Long chain Fatty Acid Receptor 4 (FFAR4) mediates EPA‐miR30b axis activation for promoting brown adipogenesis

Abstract

Emerging evidence suggests that n‐3 poly unsaturated fatty acids (PUFA) promote BAT thermogenesis. However, underlying mechanisms remain elusive. It is well established that free fatty acid receptor 4 (FFAR4) is the n‐3 PUFA receptor, and microRNAs (miR) play a key role for brown adipogenesis. However, regulation of miR by n‐3 PUFA is unknown. Here we hypothesized that activation of FFAR4 by n‐3 PUFA promote brown adipogenesis by modulating miR. To test this hypothesis, brown adipocyte precursor cells were induced to differentiate in the presence and absence of eicosapentaenoic acid (EPA) and investigated the changes of miR during brown adipogenesis. The increase of brown signature genes (e.g., Ucp1, Cidea) by EPA was positively correlated with miR‐30b. Given that miR‐30b increases brown adipogenesis by targeting RIP140, a nuclear receptor corepressor, we further hypothesized that FFAR4 mediates EPA to miR‐30b for brown adipogenesis. Treatment of GW9805, a FFAR4 agonist, recapitulated the increase of brown adipogenic marker Ucp1, Cidea and miR‐30b expression, and the decrease of RIP140. The increase of Ucp1 expression by EPA was dampened by silencing of FFAR4, but augmented by exogenous miR‐30b mimics. Intriguingly, miR‐30b mimic alone was not sufficient to stimulate Ucp1 expression in FFAR4‐silenced cells, suggesting that a signaling interaction between FFAR4 and miR‐30b. Consistently, the blockage of miR‐30b expression by LNA inhibitor remarkably attenuated GW9805‐induced Ucp1 expression. Taken together, our results demonstrate that activation of FFAR4 by n‐3 PUFA increases miR‐30b expression, which further promotes transcriptional activation of brown adipogenesis by targeting transcriptional repressor RIP140.Support or Funding InformationSupported by NIH 1P20GM104320