TY - JOUR
T1 - Adipocyte-specific FXR-deficiency protects adipose tissue from oxidative stress and insulin resistance and improves glucose homeostasis
AU - Dehondt, Hélène
AU - Marino, Arianna
AU - Butruille, Laura
AU - Mogilenko, Denis A.
AU - Nzoussi Loubota, Arielle C.
AU - Chávez-Talavera, Oscar
AU - Dorchies, Emilie
AU - Vallez, Emmanuelle
AU - Haas, Joel
AU - Derudas, Bruno
AU - Bongiovanni, Antonino
AU - Tardivel, Meryem
AU - Kuipers, Folkert
AU - Lefebvre, Philippe
AU - Lestavel, Sophie
AU - Tailleux, Anne
AU - Dombrowicz, David
AU - Caron, Sandrine
AU - Staels, Bart
N1 - Funding Information:
The authors’ research work was supported by grants from Agence Nationale pour la Recherche (ANR FXRen and ANR-10-LABX-46) and the European Union (FP6 Hepadip FP6-018734; FP7 Resolve FP7-305707). B.S. is a recipient of an Advanced ERC Grant (694717).
Funding Information:
The authors’ research work was supported by grants from Agence Nationale pour la Recherche (ANR FXRen and ANR-10-LABX-46) and the European Union (FP6 Hepadip FP6-018734; FP7 Resolve FP7-305707). B.S. is a recipient of an Advanced ERC Grant (694717).
Publisher Copyright:
© 2023 The Author(s)
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
KW - Glucose metabolism
KW - Inflammation
KW - Nuclear receptor FXR
KW - Oxidative stress
KW - White adipose tissue
U2 - 10.1016/j.molmet.2023.101686
DO - 10.1016/j.molmet.2023.101686
M3 - Article
C2 - 36746333
AN - SCOPUS:85147920701
SN - 2212-8778
VL - 69
JO - Molecular metabolism
JF - Molecular metabolism
M1 - 101686
ER -