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FTO: a critical role in obesity and obesity-related diseases

Published online by Cambridge University Press:  22 March 2023

Dan Yin
Affiliation:
Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, People’s Republic of China
Yiyang Li
Affiliation:
Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, People’s Republic of China
Xingyue Liao
Affiliation:
Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, People’s Republic of China
Dewei Tian
Affiliation:
Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, People’s Republic of China
Yunsi Xu
Affiliation:
Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, People’s Republic of China
Cuilan Zhou
Affiliation:
Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, People’s Republic of China
Jun Liu
Affiliation:
Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, People’s Republic of China
Suyun Li
Affiliation:
Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, People’s Republic of China
Jing Zhou
Affiliation:
Department of Obstetrics and Gynecology, the Second Affiliated Hospital, University of South China, 30# Jiefang Road, Hengyang, Hunan 421001, People’s Republic of China
Yulin Nie
Affiliation:
Department of Obstetrics and Gynecology, the Second Affiliated Hospital, University of South China, 30# Jiefang Road, Hengyang, Hunan 421001, People’s Republic of China
Hongqing Liao*
Affiliation:
Department of Obstetrics and Gynecology, the Second Affiliated Hospital, University of South China, 30# Jiefang Road, Hengyang, Hunan 421001, People’s Republic of China
Cuiying Peng*
Affiliation:
Department of Cell Biology and Genetics, Institute of Cytology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, Key Laboratory of Ecological Environment and Critical Human Diseases Prevention of Hunan Province Department of Education, Key Laboratory of Hengyang City on Biological Toxicology and Ecological Restoration, Key Laboratory of Typical Environmental Pollution and Health Hazards, University of South China, Hengyang, Hunan 421001, People’s Republic of China
*
*Corresponding authors: Hongqing Liao, email [email protected]; Cuiying Peng, email [email protected]
*Corresponding authors: Hongqing Liao, email [email protected]; Cuiying Peng, email [email protected]
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Abstract

In recent years, obesity is a growing pandemic in the world and has likely contributed to increasing the incidence of obesity-related diseases. Fat mass and obesity-associated gene (FTO) is the first gene discovered which has a close connection with fat. Recent studies suggested that FTO gene has played an important role in the molecular mechanisms of many diseases. Obesity is considered to be a hereditary disease and can evoke many kinds of diseases, including polycystic ovary syndrome (PCOS), type 2 diabetes mellitus (T2DM), cancer, etc., whose exact possible molecular mechanisms responsible for the effect of FTO on obesity and obesity-related diseases remain largely unknown. In this review, we comprehensively discuss the correlation between FTO gene and obesity, cancer, PCOS, T2DM, as well as the molecular mechanism involved in these diseases.

Type
Review
Copyright
© The Author(s), 2023. Published by Cambridge University Press on behalf of The Nutrition Society

The prevalence of obesity has risen sharply last several years and has become one of the most severe health issues in the world. It is estimated that obesity may be considered as a heritable trait(Reference Rohde, Keller and La Cour Poulsen1). The SNP are the common genetic variations in human genomes(Reference Stalin, Lin and Josephine Princy2). To date, it is found that 23 715 susceptibility SNP (including 283 index SNP) are located in the enhancer regions of obesity-related cell lines(Reference Dong, Zhang and Chen3), and various genes such as LEP, LEPR, NPY, ADIPOQ, FTO, MC4R, PCSK1 and POMC are implicated and have a direct role in obesity(Reference Mendoza-Pérez, Gu and Herrera4). Among these genes, the fat mass-associated gene (FTO) is considered as the first and strongest related gene causing obesity in multiple populations of different countries(Reference Loos and Bouchard5).

