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Quarta, C. ; Clemmensen, C. ; Zhu, Z.* ; Yang, B.* ; Joseph, S.S. ; Lutter, D. ; Yi, C.X.* ; Graf, E. ; García-Cáceres, C. ; Legutko, B. ; Fischer, K. ; Brommage, R. ; Zizzari, P.* ; Franklin, B.S.* ; Krueger, M.* ; Koch, M.* ; Vettorazzi, S.* ; Li, P.* ; Hofmann, S.M. ; Bakhti, M. ; Bastidas-Ponce, A. ; Lickert, H. ; Strom, T.M. ; Gailus-Durner, V. ; Bechmann, I.* ; Perez-Tilve, D.* ; Tuckermann, J.P.* ; Hrabě de Angelis, M. ; Sandoval, D.A.* ; Cota, D.* ; Latz, E.* ; Seeley, R.J.* ; Müller, T.D. ; DiMarchi, R.D.* ; Finan, B. ; Tschöp, M.H.

Molecular integration of incretin and glucocorticoid action reverses immunometabolic dysfunction and obesity.

Cell Metab. 26, 620-632.e6 (2017)
Publ. Version/Full Text Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Chronic inflammation has been proposed to contribute to the pathogenesis of diet-induced obesity. However, scarce therapeutic options are available to treat obesity and the associated immunometabolic complications. Glucocorticoids are routinely employed for the management of inflammatory diseases, but their pleiotropic nature leads to detrimental metabolic side effects. We developed a glucagon-like peptide-1 (GLP-1)-dexamethasone co-agonist in which GLP-1 selectively delivers dexamethasone to GLP-1 receptor-expressing cells. GLP-1-dexamethasone lowers body weight up to 25% in obese mice by targeting the hypothalamic control of feeding and by increasing energy expenditure. This strategy reverses hypothalamic and systemic inflammation while improving glucose tolerance and insulin sensitivity. The selective preference for GLP-1 receptor bypasses deleterious effects of dexamethasone on glucose handling, bone integrity, and hypothalamus-pituitary-adrenal axis activity. Thus, GLP-1-directed glucocorticoid pharmacology represents a safe and efficacious therapy option for diet-induced immunometabolic derangements and the resulting obesity.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Glp-1 ; Anti-inflammatory ; Co-agonist ; Conjugate ; Dexamethasone ; Drug Delivery ; Hypothalamic Inflammation ; Obesity ; Type 2 Diabetes; Beta/nf-kappa-b; Insulin-resistance; Hypothalamic Inflammation; Peptide-1 Receptor; Metabolic Disease; Adipose-tissue; Weight-loss; Glucagon; Mice; Stress
Language english
Publication Year 2017
HGF-reported in Year 2017
ISSN (print) / ISBN 1550-4131
e-ISSN 1932-7420
Journal Cell Metabolism
Quellenangaben Volume: 26, Issue: 4, Pages: 620-632.e6 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Cambridge
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Institute of Experimental Genetics (IEG)
Institute of Human Genetics (IHG)
Institute of Diabetes and Regeneration Research (IDR)
POF-Topic(s) 30502 - Diabetes: Pathophysiology, Prevention and Therapy
30201 - Metabolic Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
90000 - German Center for Diabetes Research
Research field(s) Helmholtz Diabetes Center
Genetics and Epidemiology
PSP Element(s) G-508600-007
G-502200-001
G-500600-001
G-502200-006
G-500700-001
G-502300-001
G-501900-231
G-501900-221
G-502390-001
DOI 10.1016/j.cmet.2017.08.023
WOS ID WOS:000412109700010
Scopus ID 85029691238
PubMed ID 28943448
Erfassungsdatum 2017-09-27
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