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  Plasma proteome profiles treatment efficacy of incretin dual agonism in diet-induced obese female and male mice

Sachs, S., Niu, L., Geyer, P., Jall, S., Kleinert, M., Feuchtinger, A., et al. (2021). Plasma proteome profiles treatment efficacy of incretin dual agonism in diet-induced obese female and male mice. Diabetes, Obesity and Metabolism, 23, 195-207. doi:10.1111/dom.14215.

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© 2020 The Authors. Open access funding enabled and organized by Projekt DEAL.
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 Creators:
Sachs, Stephan1, Author
Niu, Lili1, Author
Geyer, Philipp2, Author              
Jall, Sigrid1, Author
Kleinert, Maximilian1, Author
Feuchtinger, Annette1, Author
Stemmer, Kerstin1, Author
Brielmeier, Markus1, Author
Finan, Brian1, Author
DiMarchi, Richard D.1, Author
Tschop, Matthias H.1, Author
Wewer Albrechtsen, Nicolai J.2, Author              
Mann, Matthias2, Author              
Mueller, Timo D.1, Author
Hofmann, Susanna M.1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: RECEPTOR AGONIST; BIOMARKERS; DISEASE; HOMEOSTASIS; EXPRESSION; C57BL/6J; GIPEndocrinology & Metabolism; bariatric surgery; combinatorial pharmacology; incretins; obesity; plasma proteomics;
 Abstract: Aims Unimolecular peptides targeting the receptors for glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) (GLP-1/GIP co-agonist) have been shown to outperform each single peptide in the treatment of obesity and cardiometabolic disease in preclinical and clinical trials. By combining physiological treatment endpoints with plasma proteomic profiling (PPP), we aimed to identify biomarkers to advance non-invasive metabolic monitoring of compound treatment success and exploration of ulterior treatment effects on an individual basis. Materials and methods We performed metabolic phenotyping along with PPP in body weight-matched male and female diet-induced obese (DIO) mice treated for 21 days with phosphate-buffered saline, single GIP and GLP-1 mono-agonists, or a GLP-1/GIP co-agonist. Results GLP-1R/GIPR co-agonism improved obesity, glucose intolerance, non-alcoholic fatty liver disease (NAFLD) and dyslipidaemia with superior efficacy in both male and female mice compared with mono-agonist treatments. PPP revealed broader changes of plasma proteins after GLP-1/GIP co-agonist compared with mono-agonist treatments in both sexes, including established and potential novel biomarkers for systemic inflammation, NAFLD and atherosclerosis. Subtle sex-specific differences have been observed in metabolic phenotyping and PPP. Conclusions We herein show that a recently developed unimolecular GLP-1/GIP co-agonist is more efficient in improving metabolic disease than either mono-agonist in both sexes. PPP led to the identification of a sex-independent protein panel with the potential to monitor non-invasively the treatment efficacies on metabolic function of this clinically advancing GLP-1/GIP co-agonist.

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Language(s): eng - English
 Dates: 2020-122021
 Publication Status: Published in print
 Pages: 13
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000585922500001
DOI: 10.1111/dom.14215
 Degree: -

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Project name : Grant Numbers: SFB TRR 152/2, ‐P23, SFB1123‐A4, TS 226/3‐1: SFB‐TRR29: EXC 2145, SyNergy – ID 390857198
Grant ID : -
Funding program : -
Funding organization : Deutsche Forschungsgemeinschaft
Project name : AdG HypoFlam
Grant ID : 695054
Funding program : -
Funding organization : European Research Council

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Title: Diabetes, Obesity and Metabolism
  Subtitle : A Journal of Pharmacology and Therapeutics
  Abbreviation : Diabetes Obes Metab
Source Genre: Journal
 Creator(s):
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Publ. Info: 111 RIVER ST, HOBOKEN 07030-5774, NJ USA : Wiley
Pages: - Volume / Issue: 23 Sequence Number: - Start / End Page: 195 - 207 Identifier: ISSN: 1462-8902