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

被引：25

作者：

Quarta, Carmelo ^{[1
,2
,3
]}

Stemmer, Kerstin ^{[1
,2
,4
]}

Novikoff, Aaron ^{[1
,2
,5
]}

Yang, Bin ^{[6
]}

Klingelhuber, Felix ^{[1
,2
]}

Harger, Alex ^{[1
,2
]}

Bakhti, Mostafa ^{[2
,7
]}

Bastidas-Ponce, Aimee ^{[2
,7
]}

Bauge, Eric ^{[8
]}

Campbell, Jonathan E. ^{[9
]}

Capozzi, Megan ^{[9
]}

Clemmensen, Christoffer ^{[10
]}

Collden, Gustav ^{[12
]}

Cota, Perla ^{[2
,7
]}

Douros, Jon ^{[6
]}

Drucker, Daniel J. ^{[11
]}

DuBois, Barent ^{[6
]}

Feuchtinger, Annette ^{[12
]}

Garcia-Caceres, Cristina ^{[1
,2
]}

Grandl, Gerald ^{[1
,2
]}

Hennuyer, Nathalie ^{[8
]}

Herzig, Stephan ^{[2
,13
]}

Hofmann, Susanna M. ^{[2
,7
,14
]}

Knerr, Patrick J. ^{[6
]}

Kulaj, Konxhe ^{[1
,2
]}

Lalloyer, Fanny ^{[8
]}

Lickert, Heiko ^{[2
,7
]}

Liskiewicz, Arek ^{[1
,2
]}

Liskiewicz, Daniela ^{[1
,2
]}

Maity, Gandhari ^{[1
,2
]}

Perez-Tilve, Diego ^{[15
]}

Prakash, Sneha ^{[1
,2
]}

Sanchez-Garrido, Miguel A. ^{[16
]}

Zhang, Qian ^{[1
,2
]}

Staels, Bart ^{[8
]}

Krahmer, Natalie ^{[1
,2
]}

DiMarchi, Richard D. ^{[17
]}

Tschoep, Matthias H. ^{[2
,5
,18
]}

Finan, Brian ^{[6
]}

Mueller, Timo D. ^{[1
,2
]}

机构：

[1] Helmholtz Zentrum Munchen, Inst Diabet & Obes, Neuherberg, Germany

[2] German Ctr Diabet Res DZD, Neuherberg, Germany

[3] Univ Bordeaux, Neuroctr Magendie, INSERM, Bordeaux, France

[4] Univ Augsburg, Inst Theoret Med, Mol Cell Biol, Augsburg, Germany

[5] Tech Univ Munich, Dept Med, Div Metab Dis, Munich, Germany

[6] Novo Nordisk Res Ctr Indianapolis, Indianapolis, IN 46204 USA

[7] Helmholtz Zentrum Munchen, Inst Diabet & Regenerat Res, Neuherberg, Germany

[8] Univ Lille, Inst Pasteur Lille, European Genom Inst Genom, INSERM,CHU Lille, Lille, France

[9] Duke Univ, Dept Med, Div Endocrinol, Durham, NC USA

[10] Univ Copenhagen, Novo Nordisk Fdn, Fac Hlth & Med Sci, Ctr Basic Metab Res, Copenhagen, Denmark

[11] Univ Toronto, Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON, Canada

[12] Helmholtz Zentrum Munchen, Res Unit Analyt Pathol, German Res Ctr Environm Hlth, Neuherberg, Germany

[13] Helmholtz Ctr Munich, Helmholtz Diabet Ctr, Inst Diabet & Canc, Neuherberg, Germany

[14] Ludwig Maximilians Univ Munchen, Med Clin & Polyclin 4, Munich, Germany

[15] Univ Cincinnati, Coll Med, Dept Pharmacol & Syst Physiol, Cincinnati, OH USA

[16] Univ Cordoba, Fac Med, Dept Cell Biol Physiol & Immunol, Cordoba, Spain

[17] Indiana Univ, Dept Chem, Bloomington, IN USA

[18] Helmholtz Zentrum Munchen, Neuherberg, Germany

来源：

NATURE METABOLISM | 2022年 / 4卷 / 08期

基金：

欧洲研究理事会;

关键词：

PPAR-GAMMA; PEPTIDE-1; RECEPTOR; EXPRESSION; GLUCAGON; PREVENTION; REVERSES; SAFETY; TRIAL;

D O I：

10.1038/s42255-022-00617-6

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

A conjugate drug consisting of GLP-1 receptor agonist and the PPARalpha/gamma dual-agonist tesaglitazar is shown to have superior anti-diabetic effects than monotherapy. Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARalpha/gamma) 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 PPARalpha/gamma 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 PPAR gamma-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.

引用

页码：1071 / +

页数：23

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