Diet during Pregnancy is Implicated in the Regulation of Hypothalamic RNA Methylation and Risk of Obesity in Offspring

Kaspi, Antony; Khurana, Ishant; Ziemann, Mark; Connor, Timothy; Spolding, Briana; Zimmet, Paul; Walder, Ken; El‐Osta, Assam

doi:10.1002/mnfr.201800134

Cited by 12 publications

(10 citation statements)

References 42 publications

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“…It is generally believed that when m 6 A RNA is methylated, demethylase FTO will play a role after methylated transferase ( Mathiyalagan et al, 2019 ). Recent studies have correlated changes in m 6 A levels with human reproductive disorders ( Kaspi et al, 2018 ). Given that the m 6 A modification occurs at the 3’-UTR near the transcription termination site ( Lan et al, 2019 ), accumulation of hypermethylated mRNAs due to aberrant FTO expression during SA likely affects the expression levels of crucial genes.…”

Section: Discussionmentioning

confidence: 99%

RNA Demethylase FTO Mediated RNA m6A Modification Is Involved in Maintaining Maternal-Fetal Interface in Spontaneous Abortion

Qiu

Zhou

et al. 2021

Front. Cell Dev. Biol.

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The N6-methyladenosine (m6A) RNA modification regulates the expression of genes associated with various biological and pathological processes, including spontaneous abortion (SA). The aim of this study was to determine the role of the m6A demethylase fat mass and obesity (FTO)- associated protein in SA. The FTO,IGF2BP1 and IGF2BP2 mRNA levels were significantly lower in the chorionic villi obtained from spontaneously aborted pregnancies compared to that of normal pregnancies, while the expression levels of METTL3 and WTAP were significantly elevated. However, ALKBH5, YTHDF2, and IGF2BP3 were elevated with no statistical significance between groups. In addition, MDA was elevated and SOD levels were decreased in the villi tissues of the SA group compared to the normal group, which was indicative of placental oxidative stress in the former. Furthermore, the expression of FTO and HLA-G were significantly decreased in the trophoblasts of the SA patients compared to that of normal pregnant women, while that of m6A was markedly higher in the former. In addition, the HLA-G and VEGFR mRNA levels were downregulated in the SA versus the control group, and that of MMP2, MMP7, MMP9 and VEGFA were upregulated. Finally, The RIP assay showed significantly decreased levels of FTO-bound HLA-G, VEGFR and MMP9 RNA in SA patients (P < 0.05), which corresponded to an increase in transcripts enriched with the m6A antibody (P < 0.05). However, compared with normal pregnant women, the levels of HLA-G, VEGFA, VEGFR, and MMP2 mRNA bound by YTHDF2 were significantly decreased in SA patients. Compared to the normal pregnant women, both FTO- and m6A-bound MMP7 were significantly increased in SA patients (P < 0.05), but YTHDF2 almost unbound to MMP7 mRNA. In summary, the downregulation of FTO in the chorionic villi disrupts immune tolerance and angiogenesis at the maternal-fetal interface, resulting in aberrant methylation and oxidative stress that eventually leads to SA.

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Section: Discussionmentioning

confidence: 99%

RNA Demethylase FTO Mediated RNA m6A Modification Is Involved in Maintaining Maternal-Fetal Interface in Spontaneous Abortion

Qiu

Zhou

et al. 2021

Front. Cell Dev. Biol.

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“…Recently, it was reported that m 6 A RNA methylation even played an essential role in fetal developmental programming (Kaspi et al 2018). Maternal diet can regulate fetal programming through m 6 A RNA methylation.…”

Section: Discussionmentioning

confidence: 99%

Maternal heat stress regulates the early fat deposition partly through modification of m6A RNA methylation in neonatal piglets

