Adipose Rheb deficiency promotes miR-182-5p expression via the cAMP/PPARγsignaling pathway

Dysregulation of microRNAs(miRNAs)in adipocytes plays a critical role in the pathogenesis of obesity.However,the signaling mechanisms regulating miRNAs production in adipose tissue remain largely unclear.Here,we show that adipose tissue-specific knockout of Ras homolog enriched in brain(Rheb),a direct upstream activator of mTOR,increases miR-182-5p level in mouse subcutaneous white adipose tissues.Interestingly,the inhibition of mTOR signaling by rapamycin has no effect on miR-182-5p level in primary subcutaneous white adipocytes,suggesting the presence of a mTOR-independent mechanism regulating Rheb-mediated miR-182-5p expression.Consistent with this view,Rheb-ablation activates the cAMP/PPARγsignaling pathway.In addition,treatment of white adipocytes with pioglitazone,a PPARγagonist,dramatically upregulates miR-182-5p levels.Our study reveals a unique mechanism by which Rheb regulates miR-182-5p in adipocytes.Given that increasing miR-182-5p in adipose tissue promotes beige fat development,our study also suggests a unique mechanism by which Rheb promotes thermogenesis and energy expenditure.