A novel small molecule A adenosine receptor agonist, indirubin-3'-monoxime, alleviates lipid-induced inflammation and insulin resistance in 3T3-L1 adipocytes.

Saturated free fatty acid-induced adipocyte inflammation plays a pivotal role in implementing insulin resistance and type 2 diabetes. Recent reports suggest A adenosine receptor (AAR) could be an attractive choice to counteract adipocyte inflammation and insulin resistance. Thus, an effective AAR agonist devoid of any toxicity is highly appealing. Here, we report that indirubin-3'-monoxime (I3M), a derivative of the bisindole alkaloid indirubin, efficiently binds and activates AAR which leads to the attenuation of lipid-induced adipocyte inflammation and insulin resistance. Using a combination of virtual screening of potential anti-diabetic candidates and study on insulin-resistant model of 3T3-L1 adipocytes, we determined I3M through AAR activation markedly prevents lipid-induced impairment of the insulin signaling pathway in adipocytes without any toxic effects. While I3M restrains lipid-induced adipocyte inflammation by inhibiting NF-κB dependent pro-inflammatory cytokines expression, it also augments cAMP-mediated CREB activation and anti-inflammatory state in adipocytes. However, these attributes were compromised when cells were pretreated with the AAR antagonist, SCH 58261 or siRNA mediated knockdown of AAR. I3M, therefore, could be a valuable option to intervene adipocyte inflammation and thus showing promise for the management of insulin resistance and type 2 diabetes.