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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.

SUBMITTER: Quarta C

PROVIDER: S-EPMC9398908 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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

Quarta Carmelo C Stemmer Kerstin K Novikoff Aaron A Yang Bin B Klingelhuber Felix F Harger Alex A Bakhti Mostafa M Bastidas-Ponce Aimee A Baugé Eric E Campbell Jonathan E JE Capozzi Megan M Clemmensen Christoffer C Collden Gustav G Cota Perla P Douros Jon J Drucker Daniel J DJ DuBois Barent B Feuchtinger Annette A Garcia-Caceres Cristina C Grandl Gerald G Hennuyer Nathalie N Herzig Stephan S Hofmann Susanna M SM Knerr Patrick J PJ Kulaj Konxhe K Lalloyer Fanny F Lickert Heiko H Liskiewicz Arek A Liskiewicz Daniela D Maity Gandhari G Perez-Tilve Diego D Prakash Sneha S Sanchez-Garrido Miguel A MA Zhang Qian Q Staels Bart B Krahmer Natalie N DiMarchi Richard D RD Tschöp Matthias H MH Finan Brian B Müller Timo D TD

Nature metabolism 20220822 8

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/ ...[more]

PMID: 35995995

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Project description:BackgroundThe bile acid (BA) pathway plays a role in regulation of food intake and glucose metabolism, based mainly on findings in animal models. Our aim was to determine whether the BA pathway is altered and correctable in human obesity and diabetes.MethodsWe conducted 3 investigations: 1) BA receptor pathways were studied in NCI-H716 enteroendocrine cell (EEC) line, whole human colonic mucosal tissue and in human colonic EEC isolated by Fluorescence-activated Cell Sorting (ex vivo) from endoscopically-obtained biopsies colon mucosa; 2) We characterized the BA pathway in 307 participants by measuring during fasting and postprandial levels of FGF19, 7αC4 and serum BA; 3) In a placebo-controlled, double-blind, randomised, 28-day trial, we studied the effect of ileo-colonic delivery of conjugated BAs (IC-CBAS) on glucose metabolism, incretins, and lipids, in participants with obesity and diabetes.FindingsHuman colonic GLP-1-producing EECs express TGR5, and upon treatment with bile acids in vitro, human EEC differentially expressed GLP-1 at the protein and mRNA level. In Ussing Chamber, GLP-1 release was stimulated by Taurocholic acid in either the apical or basolateral compartment. FGF19 was decreased in obesity and diabetes compared to controls. When compared to placebo, IC-CBAS significantly decreased postprandial glucose, fructosamine, fasting insulin, fasting LDL, and postprandial FGF19 and increased postprandial GLP-1 and C-peptide. Increase in faecal BA was associated with weight loss and with decreased fructosamine.InterpretationsIn humans, BA signalling machinery is expressed in colonic EECs, deficient in obesity and diabetes, and when stimulated with IC-CBAS, improved glucose homeostasis. ClinicalTrials.gov number, NCT02871882, NCT02033876.FundingResearch support and drug was provided by Satiogen Pharmaceuticals (San Diego, CA). AA, MC, and NFL report grants (AA- C-Sig P30DK84567, K23 DK114460; MC- NIH R01 DK67071; NFL- R01 DK057993) from the NIH. JR was supported by an Early Career Grant from Society for Endocrinology.

Dataset Information

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

Publications

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

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