Weight loss for the treatment of obesity requires skewing the balance between energy intake and expenditure. Existing anti-obesity pharmacotherapies drive this through a reduction in intake. An alternative approach to pharmacological weight loss could instead target expenditure. Increasing energy expenditure in the adipose tissue through the upregulation of thermogenic beige fat holds promise as a targeted treatment strategy. Cold exposure is a strong natural stimulus for beige fat activation, mediated by β-adrenergic signalling that directly induces thermogenesis in adipocytes. Additionally, adipose-resident eosinophils are essential for harnessing the full thermogenic capacity of the adipose tissue during cold exposure, seemingly by secretion of pro-beiging factors we term eosinokines. Currently, it is not well understood how adipose eosinophils become activated to promote beiging.
We aimed to determine whether β-adrenergic signalling during cold exposure drives adipose eosinophils to secrete pro-beiging eosinokines. We have found that adipose eosinophils highly express the β2-adrenergic receptor (ADRB2). Using human EoL-1 cells as a model, we have shown that eosinophils are responsive to β-adrenergic signalling via this receptor. Furthermore, we have generated an ADRB2 knock-out cell line using CRISPR/Cas9 genome editing to assess the importance of this receptor during cold signalling and adipose eosinophil activation. We have used RNA-sequencing to examine differential gene expression between cells unstimulated or stimulated with a β-adrenergic agonist, as well as wildtype and knock-out cell populations. This has shown that eosinophils’ response to β-adrenergic signalling is largely mediated by ADRB2. Additionally, this dataset is enabling the identification of candidate eosinokines, which will be screened using established in vitro beiging assays. Promising candidates will be further assessed in vivo.
Understanding the mechanism of eosinophil activation following a cold stimulus and how this promotes beiging in the adipose tissue may reveal novel targets or pathways for the development of anti-obesity pharmacotherapies that drive energy expenditure.