Activation of the aryl hydrocarbon receptor in mature adipocytes does not impact diet-induced obesity in mice [RNA-seq]
Background: Despite rising awareness and advances in the field, the prevalence of obesity continues to increase. Current weight-loss treatments are often ineffective long-term, and some are associated with serious side effects. For this reason, alternative pathways need to be explored in order to identify novel pharmacological targets for the treatment of obesity.  In this study, we aim to investigate the role of the ligand-activated transcription factor, aryl hydrocarbon receptor (AHR), in the development of obesity and metabolic syndrome. Methods & Results: Using global and adipocyte-specific Ahr knock-out mouse models, we show that even though global Ahr deletion has some protective effects from diet-induced obesity and metabolic syndrome, adipocyte-specific deletion of Ahr has no effect. Furthermore, using a variety of techniques to isolate mature adipocytes, such as flotation, in-vitro differentiation, and translating ribosome affinity purification, we show no evidence that Ahr is expressed in mature white adipocytes. Finally, using single-cell RNA sequencing on cells from a Cyp1a1 fate reporter mouse line, in which eYFP can be used as a readout of AHR activation, we show that the AHR pathway is active in adipose stem and precursor cells. Using bulk RNA sequencing on adipocyte precursors stimulated with an AHR ligand in-vitro, we show evidence suggesting that Ahr may be involved in the control of adipocyte differentiation. Conclusions: Our study indicates that Ahr may play an important role in adipocyte precursors, particularly in the initiation of adipocyte differentiation. We suggest that these results warrant further research in this mechanism in the context of obesity. Overall design: Cultured mesenchimal lineage cells from the stromovascular fraction of mouse perigonadal white adipose tissue. Cells were treated with FICZ or vehicle control for 6hr in vitro.