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

• Main Authors: Hélène Dehondt (Author), Arianna Marino (Author), Laura Butruille (Author), Denis A. Mogilenko (Author), Arielle C. Nzoussi Loubota (Author), Oscar Chávez-Talavera (Author), Emilie Dorchies (Author), Emmanuelle Vallez (Author), Joel Haas (Author), Bruno Derudas (Author), Antonino Bongiovanni (Author), Meryem Tardivel (Author), Folkert Kuipers (Author), Philippe Lefebvre (Author), Sophie Lestavel (Author), Anne Tailleux (Author), David Dombrowicz (Author), Sandrine Caron (Author), Bart Staels (Author)
• Format: Book
• Published: Elsevier, 2023-03-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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.

Item Description

2212-8778
10.1016/j.molmet.2023.101686