Mature adipocytes lack functional Aryl Hydrocarbon Receptor – a study investigating its role in diet-induced obesity in mice

<ns5:p> 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 &amp; Results Using global and adipocyte-specific <ns5:italic>Ahr</ns5:italic> knock-out mouse models, we show that even though global <ns5:italic>Ahr</ns5:italic> deletion has some protective effects from diet-induced obesity and metabolic syndrome, adipocyte-specific deletion of <ns5:italic>Ahr</ns5:italic> has no effect. Furthermore, using a variety of techniques to isolate mature adipocytes, such as flotation, <ns5:italic>in-vitro</ns5:italic> differentiation, and translating ribosome affinity purification, we show no evidence that <ns5:italic>Ahr</ns5:italic> is expressed in mature white adipocytes. Finally, using single-cell RNA sequencing on cells from a <ns5:italic>Cyp1a1</ns5:italic> 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 <ns5:italic>in-vitro</ns5:italic> , we show evidence suggesting that <ns5:italic>Ahr</ns5:italic> may be involved in the control of adipocyte differentiation. Conclusions Our study indicates that <ns5:italic>Ahr</ns5:italic> may play an important role in adipocyte precursors, particularly in the initiation of adipocyte differentiation. We suggest that further investigation into this mechanism may be important to fully elucidate AHR’s effects in obesity. </ns5:p>