FTO Inhibits Insulin Secretion and Promotes NF-κB Activation through Positively Regulating ROS Production in Pancreatic β cells

Fan, Haozhi; He, Wei; Xu, Kuanfeng; Wang, Zhixiao; Xu, Xinyu; Chen, Heng

doi:10.1371/journal.pone.0127705

Cited by 27 publications

(16 citation statements)

References 36 publications

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“…Methylation level play a very important role in gene expression [33]. Two previous studies found that FTO expression level was associated with insulin secretion, which may lead T2DM [34,35].…”

Section: Discussionmentioning

confidence: 99%

Association of FTO methylation level with incident type 2 diabetes mellitus: a nested case–control study within the Rural Chinese Cohort Study

Huang

Chen²,

Zhang

et al. 2020

Preprint

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Objectives This study aimed to investigate the association of FTO methylation level with type 2 diabetes mellitus (T2DM). Methods We conducted a nested case – control study for DNA methylation of FTO in Chinese pople identified from the Rural Chinese Cohort Study with a 6-year follow-up. Controls were matched to the cases on a 1:1 basis by age, sex, ethnicity, marital status, and residence. Unconditional multivariate logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for association with Tag-single nucleotide polymorphisms (SNPs) and cytosine guanine (CpG) locus. Haploview was used to analyze the association of possible haplotypes with T2DM. Generalized Multifactor Dimensionality Reduction was used to explore the potential interaction. Results We found a significant association for the CpG9 locus located in the promoter region of FTO with T2DM. With CpG9, the risk of T2DM was 1.84 (1.21–2.80) after adjusting for potential confounders. The Tag-SNPs (rs72803657, rs1558902, rs17817449, rs11076023) nor were possible haplotypes associated with T2DM in the strong linkage disequilibrium region. We found no significant interaction between obesity indexes, serum lipid levels and methylation levels. Conclusions Our study identified a CpG locus located in the promoter region of FTO that altered the T2DM risk independent of body mass index, but the variants of FTO were not significantly associated with T2DM. Our study might provide new insights into the pathways of FTO with T2DM and offer new opportunities for risk stratification and prevention of T2DM among rural Chinese population.

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Section: Discussionmentioning

confidence: 99%

Association of FTO methylation level with incident type 2 diabetes mellitus: a nested case–control study within the Rural Chinese Cohort Study

Huang

Chen²,

Zhang

et al. 2020

Preprint

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“…In this work we decided to study whetherand how-age, metabolic status (normal birth weight vs. IUGR), and energy intake (low vs. high diet) directly influence FTO protein expression. The distribution of Fto mRNA and protein levels was previously studied by several research groups, primarily using rodent models 26,29,31,42,[47][48][49] . The role of Fto in rodents is, however, limited as compared to humans.…”

Section: Discussionmentioning

confidence: 99%

“…One of our main discovery was that FTO protein levels in the pancreas were associated with energy intake: low on low energy diet and high on high energy diet, compared to normal diet. Earlier in vitro studies showed that FTO overexpression in MIN6 (mouse insulinoma) cells significantly inhibited insulin secretion in the presence of glucose, but did not affect insulin expression 47 . As a result, we argue that increased FTO levels in the pancreas may directly influence insulin release from beta cells.…”

Section: Scientific Reports |mentioning

confidence: 99%

“…As a result, we argue that increased FTO levels in the pancreas may directly influence insulin release from beta cells. Moreover, FTO overexpression in the pancreas resulting from a high energy diet might also be a consequence of the reactive oxygen species (ROS) production and activation of the NF-κB pathway 47 . This hypothesis is plausible, because at early stages of T2D, pancreatic secretion is increased in response to the decreased number of insulin receptors in peripheral tissues and increased basal level of glucose in the blood 47 .…”

Section: Scientific Reports |mentioning

confidence: 99%

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Intracellular and tissue specific expression of FTO protein in pig: changes with age, energy intake and metabolic status

