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Finan, B. ; Yang, B.* ; Ottaway, N.* ; Stemmer, K. ; Müller, T.D. ; Yi, C.-X. ; Habegger, K.* ; Schriever, S.C. ; García-Cáceres, C. ; Kabra, D.G. ; Hembree, J.* ; Holland, J.* ; Raver, C.* ; Seeley, R.J.* ; Hans, W. ; Irmler, M. ; Beckers, J. ; Hrabě de Angelis, M. ; Tiano, J.P.* ; Mauvais-Jarvis, F.* ; Perez-Tilve, D.* ; Pfluger, P.T. ; Zhang, L.* ; Gelfanov, V.* ; DiMarchi, R.D.* ; Tschöp, M.H.

Targeted estrogen delivery reverses the metabolic syndrome.

J. Nat. Med. 18, 1847-1856 (2012)
DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1-targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1-estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter GLUCAGON-LIKE PEPTIDE-1; LEPTIN RESPONSIVENESS; DIABETES-MELLITUS; RECEPTOR-ALPHA; ENERGY-BALANCE; MICE; BINDING; OBESITY; CANCER; CELLS
Sprache englisch
Veröffentlichungsjahr 2012
HGF-Berichtsjahr 2012
ISSN (print) / ISBN 1340-3443
e-ISSN 1861-0293
Zeitschrift Journal of natural medicines
Quellenangaben Band: 18, Heft: 12, Seiten: 1847-1856 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort Tokyo [u.a.]
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)
Institute of Experimental Genetics (IEG)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Helmholtz Diabetes Center
Genetics and Epidemiology
PSP-Element(e) G-502200-001
G-500600-001
G-500600-004
G-500600-003
PubMed ID 23142820
DOI 10.1038/nm.3009
WOS ID WOS:000311999800034
Scopus ID 84870902173
Erfassungsdatum 2012-11-13
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