Milk: an epigenetic amplifier of FTO-mediated transcription? Implications for Western diseases

DC FieldValueLanguage
dc.contributor.authorMelnik, Bodo C.
dc.date.accessioned2021-12-23T15:58:38Z-
dc.date.available2021-12-23T15:58:38Z-
dc.date.issued2015
dc.identifier.urihttps://osnascholar.ub.uni-osnabrueck.de/handle/unios/3491-
dc.description.abstractSingle-nucleotide polymorphisms within intron 1 of the FTO (fat mass and obesity-associated) gene are associated with enhanced FTO expression, increased body weight, obesity and type 2 diabetes mellitus (T2DM). The N-6-methyladenosine (m(6)A) demethylase FTO plays a pivotal regulatory role for postnatal growth and energy expenditure. The purpose of this review is to provide translational evidence that links milk signaling with FTO-activated transcription of the milk recipient. FTO-dependent demethylation of m(6)A regulates mRNA splicing required for adipogenesis, increases the stability of mRNAs, and affects microRNA (miRNA) expression and miRNA biosynthesis. FTO senses branched-chain amino acids (BCAAs) and activates the nutrient sensitive kinase mechanistic target of rapamycin complex 1 (mTORC1), which plays a key role in translation. Milk provides abundant BCAAs and glutamine, critical components increasing FTO expression. CpG hypomethylation in the first intron of FTO has recently been associated with T2DM. CpG methylation is generally associated with gene silencing. In contrast, CpG demethylation generally increases transcription. DNA de novo methylation of CpG sites is facilitated by DNA methyltransferases (DNMT) 3A and 3B, whereas DNA maintenance methylation is controlled by DNMT1. MiRNA-29s target all DNMTs and thus reduce DNA CpG methylation. Cow's milk provides substantial amounts of exosomal miRNA-29s that reach the systemic circulation and target mRNAs of the milk recipient. Via DNMT suppression, milk exosomal miRNA-29s may reduce the magnitude of FTO methylation, thereby epigenetically increasing FTO expression in the milk consumer. High lactation performance with increased milk yield has recently been associated with excessive miRNA-29 expression of dairy cow mammary epithelial cells (DCMECs). Notably, the galactopoietic hormone prolactin upregulates the transcription factor STAT3, which induces miRNA-29 expression. In a retrovirus-like manner milk exosomes may transfer DCMEC-derived miRNA-29s and bovine FTO mRNA to the milk consumer amplifying FTO expression. There is compelling evidence that obesity, T2DM, prostate and breast cancer, and neurodegenerative diseases are all associated with increased FTO expression. Maximization of lactation performance by veterinary medicine with enhanced miRNA-29s and FTO expression associated with increased exosomal miRNA-29 and FTO mRNA transfer to the milk consumer may represent key epigenetic mechanisms promoting FTO/mTORC1-mediated diseases of civilization.
dc.language.isoen
dc.publisherBMC
dc.relation.ispartofJOURNAL OF TRANSLATIONAL MEDICINE
dc.subjectALPHA-KETOACID DEHYDROGENASE
dc.subjectBODY-MASS INDEX
dc.subjectCancer
dc.subjectDEPENDENT DNA-POLYMERASE
dc.subjectDiabetes
dc.subjectDNMT
dc.subjectEpigenetics
dc.subjectFTO
dc.subjectGENOME-WIDE ASSOCIATION
dc.subjectIMMUNE-RELATED MICRORNAS
dc.subjectMedicine, Research & Experimental
dc.subjectMilk
dc.subjectmiRNA-29
dc.subjectMTOR COMPLEX 1
dc.subjectmTORC1
dc.subjectN-6-Methyladenosine
dc.subjectObesity
dc.subjectOBESITY-ASSOCIATED GENE
dc.subjectPROLACTIN-INDUCED PROTEIN
dc.subjectPROSTATE-CANCER RISK
dc.subjectResearch & Experimental Medicine
dc.subjectTranscriptome
dc.subjectTRANSFER-RNA SYNTHETASE
dc.titleMilk: an epigenetic amplifier of FTO-mediated transcription? Implications for Western diseases
dc.typereview
dc.identifier.doi10.1186/s12967-015-0746-z
dc.identifier.isiISI:000367153000001
dc.description.volume13
dc.identifier.eissn14795876
dc.publisher.placeCAMPUS, 4 CRINAN ST, LONDON N1 9XW, ENGLAND
dcterms.isPartOf.abbreviationJ. Transl. Med.
dcterms.oaStatusGreen Published, gold
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