Sulfonylureas exert antidiabetic action on adipocytes by inhibition of PPARγ serine 273 phosphorylation

• DOI: 10.1016/j.molmet.2024.101956
• Publication Date: 2024-05-10T16:32:39Z
• Authors: Bodo Haas; Moritz David Seba...; Alexander Voltz; Matthias Vogel; Julia Walther; Arijit Biswas; Daniela Hass; Alexander Pfeifer
• Keywords: Rosiglitazone; Glimepiride

Sulfonylureas (SUs) are still among the mostly prescribed antidiabetic drugs with an established mode of action: release insulin from pancreatic β-cells. In addition, effects SUs on adipocytes by activation nuclear receptor peroxisome proliferator-activated γ (PPARγ) have been described, which might explain their insulin-sensitizing potential observed in patients. However, there is a discrepancy between impact action and rather moderate vitro effect PPARγ transcriptional activity. Recent studies shown that some ligands can improve sensitivity blocking Ser-273 phosphorylation without having full agonist It unknown if elicit inhibition phosphorylation. Here, we investigated binding to interfere determined actions primary human white vivo high-fat diet (HFD) obese mice. Primary preadipocytes were differentiated presence glibenclamide, glimepiride rosiglitazone SR1664 compare phosphorylation, glucose uptake adipokine expression. Transcriptional activity at was luciferase assays, quantification Western blotting CDK5 kinase assays. silico modelling performed gain insight into characteristics PPARγ. HFD mice administered for 6 days. adipose tissue (WAT), body composition, tolerance, adipocyte morphology expression levels genes involved WAT brown (BAT) evaluated. inhibit exhibit positive profile, characterized up regulation down resistance-inducing adipokines. We demonstrate directly bind assays similar extend as SR1664. reduce comparable gene rosiglitazone. BAT increase UCP1 lipid droplets sizes. Our findings indicate part extra-pancreatic probably mediated via interference than classical agonistic clinical concentrations.