Ferenc

Pilžys

Garbicz

et al. 2020

Sci Rep

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Genome-wide association studies in the FTO gene have identified SNPs correlating with obesity and type 2 diabetes. In mice, lack of Fto function leads to intrauterine growth retardation and lean phenotype, whereas in human it is lethal. The aim of this study in a pig model was to determine the localization of the FTO protein in different tissues and cell compartments, in order to investigate potential targets of FTO action. To better understand physiological role of FTO protein, its expression was studied in pigs of different age, metabolic status and nutrition, using both microscopic methods and Western blot analysis. For the first time, FTO protein was found in vivo in the cytoplasm, of not all, but specific tissues and cells e.g. in the pancreatic β-cells. Abundant FTO protein expression was found in the cerebellum, salivary gland and kidney of adult pigs. No FTO protein expression was detected in blood, saliva, and bile, excluding its role in cell-to-cell communication. In the pancreas, FTO protein expression was positively associated with energy intake, whereas in the muscles it was strictly agerelated. In IUGR piglets, FTO protein expression was much higher in the cerebellum and kidneys, as compared to normal birth body weight littermates. In conclusion, our data suggest that FTO protein may play a number of distinct, yet unknown intracellular functions due to its localization. Moreover, it may play a role in animal growth/development and metabolic state, although additional studies are necessary to clarify the detailed mechanism(s) of action. Genome-wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) in intron 1 of the FTO (Fat mass and obesity associated) gene are strongly correlated with an increased risk of obesity in humans 1-4. In the human FTO gene, the mutation (alteration p. Arg316 Gln) that inhibits catalytic activity of the protein, results in an autosomal recessive lethal syndrome 5. In Fto knockout mice, body weight and fat mass decrease 6 , while in animals overexpressing FTO they increase 7. Evidence from genetic epidemiology studies, life-course modeling, and diet-induced fetal programming data suggests that the FTO gene plays an important role in these complex biological interactions. It may provide the missing link in the developmental regulation of energy metabolism. The FTO variants associated with intrauterine growth retardation (IUGR) and, in consequence, low birth weight, confer a predisposition to obesity later in life. This finding favors the hypothesis of the existence of a common genetic denominator that predisposes to low birth weight and obesity in adults 8-10. Specifically, Fto deletion caused delayed growth, decreased white body fat, increased energy metabolism, and systemic sympathetic activation 6. For example, in wild-type mice, fasting reduced Fto mRNA levels and the number of Fto-immunoreactive cells in the hypothalamus. Interestingly, glucose treatment reversed this effect 11. However, another group of researchers showed that palatable ...

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“…Several groups have investigated the functional role of FTO in pancreatic islets using different experimental models. Overexpression of FTO in rat INS-1 cells appeared to affect first wave insulin secretion (Russell and Morgan, 2011), whereas overexpression in mouse MIN6 cells resulted in the inhibition of GSIS without changes in insulin gene expression (Fan et al, 2015). Given the discrepant results of these studies, in addition to the caveats associated with overexpression studies, perhaps the more relevant functional assessment was the use of siRNA knockdown to deplete FTO in an engineered human insulin secretion reporter rat β cell line (GRINCH) (Taneera et al, 2018).…”

Section: M6a Rna Methylationmentioning

confidence: 99%

mRNA Processing: An Emerging Frontier in the Regulation of Pancreatic β Cell Function

Moss

Sussel

2020

Front. Genet.

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Robust endocrine cell function, particularly β cell function, is required to maintain blood glucose homeostasis. Diabetes can result from the loss or dysfunction of β cells. Despite decades of clinical and basic research, the precise regulation of β cell function and pathogenesis in diabetes remains incompletely understood. In this review, we highlight RNA processing of mRNAs as a rapidly emerging mechanism regulating β cell function and survival. RNA-binding proteins (RBPs) and RNA modifications are primed to be the next frontier to explain many of the poorly understood molecular processes that regulate β cell formation and function, and provide an exciting potential for the development of novel therapeutics. Here we outline the current understanding of β cell specific functions of several characterized RBPs, alternative splicing events, and transcriptome wide changes in RNA methylation. We also highlight several RBPs that are dysregulated in both Type 1 and Type 2 diabetes, and discuss remaining knowledge gaps in the field.

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FTO Inhibits Insulin Secretion and Promotes NF-κB Activation through Positively Regulating ROS Production in Pancreatic β cells

Cited by 27 publications

References 36 publications

Association of FTO methylation level with incident type 2 diabetes mellitus: a nested case–control study within the Rural Chinese Cohort Study

Association of FTO methylation level with incident type 2 diabetes mellitus: a nested case–control study within the Rural Chinese Cohort Study

Intracellular and tissue specific expression of FTO protein in pig: changes with age, energy intake and metabolic status

mRNA Processing: An Emerging Frontier in the Regulation of Pancreatic β Cell Function

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