Adipocyte-specific FXR-deficiency protects adipose tissue from oxidative stress and insulin resistance and improves glucose homeostasis

Hélène Dehondt, Arianna Marino, Laura Butruille, Denis A. Mogilenko, Arielle C. Nzoussi Loubota, Oscar Chávez-Talavera, Emilie Dorchies, Emmanuelle Vallez, Joel Haas, Bruno Derudas, Antonino Bongiovanni, Meryem Tardivel, Folkert Kuipers, Philippe Lefebvre, Sophie Lestavel, Anne Tailleux, David Dombrowicz, Sandrine Caron*, Bart Staels

*Corresponding author voor dit werk

    OnderzoeksoutputAcademicpeer review

    12 Citaten (Scopus)
    95 Downloads (Pure)

    Samenvatting

    Objective: Obesity is associated with metabolic dysfunction of white adipose tissue (WAT). Activated adipocytes secrete pro-inflammatory cytokines resulting in the recruitment of pro-inflammatory macrophages, which contribute to WAT insulin resistance. The bile acid (BA)-activated nuclear Farnesoid X Receptor (FXR) controls systemic glucose and lipid metabolism. Here, we studied the role of FXR in adipose tissue function. Methods: We first investigated the immune phenotype of epididymal WAT (eWAT) from high fat diet (HFD)-fed whole-body FXR-deficient (FXR−/−) mice by flow cytometry and gene expression analysis. We then generated adipocyte-specific FXR-deficient (Ad-FXR−/−) mice and analyzed systemic and eWAT metabolism and immune phenotype upon HFD feeding. Transcriptomic analysis was done on mature eWAT adipocytes from HFD-fed Ad-FXR−/− mice. Results: eWAT from HFD-fed whole-body FXR−/− and Ad-FXR−/− mice displayed decreased pro-inflammatory macrophage infiltration and inflammation. Ad-FXR−/− mice showed lower blood glucose concentrations, improved systemic glucose tolerance and WAT insulin sensitivity and oxidative stress. Transcriptomic analysis identified Gsta4, a modulator of oxidative stress in WAT, as the most upregulated gene in Ad-FXR−/− mouse adipocytes. Finally, chromatin immunoprecipitation analysis showed that FXR binds the Gsta4 gene promoter. Conclusions: These results indicate a role for the adipocyte FXR-GSTA4 axis in controlling HFD-induced inflammation and systemic glucose homeostasis.

    Originele taal-2English
    Artikelnummer101686
    Aantal pagina's13
    TijdschriftMolecular metabolism
    Volume69
    DOI's
    StatusPublished - mrt.-2023

    Vingerafdruk

    Duik in de onderzoeksthema's van 'Adipocyte-specific FXR-deficiency protects adipose tissue from oxidative stress and insulin resistance and improves glucose homeostasis'. Samen vormen ze een unieke vingerafdruk.

    Citeer dit