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GQ‐130, a novel analogue of thiazolidinedione, improves obesity‐induced metabolic alterations in rats: Evidence for the involvement of PPARβ/δ pathway
Author(s) -
Silva Odair Alves,
RibeiroFilho Helder Veras,
Avelino Thayna Mendonca,
Tittanegro Thais Helena,
Figueira Ana Carolina Migliorini,
Rabelo Luiza Antas,
Pitta Ivan da Rocha,
Lahlou Saad,
Duarte Glória Pinto
Publication year - 2020
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/1440-1681.13252
Subject(s) - transactivation , endocrinology , medicine , thiazolidinedione , rosiglitazone , peroxisome proliferator activated receptor , insulin resistance , chemistry , antagonist , metabolic syndrome , receptor , biology , insulin , diabetes mellitus , type 2 diabetes , biochemistry , gene expression , gene
The present investigation aimed to characterize the effect of a short‐time treatment with a new thiazolidinedione (TZD) derivative, GQ‐130, on metabolic alterations in rats fed a high‐fat diet (HFD). We investigated whether metabolic alterations induced by GQ‐130 were mediated though a mechanism that involves PPARβ/δ transactivation. Potential binding and transactivation of PPARα, PPARβ/δ or PPARγ by GQ‐130 were examined through cell transactivation, 8‐anilino‐1‐naphthalenesulfonic acid (ANS) fluorescence quenching assays and thermal shift assay. For in vivo experiments, male 8‐week‐old Wistar rats were divided into three groups fed for 6 weeks with: (a) a standard rat chow (14% fat) (control group), (b) a HFD (57.8% fat) alone (HFD group), or (c) a HFD associated with an oral treatment with GQ‐130 (10 mg/kg/d) during the last week (HFD‐GQ group). In 293T cells, unlike rosiglitazone, GQ‐130 did not cause significant transactivation of PPARγ but was able to activate PPARβ/δ by 153.9 folds in comparison with control values (DMSO). Surprisingly, ANS fluorescence quenching assay reveals that GQ‐130 does not bind directly to PPARβ/δ binding site, a finding that was further corroborated by thermal shift assay which evaluates the thermal stability of PPARβ/δ in the presence of GQ‐130. Compared to the control group, rats of the HFD group showed obesity, increased systolic blood pressure (SBP), insulin resistance, impaired glucose intolerance, hyperglycaemia, and dyslipidaemia. GQ‐130 treatment abolished the increased SBP and improved all metabolic dysfunctions observed in the HFD group. Oral treatment with GQ‐130 was effective in improving HFD‐induced metabolic alterations probably through a mechanism that involves PPARβ/δ activation.