Milk is not just food but most likely a genetic transfection system activating mTORC1 signaling for postnatal growth

Abstract

Milk has been recognized to represent a functionally active nutrient system promoting neonatal growth of mammals. Cell growth is regulated by the nutrient-sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1). There is still a lack of information on the mechanisms of mTORC1 up-regulation by milk consumption. This review presents milk as a materno-neonatal relay system functioning by transfer of preferential amino acids, which increase plasma levels of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), insulin, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) for mTORC1 activation. Importantly, milk exosomes, which regularly contain microRNA-21, most likely represent a genetic transfection system enhancing mTORC1-driven metabolic processes. Whereas human breast milk is the ideal food for infants allowing appropriate postnatal growth and species-specific metabolic programming, persistent high milk signaling during adolescence and adulthood by continued cow´s milk consumption may promote mTORC1-driven diseases of civilization.

Figure 1

Mean (± SD) postprandial leucine, tryptophan and insulin serum levels and postprandial GIP plasma levels after a 30 g whey protein drink (WD) of 10 healthy volunteers (8 males, 2 females, mean age 25.6 ± 6.0 yrs).

Figure 2

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).