FTO gene is a DNA/RNA methylase that encodes Fe(II)/2-OG-dependent demethylase, which is the ninth AlkB family protein (also known as ALKBH9)(Reference Gerken, Girard and Tung6). The FTO gene was firstly cloned from the identification of a fusion toe mutant mouse which phenotypically caused by a 1·6-Mb deletion of six genes, including FTO (Reference Peters, Ausmeier and Ruther7). In 2007, FTO was described as the first gene which was associated with the common obesity. Because FTO has a strong preference for 3-methylthymine (3-meT) and 3-methyluracil (3-meU) single-stranded DNA and RNA(Reference Gerken, Girard and Tung6), it has been demonstrated that FTO can oxidise demethylated 3-meT and 3-meU in single-stranded DNA (ssDNA) and single-stranded RNA (ssRNA) in vitro (Reference Jia, Yang and Yang8). FTO also can demethylate N6-methyladenosine (m6A) and N6, 2'-O-methyladenosine (m6Am) in mRNA, m6A in U6RNA, m6Am in snRNAs and N1-methyladenosine (m1A) in tRNA(Reference Wei, Liu and Lu9). FTO has been reported to be associated with many diseases, including type 2 diabetes mellitus (T2DM), polycystic ovary syndrome (PCOS) and various malignancies such as breast(Reference Tan, Dang and Chen10), thyroid(Reference Sigurdson, Brenner and Roach11) and endometrial cancer(Reference Zhu, Shen and Gao12).

Molecular mechanisms

FTO have an effect on the molecular mechanisms of diseases mainly through regulating the expression levels of m6A in the relative diseases. The insulin resistance, obesity, hyperandrogenism, etc., are the major features of PCOS; previous study reported that FTO is the positive regulator of FLOT2 in KGN cells and decreases m6A levels in mRNA of FLOT2 and increases the stability of FLOT2 mRNA to enhance the expression of FLOT2 so that it promotes cell proliferation, inhibits cell apoptosis and reduces GLUT4 membrane transport by insulin induced in KGN cells. The deletion of FLOT2 may weak the influence of FTO overexpression to GCs cell proliferation/apoptosis and insulin resistance(Reference Zhou, Han and Li13). FTO variation may impact the baseline lipid oxidation in PCOS patients(Reference Kowalska, Adamska and Malecki14), and obesity PCOS women rose the lipid oxidation level in the condition with insulin induced(Reference Hojlund, Glintborg and Andersen15). It is reasonable to assume that FTO gene might be one of the underlying mechanisms in the weight of PCOS patients. Moreover, FTO variation may play a significant role in hyperandrogenism state, and the high free testosterone levels have a significant association with rs9939609 A allele in FTO (Reference Wehr, Schweighofer and Moller16).

In T2DM, the reduction of expression levels of m6A in diabetes and obesity patients is negatively correlated with the increasing expression of FTO (Reference Onalan, Yakar and Onalan17). The high demethylases (FTO and ALKBH5) may cause a decrease in m6A RNA expression and result in obesity(Reference Wei, Ji and Guo18). FTO protein may induce the mRNA expression of four genes (FOXO1, FASN, G6PC and DGAT2) involved in glycolipid metabolism. High-glucose-enhanced FTO mRNA expression resulted in the up-regulated methyltransferase to abate the m6A levels, and the up-regulated expression levels in those four genes were closely associated with the hyperglycaemia and dyslipidemia in T2DM patients(Reference Yang, Shen and Huang19). There was a 2·797-fold increased risk of T2DM with a one-unit increase in FTO mRNA level, and the enhancement of FTO mRNA levels may be responsible for the reduction of m6A in T2DM, which can further trigger the complications of T2DM(Reference Shen, Huang and Huang20). In the aggregate, FTO may involve in the molecular mechanisms of T2DM.

N6-methyladenosine (m6A) also plays a pivotal role in tumorigenesis. The main pathway is up-regulated the mRNA and protein levels of m6A-related genes through down-regulating the expression of FTO protein to inhibit tumorigenesis. It has been proved that m6A demethylase includes FTO protein and ALKBH5. A study emphasised a decrease in the percentage of total RNA m6A in the hepatocellular carcinoma (HCC) tissues compared with normal samples(Reference Li, Zhu and Shi21). The ectopic overexpression of FTO protein not only suggested poor prognosis but also associated with low m6A content in HCC(Reference Li, Zhu and Shi21) (Fig. 1(c)). FTO-mediated n-6,2-O-dimethyladenosine (m6Am) demethylation played a minimal role in FTO-induced inhibition of proliferation and activation of apoptosis in acute myelogenous leukemia cells(Reference Huang, Su and Sheng22). The modification of m6A in RNA reduced the proliferation and cell viability of melanoma cells, which confirmed that m6A could inhibit the growth of melanoma(Reference Yang, Wei and Cui23). FTO, as a m6A demethylase, played a crucial role in promoting melanoma development and anti-pd-1 resistance. FTO protein inhibition and anti-pd-1 blockade might reduce the drug resistance of melanoma immunotherapy. Additionally, m6A content was increased by knock-out FTO to inhibit the proliferation of A549 lung cancer cells(Reference Shi, Zhao and Han24). The growth of cancer cells can be inhibited by regulating the m6A level so as to target cancer therapy.

