Mouse Maternal High-Fat Intake Dynamically Programmed mRNA m6A Modifications in Adipose and Skeletal Muscle Tissues in Offspring

Abstract

Epigenetic mechanisms have an important role in the pre- and peri-conceptional programming by maternal nutrition. Yet, whether or not RNA m6A methylation—an old epigenetic marker receiving increased attention recently—is involved remains an unknown question. In this study, mouse high-fat feeding prior to conception was shown to induce overweight and glucose intolerant dams, which then continued to be exposed to a high-fat diet during gestation and lactation. The dams on a standard diet throughout the whole experiment were used as a control. Results showed that maternal high-fat intake impaired postnatal growth in male offspring, indicated by decreased body weight and Lee’s index at 3, 8 and 15 weeks old, but the percentages of visceral fat and tibialis anterior relative to the whole body weights were significantly increased at eight weeks of age. The maternal high-fat exposure significantly increased mRNA N6-methyladenosine (m6A) levels in visceral fat at three weeks old, combined with downregulated Fat mass and obesity-associated gene (FTO) and upregulated Methyltransferase like 3 (METTL3) transcription, and these changes were reversed at eight weeks of age. In the tibialis anterior muscle, the maternal high-fat diet significantly enhanced m6A modifications at three weeks, and lowered m6A levels at 15 weeks of age. Accordingly, FTO transcription was significantly inhibited at three weeks and stimulated at 15 weeks of age, and METTL3 transcripts were significantly improved at three weeks. Interestingly, both FTO and METTL3 transcription was significantly elevated at eight weeks of age, and yet the m6A modifications remained unchanged. Our study showed that maternal high-fat intake could affect mRNA m6A modifications and its related genes in offspring in a tissue-specific and development-dependent way, and provided an interesting indication of the working of the m6A system during the transmission from maternal nutrition to subsequent generations.

Curcumin Attenuates Lipopolysaccharide‐Induced Hepatic Lipid Metabolism Disorder by Modification of m6A RNA Methylation in Piglets

“…These observations highlight that m 6 A RNA methylation plays an important role in energy and lipid metabolism. Interestingly, mouse maternal high‐fat diet affects mRNA m 6 A modifications and its related genes in the offspring (Li et al, ), suggesting that dietary factors affect the mRNA m 6 A levels. Here we observed that dietary curcumin increased the content of m 6 A and affected its related gene expressions in the liver of piglets.…”

“…In addition, m 6 A RNA methylation affects many biological processes, including cellular differentiation, body mass, and metabolism, indicating its role in obesity, cancer, and other human diseases (Lin, Choe, Du, Triboulet, & Gregory, ; Wang, Li, et al, ; Zheng et al, ). Recent studies have shown that dietary factors affect the RNA m 6 A levels (Li et al, ). However, the effect of curcumin on m 6 A RNA methylation is unknown.…”

Multifaceted Functions and Novel Insight Into the Regulatory Role of RNA N6-Methyladenosine Modification in Musculoskeletal Disorders

“…For instance, upregulation of FTO gene expression was closely associated with skeletal muscle mass increase in overweight individuals ( Doaei et al, 2019 ). Moreover, maternal high-fat intake could even disturb the m 6 A modification and FTO gene expression in skeletal muscle of its offspring ( Li et al, 2016 ). Wu et al (2017) have confirmed that activation of AMPK decreases the lipid accumulation in skeletal muscle cells through inversely regulating FTO expression and FTO-mediated demethylation.…”

Emerging role of m6A RNA methylation in nutritional physiology and metabolism

“…Li et al . (2016) indicated that a maternal high‐fat diet downregulated FTO and upregulated the METTL3 levels, resulting in increased m 6 A methylation in the visceral fat of three‐week‐old mice . However, FTO expression in the hypothalamus was significantly increased in rats fed a high‐fat diet, resulting in obesity .…”