Deleting adipose FXR exacerbates metabolic defects and induces endocannabinoid lipid, 2-oleoyl glycerol, in obesity.

Abstract

The nutrient sensor farnesoid X receptor (FXR) transcriptionally regulates whole-body lipid and glucose homeostasis. Several studies examined targeting FXR as a modality to treat obesity with varying conflicting results, emphasizing the need to study tissue-specific roles of FXR. We show that deletion of adipocyte Fxr results in increased adipocyte hypertrophy and suppression of several metabolic genes that is akin to some of the changes noted in high fat diet (HFD)-fed control mice. Moreover, upon high fat diet challenge, these effects are worsened in adipocyte-specific Fxr knockout (Ad-FxrKO) mice. We uncover that FXR regulates fatty acid amide hydrolase (Faah) such that its deletion lowers Faah expression. Conversely, FXR activation by its ligand, chenodeoxycholic acid, induces Faah transcription. Notably, HFD results in the reduction of adipose Faah expression in control mice and that either Faah inhibition or deletion leads to obesity. We report that the adipocyte FXR-Faah axis controls local 2-oleoyl glycerol and systemic N-acyl ethanolamine levels, which is associated with obesity-related phenotypes. Taken together, these findings show that loss of adipose FXR may contribute to the pathogenesis of obesity and subsequent metabolic defects.