GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice

Research output: Contribution to journal › Journal article › Research › peer-review

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GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice. / Quarta, Carmelo; Stemmer, Kerstin; Novikoff, Aaron; Yang, Bin; Klingelhuber, Felix; Harger, Alex; Bakhti, Mostafa; Bastidas-Ponce, Aimee; Baugé, Eric; Campbell, Jonathan E.; Capozzi, Megan; Clemmensen, Christoffer; Collden, Gustav; Cota, Perla; Douros, Jon; Drucker, Daniel J.; DuBois, Barent; Feuchtinger, Annette; Garcia-Caceres, Cristina; Grandl, Gerald; Hennuyer, Nathalie; Herzig, Stephan; Hofmann, Susanna M.; Knerr, Patrick J.; Kulaj, Konxhe; Lalloyer, Fanny; Lickert, Heiko; Liskiewicz, Arek; Liskiewicz, Daniela; Maity, Gandhari; Perez-Tilve, Diego; Prakash, Sneha; Sanchez-Garrido, Miguel A.; Zhang, Qian; Staels, Bart; Krahmer, Natalie; DiMarchi, Richard D.; Tschöp, Matthias H.; Finan, Brian; Müller, Timo D.

In: Nature Metabolism, Vol. 4, No. 8, 2022, p. 1071-1083.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Quarta, C, Stemmer, K, Novikoff, A, Yang, B, Klingelhuber, F, Harger, A, Bakhti, M, Bastidas-Ponce, A, Baugé, E, Campbell, JE, Capozzi, M, Clemmensen, C, Collden, G, Cota, P, Douros, J, Drucker, DJ, DuBois, B, Feuchtinger, A, Garcia-Caceres, C, Grandl, G, Hennuyer, N, Herzig, S, Hofmann, SM, Knerr, PJ, Kulaj, K, Lalloyer, F, Lickert, H, Liskiewicz, A, Liskiewicz, D, Maity, G, Perez-Tilve, D, Prakash, S, Sanchez-Garrido, MA, Zhang, Q, Staels, B, Krahmer, N, DiMarchi, RD, Tschöp, MH, Finan, B & Müller, TD 2022, 'GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice', Nature Metabolism, vol. 4, no. 8, pp. 1071-1083. https://doi.org/10.1038/s42255-022-00617-6

APA

Quarta, C., Stemmer, K., Novikoff, A., Yang, B., Klingelhuber, F., Harger, A., Bakhti, M., Bastidas-Ponce, A., Baugé, E., Campbell, J. E., Capozzi, M., Clemmensen, C., Collden, G., Cota, P., Douros, J., Drucker, D. J., DuBois, B., Feuchtinger, A., Garcia-Caceres, C., ... Müller, T. D. (2022). GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice. Nature Metabolism, 4(8), 1071-1083. https://doi.org/10.1038/s42255-022-00617-6

Vancouver

Quarta C, Stemmer K, Novikoff A, Yang B, Klingelhuber F, Harger A et al. GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice. Nature Metabolism. 2022;4(8):1071-1083. https://doi.org/10.1038/s42255-022-00617-6

Author

Quarta, Carmelo ; Stemmer, Kerstin ; Novikoff, Aaron ; Yang, Bin ; Klingelhuber, Felix ; Harger, Alex ; Bakhti, Mostafa ; Bastidas-Ponce, Aimee ; Baugé, Eric ; Campbell, Jonathan E. ; Capozzi, Megan ; Clemmensen, Christoffer ; Collden, Gustav ; Cota, Perla ; Douros, Jon ; Drucker, Daniel J. ; DuBois, Barent ; Feuchtinger, Annette ; Garcia-Caceres, Cristina ; Grandl, Gerald ; Hennuyer, Nathalie ; Herzig, Stephan ; Hofmann, Susanna M. ; Knerr, Patrick J. ; Kulaj, Konxhe ; Lalloyer, Fanny ; Lickert, Heiko ; Liskiewicz, Arek ; Liskiewicz, Daniela ; Maity, Gandhari ; Perez-Tilve, Diego ; Prakash, Sneha ; Sanchez-Garrido, Miguel A. ; Zhang, Qian ; Staels, Bart ; Krahmer, Natalie ; DiMarchi, Richard D. ; Tschöp, Matthias H. ; Finan, Brian ; Müller, Timo D. / GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice. In: Nature Metabolism. 2022 ; Vol. 4, No. 8. pp. 1071-1083.

