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Wittrisch, S.* ; Klöting, N. ; Mörl, K.* ; Chakaroun, R. ; Blüher, M. ; Beck-Sickinger, A.G.*

NPY1R-targeted peptide-mediated delivery of a dual PPAR alpha/gamma agonist to adipocytes enhances adipogenesis and prevents diabetes progression.

Mol. Metab. 31, 163-180 (2020)
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Open Access Gold
Creative Commons Lizenzvertrag
Objective: PPAR alpha/gamma dual agonists have been in clinical development for the treatment of metabolic diseases including type 2 diabetes and dyslipidemia. However, severe adverse side effects led to complications in clinical trials. As most of the beneficial effects rely on the compound activity in adipocytes, the selective targeting of this cell type is a cutting-edge strategy to develop safe anti-diabetic drugs. The goal of this study was to strengthen the adipocyte-specific uptake of the PPAR alpha/gamma agonist tesaglitazar via NPY1R-mediated internalization.Methods: NPY1R-preferring peptide tesaglitazar-[F-7, P-34]-NPY (tesa-NPY) was synthesized by a combination of automated SPPS and manual couplings. Following molecular and functional analyses for proof of concept, cell culture experiments were conducted to monitor the effects on adipogenesis. Mice treated with peptide drug conjugates or vehicle either by gavage or intraperitoneal injection were characterized phenotypically and metabolically. Histological analysis and transcriptional profiling of the adipose tissue were performed.Results: In vitro studies revealed that the tesaglitazar-[F-7, P-34]-NPY conjugate selectively activates PPAR gamma in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells. In vivo studies using db/db mice demonstrated that the anti-diabetic activity of the peptide conjugate is as efficient as that of systemically administered tesaglitazar. Additionally, tesa-NPY induces adipocyte differentiation in vivo.Conclusions: The use of the tesaglitazar-[F7, P34]-NPY conjugate is a promising strategy to apply the beneficial PPAR alpha/gamma effects in adipocytes while potentially omitting adverse effects in other tissues.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Adipocyte Targeting ; Npy1r ; Peptide Drug Conjugate ; Tesaglitazar ; Type 2 Diabetes; Protein-coupled Receptor; Neuropeptide-y Analogs; Insulin-resistance; Gamma Activation; Skeletal-muscle; Adipose-tissue; Metabolic Abnormalities; Pancreatic-polypeptide; Myocardial-infarction; Body-temperature
Sprache
Veröffentlichungsjahr 2020
Prepublished im Jahr 2019
HGF-Berichtsjahr 2019
ISSN (print) / ISBN 2212-8778
e-ISSN 2212-8778
Zeitschrift Molecular Metabolism
Quellenangaben Band: 31, Heft: , Seiten: 163-180 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort Amsterdam
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-506500-001
DOI 10.1016/j.molmet.2019.11.009
WOS ID WOS:000505805400014
Scopus ID 85076677651
Erfassungsdatum 2020-01-22
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