the first effective treatment options for patients with obesity, many still fail to reach their target weight. Interleukin (IL)-22 has emerged as a promising therapeutic due to its ability to modulate key metabolic factors. This study evaluated the potential of a novel long-acting lipidated IL-22 analogue as a complementary treatment to GLP-1RAs in mouse models. Lipidated IL-22 induced up to 20% weight reduction as a monotherapy and up to 40% in combination with GLP-1RAs, demonstrating additive efficacy. Lipidated IL-22 preserved lean body mass with less than half the lean mass loss of GLP-1RAs or caloric restriction. Glycemic control was also enhanced, with lipidated IL-22 normalizing blood glucose, and improving insulin sensitivity independent of food intake. Mechanistically, lipidated IL-22 enhanced intestinal secretion of anorectic factors like PYY and doubled fecal energy loss through reduced intestinal calorie absorption. These findings demonstrate the novel intestinal mechanisms of action of lipidated IL-22 and its additive potential to GLP-1RA treatment. Therefore, lipidated IL-22 is strongly positioned as a novel anti-obesity treatment that can address critical unmet needs in the treatment of metabolic diseases.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Glp-1 ; Interleukin-22 ; Obesity ; Pharmacotherapy ; Type 2 Diabetes
ISSN (print) / ISBN 1525-0016
e-ISSN 1525-0024
Journal Molecular Therapy
Quellenangaben Volume: 34, Issue: 6, Pages: 3568-3578 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place 50 Hampshire St, Floor 5, Cambridge, Ma 02139 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Cancer (IDC)
Institute of Experimental Genetics (IEG)
Grants German Center for Diabetes Research (DZD)
German Center for Diabetes Research Next Grant (DZD)
Helmholtz Association-Initiative and Networking Fund