A novel small molecule A 2A 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 _2A adenosine receptor (A _2A AR) could be an attractive choice to counteract adipocyte inflammation and insulin resistance. Thus, an effective A _2A AR 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 A _2A AR which leads to the attenuation of lipid-induced adipocyte inflammation and insulin resistance. Using a combination of in silico virtual screening of potential anti-diabetic candidates and in vitro study on insulin-resistant model of 3T3-L1 adipocytes, we determined I3M through A _2A AR 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 A _2A AR antagonist, SCH 58261 or siRNA mediated knockdown of A _2A AR. 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.
(© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)