Heng

Tian

Zhang

et al. 2019

Cell Stress and Chaperones

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It is known that heat stress induces various physiological challenges in livestock production including changes in lipid metabolism. However, the molecular mechanism of how heat stress regulates lipid metabolism at the mRNA level is still largely unknown. N 6 -methyl-adenosine (m 6 A) is the most common and abundant modification on RNA molecules present in eukaryotes, which affects almost all aspects of RNA metabolism and thus gives us the hint that it may participate in changes of gene expression of lipid metabolism during heat stress. Therefore, the purpose of the present study was to investigate the effect of heat stress on fat metabolism in 21-day Large White × Landrace piglets from sows challenged by heat stress from day 85 of gestation until day 21 of lactation. We measured the expression of heat shock proteins (HSPs), genes associated with lipid metabolism, m 6 A-related enzymes, and m 6 A levels in abdominal fat and liver of offspring piglets. Our results showed that high ambient temperature significantly increased the expression of HSP70 (P < 0.01) in both liver and abdominal fat and upregulated HSP27 in the liver (P < 0.05). Additionally, genes involved in fat metabolism such as ACACA, FASN, DGAT1, PPAR-γ, SREBP-1c, and FABP4 were upregulated in abdominal fat in the experimental group challenged by high ambient temperature. In the liver, heat stress increased the mRNA expression of DGAT1, SREBP-1c, and CD36 and decreased ATGL and CPT1A expression (P < 0.05). The m 6 A level was higher in the heat stress group compared with the control group in the liver and abdominal fat of offspring piglets (P < 0.01). Notably, heat stress also increased gene expression of METTL14, WTAP, FTO, and YTHDF2 (P < 0.05) in both abdominal fat and liver. The protein abundances of METTL3, METTL14, and FTO were upregulated after heat stress in abdominal fat (P < 0.05) but not in the liver. Although there was no difference in the protein abundance of YTHDF2 in abdominal fat, its level was increased in the liver (P < 0.05). In conclusion, our findings showed that heat stress increased expression of genes involved in lipogenesis, which provided scientific evidence to the observation of increased fatness in pigs under heat stress. We also demonstrated a possible mechanism that m 6 A RNA modification may be associated with these changes in lipid metabolism upon heat stress.

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“…Although the Metabolic Syndrome, including type 2 diabetes mellitus (T2DM) and depression, is associated with disturbances of circadian rhythms, most studies of these diseases use nocturnal mice and rats whilst modelling diurnal humans. A diurnal, well-accepted and extensively studied model for T2DM [48,51,[100][101][102][103] is the sand rat, (Psammomys obesus). When the sand rats are fed normal rodents chow they develop T2DM characterized by enhanced insulin secretion and insulin resistance at the early stages and insulin deficiency at an advanced stage [100,102].…”

Section: Boxmentioning

confidence: 99%

“…It is noteworthy that these epigenetic modifications can be transmitted intergenerationally. For example, studies in Psammomys obesus have shown parental diet regulates DNA and RNA methylation and the expression of genes implicated with the increased risk of obesity in offspring .…”

Section: Introductionmentioning

confidence: 99%

The Circadian Syndrome: is the Metabolic Syndrome and much more!

Zimmet

Alberti

Stern³

et al. 2019

J Intern Med

226

192

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The Metabolic Syndrome is a cluster of cardio‐metabolic risk factors and comorbidities conveying high risk of both cardiovascular disease and type 2 diabetes. It is responsible for huge socio‐economic costs with its resulting morbidity and mortality in most countries. The underlying aetiology of this clustering has been the subject of much debate. More recently, significant interest has focussed on the involvement of the circadian system, a major regulator of almost every aspect of human health and metabolism. The Circadian Syndrome has now been implicated in several chronic diseases including type 2 diabetes and cardiovascular disease. There is now increasing evidence connecting disturbances in circadian rhythm with not only the key components of the Metabolic Syndrome but also its main comorbidities including sleep disturbances, depression, steatohepatitis and cognitive dysfunction. Based on this, we now propose that circadian disruption may be an important underlying aetiological factor for the Metabolic Syndrome and we suggest that it be renamed the ‘Circadian Syndrome’. With the increased recognition of the ‘Circadian Syndrome’, circadian medicine, through the timing of exercise, light exposure, food consumption, dispensing of medications and sleep, is likely to play a much greater role in the maintenance of both individual and population health in the future.

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Diet during Pregnancy is Implicated in the Regulation of Hypothalamic RNA Methylation and Risk of Obesity in Offspring

Abstract: We propose the regulatory capacity is now broadened for the first time to include m6A in developmental programming and obesity phenotype.

Cited by 12 publications

References 42 publications

RNA Demethylase FTO Mediated RNA m6A Modification Is Involved in Maintaining Maternal-Fetal Interface in Spontaneous Abortion

RNA Demethylase FTO Mediated RNA m6A Modification Is Involved in Maintaining Maternal-Fetal Interface in Spontaneous Abortion

Maternal heat stress regulates the early fat deposition partly through modification of m6A RNA methylation in neonatal piglets

The Circadian Syndrome: is the Metabolic Syndrome and much more!

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