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Objective: PPARα/γ 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 PPARα/γ agonist tesaglitazar via NPY 1 R-mediated internalization.

Methods: NPY 1 R-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 PPARγ in NPY 1 R-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 PPARα/γ effects in adipocytes while potentially omitting adverse effects in other tissues.

Titel:	NPY <subscript>1</subscript> R-targeted peptide-mediated delivery of a dual PPARα/γ agonist to adipocytes enhances adipogenesis and prevents diabetes progression.
Autor/in / Beteiligte Person:	Wittrisch, S ; Klöting, N ; Mörl, K ; Chakaroun, R ; Blüher, M ; Beck-Sickinger, AG
Link:	Full Text Finder (Volltext)
Zeitschrift:	Molecular metabolism, Jg. 31 (2020), S. 163-180
Veröffentlichung:	[München] : Elsevier GmbH, 2012-, 2020
Medientyp:	academicJournal
ISSN:	2212-8778 (electronic)
DOI:	10.1016/j.molmet.2019.11.009
Schlagwort:	3T3-L1 Cells Adipocytes metabolism Adipogenesis drug effects Alkanesulfonates administration & dosage Alkanesulfonates chemistry Animals COS Cells Cell Differentiation drug effects Cells, Cultured Chlorocebus aethiops Diabetes Mellitus, Experimental metabolism Diabetes Mellitus, Experimental pathology Diabetes Mellitus, Type 2 metabolism Diabetes Mellitus, Type 2 pathology Dose-Response Relationship, Drug Female HEK293 Cells Humans Mice Mice, Inbred C57BL Molecular Conformation PPAR alpha agonists PPAR alpha metabolism PPAR gamma agonists PPAR gamma metabolism Peptides administration & dosage Peptides chemistry Phenylpropionates administration & dosage Phenylpropionates chemistry Structure-Activity Relationship Adipocytes drug effects Alkanesulfonates pharmacology Diabetes Mellitus, Experimental prevention & control Diabetes Mellitus, Type 2 prevention & control Peptides pharmacology Phenylpropionates pharmacology Receptors, Neuropeptide Y metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Mol Metab] 2020 Jan; Vol. 31, pp. 163-180. <i>Date of Electronic Publication: </i>2019 Nov 16. MeSH Terms: Adipocytes / drug effects ; Alkanesulfonates / pharmacology ; Diabetes Mellitus, Experimental / prevention & control ; Diabetes Mellitus, Type 2 / prevention & control ; Peptides / pharmacology ; Phenylpropionates / pharmacology ; Receptors, Neuropeptide Y / *metabolism ; 3T3-L1 Cells ; Adipocytes / metabolism ; Adipogenesis / drug effects ; Alkanesulfonates / administration & dosage ; Alkanesulfonates / chemistry ; Animals ; COS Cells ; Cell Differentiation / drug effects ; Cells, Cultured ; Chlorocebus aethiops ; Diabetes Mellitus, Experimental / metabolism ; Diabetes Mellitus, Experimental / pathology ; Diabetes Mellitus, Type 2 / metabolism ; Diabetes Mellitus, Type 2 / pathology ; Dose-Response Relationship, Drug ; Female ; HEK293 Cells ; Humans ; Mice ; Mice, Inbred C57BL ; Molecular Conformation ; PPAR alpha / agonists ; PPAR alpha / metabolism ; PPAR gamma / agonists ; PPAR gamma / metabolism ; Peptides / administration & dosage ; Peptides / chemistry ; Phenylpropionates / administration & dosage ; Phenylpropionates / chemistry ; Structure-Activity Relationship References: Angew Chem Int Ed Engl. 2014 Sep 15;53(38):10067-71. 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(PMID: 521037) ; Am J Pathol. 2011 Jan;178(1):245-52. (PMID: 21224061) ; Nat Med. 2012 Dec;18(12):1847-56. (PMID: 23142820) Contributed Indexing: Keywords: Adipocyte targeting; NPY(1)R; Peptide drug conjugate; Tesaglitazar; Type 2 diabetes Substance Nomenclature: 0 (Alkanesulfonates) ; 0 (PPAR alpha) ; 0 (PPAR gamma) ; 0 (Peptides) ; 0 (Phenylpropionates) ; 0 (Receptors, Neuropeptide Y) ; 0 (neuropeptide Y-Y1 receptor) ; 6734037O3L (tesaglitazar) Entry Date(s): Date Created: 20200111 Date Completed: 20210101 Latest Revision: 20210101 Update Code: 20240513 PubMed Central ID: PMC6931124

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NPY <subscript>1</subscript> R-targeted peptide-mediated delivery of a dual PPARα/γ agonist to adipocytes enhances adipogenesis and prevents diabetes progression.