Predicted model of milk exosome (MEX) miR-mediated suppression of estrogen-related receptor γ (ERRγ). MiR-148a targets ESRRG mRNA and thus impairs ERRγ expression, a negative regulator of glycolysis. MiR-148a and miR-21 promote glycolysis via targeting hypoxia-inducible factor 1α inhibitor (HIF1AN) and von Hippel-Lindau tumor suppressor (VHL), respectively. Both are key negative regulators of hypoxia-inducible factor 1α (HIF-1α), the key transcription factor of glycolysis, which is required for cell proliferation. Functional maturation of β cells after weaning is associated with fading MEX miR signaling, enhancing the expression of ERRγ, the key transcription factor of mitochondrial oxidative phosphorylation. ERRγ may also promote the expression of DNA methyltransferase 3A (DNMT3A), which, via promoter methylation, may suppress “disallowed genes” involved in glycolysis. ERRγ/DNMT3A signaling may stimulate insulin secretion coupled to glucose levels.