Adipose Rheb deficiency promotes miR-182-5p expression via the cAMP/PPARg signaling 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/ PPARg signaling pathway. In addition, treatment of white adipocytes with pioglitazone, a PPARg agonist, dramatically upregulates miR-182-5p levels. Our study reveals a unique mechanism by which Rheb reg-ulates 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. Copyright (c) 2022, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.