PMID- 26691922
OWN - NLM
STAT- MEDLINE
DCOM- 20160923
LR  - 20220311
IS  - 1479-5876 (Electronic)
IS  - 1479-5876 (Linking)
VI  - 13
DP  - 2015 Dec 21
TI  - Milk: an epigenetic amplifier of FTO-mediated transcription? Implications for 
      Western diseases.
PG  - 385
LID - 10.1186/s12967-015-0746-z [doi]
LID - 385
AB  - Single-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.
FAU - Melnik, Bodo C
AU  - Melnik BC
AD  - Department of Dermatology, Environmental Medicine and Health Theory, University 
      of Osnabruck, Sedanstrasse 115, 49090, Osnabruck, Germany. melnik@t-online.de.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20151221
PL  - England
TA  - J Transl Med
JT  - Journal of translational medicine
JID - 101190741
RN  - 0 (DNMT3A protein, human)
RN  - 0 (Proteins)
RN  - EC 1.14.11.33 (Alpha-Ketoglutarate-Dependent Dioxygenase FTO)
RN  - EC 1.14.11.33 (FTO protein, human)
RN  - EC 2.1.1.37 (DNA Methyltransferase 3A)
SB  - IM
MH  - Alpha-Ketoglutarate-Dependent Dioxygenase FTO
MH  - Animals
MH  - Cattle
MH  - DNA Methyltransferase 3A
MH  - *Epigenesis, Genetic
MH  - Humans
MH  - *Milk
MH  - Proteins/genetics/*physiology
MH  - *Transcription, Genetic
PMC - PMC4687119
EDAT- 2015/12/23 06:00
MHDA- 2016/09/24 06:00
PMCR- 2015/12/21
CRDT- 2015/12/23 06:00
PHST- 2015/09/14 00:00 [received]
PHST- 2015/12/04 00:00 [accepted]
PHST- 2015/12/23 06:00 [entrez]
PHST- 2015/12/23 06:00 [pubmed]
PHST- 2016/09/24 06:00 [medline]
PHST- 2015/12/21 00:00 [pmc-release]
AID - 10.1186/s12967-015-0746-z [pii]
AID - 746 [pii]
AID - 10.1186/s12967-015-0746-z [doi]
PST - epublish
SO  - J Transl Med. 2015 Dec 21;13:385. doi: 10.1186/s12967-015-0746-z.