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MicroRNAs expressed in adipocytes are involved in transcriptional regulation of target mRNAs in obesity, but miRNAs critically involved in this process is not well characterized. Here, we identified upregulation of miR-221-3p and miR-222-3p in the white adipose tissues in C57BL/6 mice fed with high fat-high sucrose (HFHS) chow by RNA sequencing.  Mir221  and  Mir222  are paralogous genes and share the common seed sequence and  Mir221/222AdipoKO  mice fed with HFHS chow demonstrated resistance to the development of obesity compared with  Mir221/222 flox/y  .  Ddit4  is a direct target of  Mir221  and  Mir222 , and the upregulation of  Ddit4  in  Mir221/222AdipoKO  was associated with the suppression of TSC2 (tuberous sclerosis complex 2)/mammalian target of rapamycin complex 1 (mTORC1)/S6K (ribosomal protein S6 kinase) pathway. The overexpression of  miR-222-3p linked to enhanced adipogenesis, and it may be a potential candidate for miRNA-based therapy.

Adipocyte-Specific Inhibition of Mir221/222 Ameliorates Diet-Induced Obesity Through Targeting Ddit4