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

Abstract

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 N6-methyladenosine (m6A) 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 m6A 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.

Impact of FTO SNPs rs9930506 and rs9939609 in Prostate Cancer Severity in a Cohort of Puerto Rican Men

“…We cannot conclude that FTO is responsible for PCa development at early age in PR, but the poor dietary patterns in this population [29,34,55] may influence the FTO effect on obesity and hence in PCa. Studies in other populations with a high European heritage had suggested that consumption of animal protein, milk and dairy protein might increase the PCa risk by hormonal changes [17,56]. …”

“…Milk contains high concentrations of miRNA-29s rich exosomes, which attack DNA methyltransferases, reducing the methylation of FTO CpG islands, stimulating FTO expression [17]. Moreover, in animal model’s overexpression of FTO increases the expression of the RUNX1T1 transcription factor in embryonic fibroblasts stimulating the number of adipocytes [57].…”

“…BMI was calculated according to the World Health Organization and the Centers for Disease Control formula (weight [kg] / height 2 [m 2 ]) [17] and dichotomized in two categories established for statistical purposes: normal/underweight (<25 kg/m 2 ) and overweight/obese (≥ 25 kg/m 2 ).…”

“…Located at the 16q12.2, the FTO gene (HGNC: 24678) codes for a 2-oxoglutarate dependent nucleic acid demethylase implicated in DNA repair, post-translational modification and gene modification [10–14]. Genome-wide association studies (GWAS) have associated FTO with several systemic conditions, lipids’ metabolism [9,12–17], body mass index (BMI) [18–22] and particularly, with obesity [12,19,20]. Some meta-analysis studies have found a relationship among FTO and specific cancer types, including PCa [16,21–23].…”

Milk MicroRNAs in Health and Disease

“…The same way as for other biological fluids, the detection of microRNAs in milk from various species (Melnik, 2015a;Melnik & Schmitz, 2017a) opened the way for prognostic, diagnostic, and functional studies on milk microRNAs (Cui, Zhou, Ross, & Zempleni, 2017;Zempleni et al, 2016), especially because milk is the biological fluid that contains the highest level of microRNAs relative to its volume (Weber et al, 2010).…”