Molecular Mechanism Of MiR-103 In Regulating Adipocyte Development By Binding Circrnas

miR-103 is a key member of miRNA families,which function by targeting downstream mRNAs.miR-103 was originally identified from Hela cells in 2002 by Mourelatos et al.In recent years,researches on miR-103 had received increasing attention.Studies had found that miR-103 regulates cell fission,metabolism and stress response.miR-103 is abundant in adipose tissue.It had been reported that miR-103 promoted adipocytes differentiation and impairs insulin resistance.circRNAs are a circular non-coding RNA linked by a 3'-5' covalent bond.circ RNAs contain rich miRNA binding sites,and they sponge miRNAs and relieve the inhibitions of miRNAs target genes,thereby regulating body development.However,it's not fully understood the effects of miR-103 in adipose tissue.In this study,miR-103 was regarded as a research center to search for the downstream targeted mRNAs and the upstream circRNAs,examine their effects on adipocytes apoptosis,inflammation and browning,and explore the molecular mechanisms.Our study provided therapeutic targets for obesity and obesity-related metabolic diseases.The main results include:1.miR-103 promoted endoplasmic reticulum(ER)stress mediated apoptosis by targeting Wnt3a/?-catenin/ATF6 in preadipocytes.(1)miR-103 was up-regulated in preadipocytes apoptosis models and closely related to ER stress;(2)Preadipocytes were treated with miR-103 mimics/inhibitor.The results revealed miR-103 promoted preadipocytes apoptosis and ER stress;(3)Wnt3a is a target genes of miR-103,and miR-103 promoted preadipocytes apoptosis and ER stress by targeting Wnt3a;(4)miR-103 promoted preadipocytes apoptosis and ER stress via Inhibiting Wnt/?-catenin signaling pathway;(5)ATF6 is a downstream target of the Wnt/?-catenin signaling pathway,and Bcl2 transcriptional regulates ATF6,making that preadipocytes apoptosis induced by miR-103 was mediated by ER stress.2.circARF3 relieved mitophagy-mediated inflammation by targeting miR-103/TRAF3 in mice adipose tissue.(1)miR-103 was upregulated in inflammation models.miR-103 overexpression in adipocytes and mice adipose tissue promoted adipose inflammation and inhibited mitophagy;(2)EtBr treatment,which promoted mitophagy,relieved miR-103-induced adipocytes inflammation.CsA,a mitophagy inhibitor,worsened miR-103-induced adipocytes inflammation,demonstrating that miR-103 promoted adipocytes inflammation through inhibiting mitophagy;(3)TRAF3 is a downstream targets of miR-103,and miR-103 promoted mitophagy mediated adipocytes inflammation by targeting TRAF3;(4)circARF3 acted as a miR-103 sponge to relieve mitophagy mediated adipocytes inflammation;(5)circARF3 relieved mitophagy mediated adipocyte inflammation by inhibiting NF-?B signaling pathway.3.circNrxn2-miR103-FGF10 promoted white adipose tissue(WAT)browning by facilitating M2 Adipose Tissue Macrophages(ATMs)polarization.(1)circNrxn2 sponges miR-103,and miR-103 targets FGF10,thus constitute a regulatory loop in adipose tissue;(2)In adipocytes and mice adipose tissue,overexpressing of circNrxn2 promoted the WAT browning,and miR-103 or siFGF10 addition inhibited it;(3)circNrxn2 overexpression promoted macrophages and ATMs polarization,and miR-103 or siFGF10 addition reversed the effects;(4)Clodronate treatment inhibited WAT browning which was induced by circNrxn2 In vivo.Simulation co-culture of macrophages and adipocytes results showed circNrxn2 treated promoted adipocytes browning,and miR-103 or siFGF10 addition reversed these effects.These data proved that circNrxn2 promoted WAT browning by facilitating M2 ATMs polarization.In summary,miR-103 is an important miRNA that regulates adipose tissue functions.In this study,we searched the circRNAs and mRNAs that interacted with miR-103,and detected their roles in apoptosis,inflammation and browning of adipocytes.This study provides a molecular basis for the study of non-coding RNAs regulatory networks in adipose tissue and offers an important reference for obesity and obesity associated metabolic disorders.