FTO mediates cell-autonomous effects on adipogenesis and adipocyte lipid content by regulating gene expression via 6mA DNA modifications

Carli, Jayne F. Martin; LeDuc, Charles A.; Zhang, Yiying; Stratigopoulos, George; Leibel, Rudolph L.

doi:10.1194/jlr.m085555

Cited by 21 publications

(16 citation statements)

References 91 publications

(129 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Fat Mass and Obesity Associated gene ( FTO ), which plays an important role in adipocytes, is the single strongest GWAS candidate gene associated with obesity in most worldwide populations, and is the focus of intense research 38 . FTO expression increased during adipogenesis 39 . Knockdown of FTO expression in the 3T3-L1 mouse adipocyte cell line was associated with a 70% increase in AKT phosphorylation and a 230% decrease in glucose uptake 40 .…”

Section: Discussionmentioning

confidence: 98%

Further evidence supporting a potential role for ADH1B in obesity

Morales

Cromack

Tripathy

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Insulin is an essential hormone that regulates glucose homeostasis and metabolism. Insulin resistance (IR) arises when tissues fail to respond to insulin, and it leads to serious health problems including Type 2 Diabetes (T2D). Obesity is a major contributor to the development of IR and T2D. We previously showed that gene expression of alcohol dehydrogenase 1B (ADH1B) was inversely correlated with obesity and IR in subcutaneous adipose tissue of Mexican Americans. In the current study, a meta-analysis of the relationship between ADH1B expression and BMI in Mexican Americans, African Americans, Europeans, and Pima Indians verified that BMI was increased with decreased ADH1B expression. Using established human subcutaneous pre-adipocyte cell lines derived from lean (BMI < 30 kg m−2) or obese (BMI ≥ 30 kg m−2) donors, we found that ADH1B protein expression increased substantially during differentiation, and overexpression of ADH1B inhibited fatty acid binding protein expression. Mature adipocytes from lean donors expressed ADH1B at higher levels than obese donors. Insulin further induced ADH1B protein expression as well as enzyme activity. Knockdown of ADH1B expression decreased insulin-stimulated glucose uptake. Our findings suggest that ADH1B is involved in the proper development and metabolic activity of adipose tissues and this function is suppressed by obesity.

show abstract

Section: Discussionmentioning

confidence: 98%

Further evidence supporting a potential role for ADH1B in obesity

Morales

Cromack

Tripathy

et al. 2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Some of these genes affect brain development and function ( IRX3 , IRX5 , and RPGRIP1L ) and may implicate reward and/or cognitive‐control neural circuits. Others influence energy expenditure by adipocytes ( ARID5B ) or the development of adipocytes .…”

Section: Discussionmentioning

confidence: 99%

The FTO Gene and Measured Food Intake in 5‐ to 10‐Year‐Old Children Without Obesity

Ranzenhofer

Mayer

Davis

et al. 2019

Obesity

Self Cite

View full text Add to dashboard Cite

Objective: Genetic variation in the first intron of FTO (e.g., single-nucleotide polymorphism [SNP] rs9939609) is strongly associated with adiposity. This effect is thought to be mediated (at least in part) via increasing caloric intake, although the precise molecular genetic mechanisms are not fully understood. Prior pediatric studies of FTO have included youth with overweight and obesity; however, they have not informed whether a genotypic effect on ingestive behavior is present prior to obesity onset. Therefore, this study investigated the association between FTO and caloric intake in children aged 5 to 10 years without obesity (adiposity ≤ 95th percentile). Methods: A total of 122 children were genotyped for rs9939609 and ate ad libitum from a laboratory lunch buffet following a standardized breakfast. Linear regressions, adjusting for body mass, were used to examine the association between FTO "dose" (number of copies of SNP rs9939609) and intake variables. Results: There was a significant association between FTO and total intake. Each risk allele predicted an additional 64 calories, accounting for 3% of the variance. There were no associations between FTO and macronutrient preference, energy density, or diet variety. Results were influenced by race. Conclusions: Results corroborate and extend prior work by showing a dose-dependent effect on food intake in children without obesity.

show abstract

“…[ 120 ] Thus, C/EBP β may not be the direct target of RNA m 6 A modification in BMSCs, which has also been demonstrated in 3T3‐L1 cell line by some groups. [ 139 ] In our previous study, RNA m 6 A modification was also not detected in the mRNA of C/EBP β in 3T3‐L1 cell line with or without adipogenic induction. [ 28 ] Thus, m 6 A might modulate the upstream regulators of key transcription factors to inhibit adipogenesis.…”

Section: Orchestration Of Transcriptional and Post‐transcriptional Rementioning

confidence: 94%

“…[142] Furthermore, FTO was also reported to demethylate DNA N6methyldeoxyadenosine (6mA), and affect the transcriptional activation of C/EBP by demethylating 6mA at the promoter of C/EBP in adipogenesis. [139] For methyltransferases, METTL3/14-WTAP is distributed in nucleus to bind the DNA sequence of target genes to regulate their transcription. It was observed that METTL3 and/or METTL14 are located in the relevant chromatin sites, which cooccurs with accumulated m 6 A methylation.…”

Section: A-related Proteins Bind the Dna Sequence Of Target Genesmentioning

confidence: 99%

Novel Insights into Adipogenesis from the Perspective of Transcriptional and RNA N6‐Methyladenosine‐Mediated Post‐Transcriptional Regulation

et al. 2020

View full text Add to dashboard Cite

Obesity is a critical risk factor causing the development of metabolic diseases and cancers. Its increasing prevalence worldwide has aroused great concerns of the researchers on adipose development and metabolic function. During adipose expansion, adipogenesis is a way to store lipids as well as to avoid lipotoxicity in other tissues, and may be an approach to offset the negative metabolic effects of obesity. In this Review, the transcriptional regulation of adipogenesis is outlined to characterize numerous biological processes in research on the determination of adipocyte fate and regulation of adipogenic differentiation. Notably, one of the post‐transcriptional modifications of mRNA, namely, N 6 ‐methyladenosine (m 6 A), has been recently found to play a role in adipogenesis. Here, the roles of m 6 A‐related enzymes and proteins in adipogenesis, with a particular focus on how these m 6 A‐related proteins function at different stages of adipogenesis, are mainly discussed. The Review also highlights the coordination role of the transcriptional and post‐transcriptional (RNA m 6 A methylation) regulation in adipogenesis and related biological processes. In this context, a better understanding of adipogenesis at both the transcriptional and post‐transcriptional levels may facilitate the development of novel strategies to improve metabolic health in obesity.

show abstract

FTO mediates cell-autonomous effects on adipogenesis and adipocyte lipid content by regulating gene expression via 6mA DNA modifications

Cited by 21 publications

References 91 publications

Further evidence supporting a potential role for ADH1B in obesity

Further evidence supporting a potential role for ADH1B in obesity

The FTO Gene and Measured Food Intake in 5‐ to 10‐Year‐Old Children Without Obesity

Novel Insights into Adipogenesis from the Perspective of Transcriptional and RNA N6‐Methyladenosine‐Mediated Post‐Transcriptional Regulation

Contact Info

Product

Resources

About