Bibtex

@article{2441e39ee9764f57b08576ecac36b1de,
title = "GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice",
abstract = "Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARɑ/ɣ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/tesaglitazar does not differ from the pharmacokinetically matched GLP-1RA in GLP-1R signalling, but shows GLP-1R-dependent PPARɣ-retinoic acid receptor heterodimerization and enhanced improvements of body weight, food intake and glucose metabolism relative to the GLP-1RA or tesaglitazar alone in obese male mice. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout mice and shows preserved effects in obese mice at subthreshold doses for the GLP-1RA and tesaglitazar. Liquid chromatography–mass spectrometry-based proteomics identified PPAR regulated proteins in the hypothalamus that are acutely upregulated by GLP-1RA/tesaglitazar. Our data show that GLP-1RA/tesaglitazar improves glucose control with superior efficacy to the GLP-1RA or tesaglitazar alone and suggest that this conjugate might hold therapeutic value to acutely treat hyperglycaemia and insulin resistance.",
author = "Carmelo Quarta and Kerstin Stemmer and Aaron Novikoff and Bin Yang and Felix Klingelhuber and Alex Harger and Mostafa Bakhti and Aimee Bastidas-Ponce and Eric Baug{\'e} and Campbell, {Jonathan E.} and Megan Capozzi and Christoffer Clemmensen and Gustav Collden and Perla Cota and Jon Douros and Drucker, {Daniel J.} and Barent DuBois and Annette Feuchtinger and Cristina Garcia-Caceres and Gerald Grandl and Nathalie Hennuyer and Stephan Herzig and Hofmann, {Susanna M.} and Knerr, {Patrick J.} and Konxhe Kulaj and Fanny Lalloyer and Heiko Lickert and Arek Liskiewicz and Daniela Liskiewicz and Gandhari Maity and Diego Perez-Tilve and Sneha Prakash and Sanchez-Garrido, {Miguel A.} and Qian Zhang and Bart Staels and Natalie Krahmer and DiMarchi, {Richard D.} and Tsch{\"o}p, {Matthias H.} and Brian Finan and M{\"u}ller, {Timo D.}",
note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
doi = "10.1038/s42255-022-00617-6",
language = "English",
volume = "4",
pages = "1071--1083",
journal = "Nature Metabolism",
issn = "2522-5812",
publisher = "Springer",
number = "8",

}

RIS

TY - JOUR

T1 - GLP-1-mediated delivery of tesaglitazar improves obesity and glucose metabolism in male mice

AU - Quarta, Carmelo

AU - Stemmer, Kerstin

AU - Novikoff, Aaron

AU - Yang, Bin

AU - Klingelhuber, Felix

AU - Harger, Alex

AU - Bakhti, Mostafa

AU - Bastidas-Ponce, Aimee

AU - Baugé, Eric

AU - Campbell, Jonathan E.

AU - Capozzi, Megan

AU - Clemmensen, Christoffer

AU - Collden, Gustav

AU - Cota, Perla

AU - Douros, Jon

AU - Drucker, Daniel J.

AU - DuBois, Barent

AU - Feuchtinger, Annette

AU - Garcia-Caceres, Cristina

AU - Grandl, Gerald

AU - Hennuyer, Nathalie

AU - Herzig, Stephan

AU - Hofmann, Susanna M.

AU - Knerr, Patrick J.

AU - Kulaj, Konxhe

AU - Lalloyer, Fanny

AU - Lickert, Heiko

AU - Liskiewicz, Arek

AU - Liskiewicz, Daniela

AU - Maity, Gandhari

AU - Perez-Tilve, Diego

AU - Prakash, Sneha

AU - Sanchez-Garrido, Miguel A.

AU - Zhang, Qian

AU - Staels, Bart

AU - Krahmer, Natalie

AU - DiMarchi, Richard D.

AU - Tschöp, Matthias H.

AU - Finan, Brian

AU - Müller, Timo D.

N1 - Publisher Copyright: © 2022, The Author(s).

PY - 2022

Y1 - 2022

N2 - Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARɑ/ɣ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/tesaglitazar does not differ from the pharmacokinetically matched GLP-1RA in GLP-1R signalling, but shows GLP-1R-dependent PPARɣ-retinoic acid receptor heterodimerization and enhanced improvements of body weight, food intake and glucose metabolism relative to the GLP-1RA or tesaglitazar alone in obese male mice. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout mice and shows preserved effects in obese mice at subthreshold doses for the GLP-1RA and tesaglitazar. Liquid chromatography–mass spectrometry-based proteomics identified PPAR regulated proteins in the hypothalamus that are acutely upregulated by GLP-1RA/tesaglitazar. Our data show that GLP-1RA/tesaglitazar improves glucose control with superior efficacy to the GLP-1RA or tesaglitazar alone and suggest that this conjugate might hold therapeutic value to acutely treat hyperglycaemia and insulin resistance.

AB - Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARɑ/ɣ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/tesaglitazar does not differ from the pharmacokinetically matched GLP-1RA in GLP-1R signalling, but shows GLP-1R-dependent PPARɣ-retinoic acid receptor heterodimerization and enhanced improvements of body weight, food intake and glucose metabolism relative to the GLP-1RA or tesaglitazar alone in obese male mice. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout mice and shows preserved effects in obese mice at subthreshold doses for the GLP-1RA and tesaglitazar. Liquid chromatography–mass spectrometry-based proteomics identified PPAR regulated proteins in the hypothalamus that are acutely upregulated by GLP-1RA/tesaglitazar. Our data show that GLP-1RA/tesaglitazar improves glucose control with superior efficacy to the GLP-1RA or tesaglitazar alone and suggest that this conjugate might hold therapeutic value to acutely treat hyperglycaemia and insulin resistance.

U2 - 10.1038/s42255-022-00617-6

DO - 10.1038/s42255-022-00617-6

M3 - Journal article

C2 - 35995995

AN - SCOPUS:85136756519

VL - 4

SP - 1071

EP - 1083

JO - Nature Metabolism

JF - Nature Metabolism

SN - 2522-5812

IS - 8

ER -

ID: 319242566