Adipocyte RNA-binding protein CELF1 promotes beiging of white fat through stabilizing Dio2 mRNA

RNA-binding proteins (RBPs) regulate diverse cellular processes at post-transcriptional level and play roles in adipocyte development. However, their involvement in the beiging of white fat remains unclear. Here we screened RBPs in inguinal adipose tissues in response to cold stimulation and identified CUG-BP Elav-like family member 1 (CELF1) as a novel regulator that promotes white fat beiging. Adipocyte-specific Celf1 deficiency impairs cold-induced beiging and reduces energy expenditure. Mechanistically, RNA immunoprecipitation RNA-seq (RIP-seq) and functional experiments revealed that CELF1 stabilizes the mRNA of the key thermogenic regulator Dio2 by binding to its 3'UTR, thereby promoting local triiodothyronine (T3) production. CELF1 augments isoproterenol-induced activation of beige adipocytes and increases mitochondria respiration capacity in vitro, and CELF1 overexpression ameliorates diet-induced obesity and metabolic dysfunction. Hence, our study identifies CELF1 as a physiological regulator of metabolic stress in activating thermogenesis and promoting energy expenditure at the post-transcriptional level, suggesting that targeting CELF1 to locally increase the T3 production may serve as a promising therapeutic strategy for combating obesity and related metabolic disorders. To find the target of CELF1 regulating white fat beiging, we performed RNA immunoprecipitation followed by RNA sequencing (RIP-seq) using IgG or CELF1 antibody in differentiated primary adipocytes treated with isoproterenol.