miR-210-3p promotes obesity-induced adipose tissue inflammation and insulin resistance by targeting SOCS1 mediated NF-κB pathway.

Under the condition of chronic obesity, an increased level of free fatty acids along with low oxygen tension in the adipose tissue creates a pathophysiological adipose tissue microenvironment (ATenv) leading to the impairment of adipocyte function and insulin resistance. Here, we found the synergistic effect of hypoxia and lipid (HL) surge in fostering adipose tissue macrophages(ATMs) inflammation and its polarization. ATenv significantly increased miR-210-3p expression in ATMs which promotes NF-ĸB activation-dependent proinflammatory cytokines expressions along with the downregulation of anti-inflammatory cytokines expression. Interestingly, delivery of miR-210-3p mimic significantly increased the macrophage inflammation in absence of HL co-stimulation; while miR-210-3p inhibitor notably compromised HL-induced macrophage inflammation through increased production of SOCS1 (suppressor of cytokine signalling 1), a negative regulator of NF-ĸB inflammatory signalling pathway. Mechanistically, miR-210 directly binds to 3' UTR of SOCS1 mRNA and silenced its expression and thus preventing proteasomal degradation of NF-ĸB p65. Direct delivery of anti-miR-210-3p LNA in the ATenv markedly rescued mice from obesity-induced adipose tissue inflammation and insulin resistance. Thus, miR-210-3p inhibition in ATMs could serve as a novel therapeutic strategy for managing obesity-induced type 2 diabetes.