biostudies-literatureDehondt HEuropean Research CouncilAgence Nationale de la RechercheSeventh Framework ProgrammeEuropean CommissionEuropean Commission Sixth Framework Programme101686https://www.ebi.ac.uk/biostudies/studies/S-EPMC9958065biostudies-literatureUnknown69<h4>Objective</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>These results indicate a role for the adipocyte FXR-GSTA4 axis in controlling HFD-induced inflammation and systemic glucose homeostasis.Molecular metabolismAdipocyte-specific FXR-deficiency protects adipose tissue from oxidative stress and insulin resistance and improves glucose homeostasis.PMC9958065ANR-10-LABX-46FP7-305707FP6 Hepadip FP6-018734694717Nzoussi Loubota ACCaron SLefebvre PBongiovanni AChavez-Talavera OVallez EDehondt HLestavel SStaels BHaas JDerudas BButruille LMarino ATardivel MTailleux ADombrowicz DDorchies EKuipers FMogilenko DAfalseAdipocyte-specific FXR-deficiency protects adipose tissue from oxidative stress and insulin resistance and improves glucose homeostasis.<h4>Objective</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>These results indicate a role for the adipocyte FXR-GSTA4 axis in controlling HFD-induced inflammation and systemic glucose homeostasis.2023-01-01T00:00:00Z2023 Feb2025-05-29T22:24:17.792Z2025-04-03T22:08:57.795ZS-EPMC99580653674633310.1016/j.molmet.2023.101686