GQ-130, a novel analogue of thiazolidinedione, improves obesity-induced metabolic alterations in rats: evidence for the involvement of PPARβ/δ pathway.

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 PPAR beta/delta transactivation. Potential binding and transactivation of PPAR alpha, PPAR beta/delta or PPAR gamma 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 PPAR gamma but was able to activate PPAR beta/delta by 153.9 folds in comparison with control values (DMSO). Surprisingly, ANS fluorescence quenching assay reveals that GQ-130 does not bind directly to PPAR beta/delta binding site, a finding that was further corroborated by thermal shift assay which evaluates the thermal stability of PPAR beta/delta 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 PPAR beta/delta activation.