A novel small molecule A2A adenosine receptor agonist, indirubin-3′-monoxime, alleviates lipid-induced inflammation and insulin resistance in 3T3-L1 adipocytes. Issue 16 (30th August 2019)

• Record Type: Journal Article
• Authors: Choudhary, Saynaz A.; Bora, Nikita; Banerjee, Dipanjan; Arora, Leena; Das, Anindhya Sundar; Yadav, Rakesh; Klotz, Karl-Norbert; Pal, Durba; Jha, Anupam Nath; Dasgupta, Suman
• Is Part Of: Biochemical journal. Volume 476:Issue 16(2019)
• Page Start: 2371
• Page End: 2391
• Publication Date: 2019-08-30
• Subjects: A2AAR activation -- adipocyte inflammation -- indirubin-3′-monoxime -- insulin resistance -- saturated free fatty acid; Biochemistry -- Periodicals; 572
• DOI: 10.1042/BCJ20190251
• Languages: English
• ISSNs: 0264-6021

Abstract

Abstract : Saturated free fatty acid-induced adipocyte inflammation plays a pivotal role in implementing insulin resistance and type 2 diabetes. Recent reports suggest A2A adenosine receptor (A2A AR) could be an attractive choice to counteract adipocyte inflammation and insulin resistance. Thus, an effective A2A 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 A2A 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 A2A 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 A2A AR antagonist, SCH 58261 or siRNA mediated knockdown of A2A 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.