miR-210-3pPromotes Obesity-Induced Adipose Tissue Inflammation and Insulin Resistance by Targeting SOCS1-Mediated NF-κB Pathway

• DOI: 10.2337/db22-0284
• Publication Date: 2022-12-05T16:16:27Z
• Authors: Debarun Patra; Soumyajit Roy; Leena Arora; Shaheen Wasil Kabeer; Satpal Singh; Upalabdha Dey; Dipanjan Banerjee; Archana Sinha; Suman Dasgupta; Kulbhushan Tikoo; Aditya Kumar; Durba Pal
• Keywords: Inflammation; 0301 basic medicine; 2. Zero hunger; NF-kappa B; 3. Good health; Mice; MicroRNAs; 03 medical and health sciences; Suppressor of Cytokine Signaling 1 Protein; 0302 clinical medicine; Diabetes Mellitus, Type 2; Adipose Tissue; Animals; Cytokines; Obesity; Insulin Resistance; Hypoxia

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 (H + L) surge in fostering adipose tissue macrophage (ATM) inflammation and polarization. ATenv significantly increased miR-210-3p expression in ATMs which promotes NF-κB activation–dependent proinflammatory cytokine expression along with the downregulation of anti-inflammatory cytokine expression. Interestingly, delivery of miR-210-3p mimic significantly increased macrophage inflammation in the absence of H + L co-stimulation, while miR-210-3p inhibitor notably compromised H + L–induced macrophage inflammation through increased production of suppressor of cytokine signaling 1 (SOCS1), a negative regulator of the NF-κB inflammatory signaling pathway. Mechanistically, miR-210 directly binds to the 3′-UTR of SOCS1 mRNA and silences its expression, thus preventing proteasomal degradation of NF-κB 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.