内科学
内分泌学
法尼甾体X受体
脂肪细胞
白色脂肪组织
胰岛素抵抗
脂肪组织
葡萄糖稳态
生物
炎症
胰岛素
医学
核受体
转录因子
生物化学
基因
作者
Hélène Dehondt,A Marino,Laura Butruille,Denis A. Mogilenko,Arielle C. Nzoussi Loubota,Oscar Chávez-Talavera,Emilie Dorchies,Emmanuelle Vallez,Joel T. Haas,Bruno Derudas,Antonino Bongiovanni,Meryem Tardivel,Folkert Kuipers,Philippe Lefèbvre,Sophie Lestavel,Anne Tailleux,David Dombrowicz,Sandrine Caron,Bart Staels
标识
DOI:10.1016/j.molmet.2023.101686
摘要
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.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.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.These results indicate a role for the adipocyte FXR-GSTA4 axis in controlling HFD-induced inflammation and systemic glucose homeostasis.
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