Fig. 4

Dairy milk exosomes and adipogenesis. miR-21 induces the differentiation of mesenchymal stem cells (MSCs) towards adipocytes via activation of peroxisome proliferator-activated receptor PPARγ (PPARγ). miR-148a directly targets and suppresses the inhibitors of adipogenesis Wingless 1 (WNT1) and WNT10B increasing the expression of PPARγ and CCAAT/enhancer binding protein α (C/EBPα). miR-148a-mediated suppression of DNMT1 via promoter hypomethylation increases the expression of fat mass and obesity-associated gene (FTO), PPARγ and sterol regulatory element binding-transcription factor 1 (SREBF1). The mRNA demethylase FTO removes a m⁶A mark on RUNX1T1 mRNA generating its short splice variant RUNX1T1-S, which relieves RUNX1T1-mediated inhibition of C/EBPβ. Activated C/EBPβ activates the key adipogenic transcription factors C/EBPα and PPARγ. miR-148a targets PRKAA1, the catalytic α-unit of AMP-activated protein kinase (AMPK), the key negative regulator of mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 activation enhances the expression of PPARγ and SREBF1, key lipogenic transcription factors. In addition, miR-148a targets salt-inducible kinase 1 (SIK1), and thereby relieves its inhibitory action on SREBF1. Milk exosome-derived miR-148a is thus an adipogenesis promoting factor that operates at pivotal regulatory checkpoints enhancing the risk of obesity