Plasma proteome profiles treatment efficacy of incretin dual agonism in diet-induced obese female and male mice
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Plasma proteome profiles treatment efficacy of incretin dual agonism in diet-induced obese female and male mice. / Sachs, Stephan; Niu, Lili; Geyer, Philipp; Jall, Sigrid; Kleinert, Maximilian; Feuchtinger, Annette; Stemmer, Kerstin; Brielmeier, Markus; Finan, Brian; DiMarchi, Richard D.; Tschop, Matthias H.; Wewer Albrechtsen, Nicolai; Mann, Matthias; Mueller, Timo D.; Hofmann, Susanna M.
I: Diabetes, Obesity and Metabolism, Bind 23, Nr. 1, 2020, s. 195-207.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Plasma proteome profiles treatment efficacy of incretin dual agonism in diet-induced obese female and male mice
AU - Sachs, Stephan
AU - Niu, Lili
AU - Geyer, Philipp
AU - Jall, Sigrid
AU - Kleinert, Maximilian
AU - Feuchtinger, Annette
AU - Stemmer, Kerstin
AU - Brielmeier, Markus
AU - Finan, Brian
AU - DiMarchi, Richard D.
AU - Tschop, Matthias H.
AU - Wewer Albrechtsen, Nicolai
AU - Mann, Matthias
AU - Mueller, Timo D.
AU - Hofmann, Susanna M.
N1 - CURIS 2021 NEXS 004
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - bariatric surgery
KW - combinatorial pharmacology
KW - incretins
KW - obesity
KW - plasma proteomics
KW - RECEPTOR AGONIST
KW - BIOMARKERS
KW - DISEASE
KW - HOMEOSTASIS
KW - EXPRESSION
KW - C57BL/6J
KW - GIP
U2 - 10.1111/dom.14215
DO - 10.1111/dom.14215
M3 - Journal article
C2 - 33001570
VL - 23
SP - 195
EP - 207
JO - Diabetes, Obesity and Metabolism
JF - Diabetes, Obesity and Metabolism
SN - 1462-8902
IS - 1
ER -
ID: 251578807