Synoptic model of amino acid- and exosomal miR-mediated signaling of milk for the activation of mTORC1-mediated postnatal growth. Whey protein (WP)-derived leucine, isoleucine and valine stimulate insulin synthesis. WP (especially Trp) induces the incretrin GIP, which will further enhance insulin synthesis. Peptide fragments of WP hydrolysis competitively inhibit DPPIV, thereby extending GIP bioactivity. GIP via GIP-R on somatotroph pituitary cells stimulates the synthesis of GH, which up-regulates hepatic IGF-1-synthesis, further augmented by insulin and Trp. Leucine derived from milk proteins increases GLP-1. Increased insulin/IGF-1 signaling via inhibition of TSC2 activates mTORC1. WP-derived leucine via Rag/Ragulator interaction promotes the activation of mTORC1. mTORC1 stimulates lipid synthesis by phosphorylation of lipin1 and activation of S6K1, which enhance lipogenesis. Milk is hypothesized to operate as an exosome-driven miR transfection system of metabolism to increase mTORC1-driven anabolic reactions of the milk recipient. Especially, milk exosomes containing miR-21 may enhance mTORC1 signaling by suppression of tumor suppressor proteins PTEN, Sprouty and PDCD4 (see list of abbreviations).
Melnik et al. Nutrition Journal 2013 12:103 doi:10.1186/1475-2891-12-103