Fig. 1. FTO overexpression promotes tumorigenesis via different signal pathways by Figdraw (www.figdraw.com). (a) Enhancing the expression of FTO in human endometrial cancer cells (KLE) and the m6A of HOXB13 mRNA decreases to activate the WNT signalling pathway so that the ability of migration and invasion was significantly increased. (b) FTO upregulates ARL5B by inhibiting miR-181b-3p. The carcinogenic activity of FTO/MIR-181B-3P/ARL5B signalling pathway promotes invasion and migration in breast cancer cells. (c) FTO overexpression downregulates the m6A of GNAO1 mRNA to increase the HCC cells level and HCC tumorigenesis. HCC, HCC, hepatocellular carcinoma.

Fig. 2. The relationships between FTO SNP and obesity with its diseases. PCOS, polycystic ovary syndrome; T2DM, type 2 diabetes mellitus.

The functions of FTO SNP

Different FTO SNP caused the accumulation of fat in various parts of the body. Individuals of FTO rs17817449 TT genotype have easier fat deposition in the thoracic and breast region(Reference Zermeño-Rivera, Astocondor-Pérez and Valle25). FTO rs1421085 C/C alleles inhibit the expression of mitochondrial and thermogenesis genes, and human adipose-derived stromal cells from the different position of human neck keep differing propensity for adipocyte browning by the influence of the alleles(Reference Tóth, Arianti and Shaw26). The mRNA levels of FTO rs9939609 A allele are up-regulated with peripheral protein and the expression of peripheral protein, which elucidated the most significant associations for FTO in regulating lipoclasis and total body fat(Reference Zabena, González-Sánchez and Martínez-Larrad27).

FTO SNP may have underlying associations with the children and pregnant women. In children, FTO SNP rs8050136 took part in the risk of adjusting attention-deficit/hyperactivity disorder, especially who were not exposed in maternal smoking during pregnancy(Reference Choudhry, Sengupta and Grizenko28). Among the pregnant women, the maternal and infant AA genotype of the obesity-associated FTO rs9939609 SNP associates with increased risk for small-for-gestational-age pregnancy and spontaneous preterm birth, and the SNP might play a significant role in calculating the risk of pregnancy complications and subsequent vascular diseases(Reference Andraweera, Dekker and Leemaqz29). FTO rs9939609 TA genotype only related with the risk reduction of intra-uterine growth restriction in male offspring(Reference Barbieri, Fontes and Barbieri30).

FTO and obesity

Obese patients are influenced by diet intakes and living habits, which are generally associated with a specific FTO polymorphisms. SNP are the main form of variation that regulates gene expression in the DNA sequence of the human genome. The A (risk) allele of rs9939609 in the FTO gene was strongly associated with greater obesity(Reference Moleres, Ochoa and Rendo-Urteaga31). High-fibre diets may have positive effects on anthropometric parameters but may also worsen lipid profiles dependent on the FTO genotypes(Reference Czajkowski, Adamska-Patruno and Bauer32). FTO rs1421085 TC + CC genotypes were associated with fat intake(Reference Al-Jawadi, Priliani and Oktavianthi33). Moreover, FTO rs1421085 C-allele was linked with the degree of abdominal fat accumulation in adolescent males and females, but the effect of FTO rs1421085 risk allele C on obesity was not mediated by daily energy intake, macronutrient intake or physical activity(Reference Katus, Villa and Ringmets34). FTO gene polymorphisms may play a significant role in dietary habits, which might associate with FTO SNP. For example, the decline in emotional eating with age was greater in the rs9939609 FTO polymorphism of AA + AT genotype group(Reference Abdella, El Farssi and Broom35). Individuals with minor allele carriers of rs9939973, rs8050136, rs1781749 and rs3751812 had lower risk of obesity when they had higher Mediterranean dietary score, compared with wild-type homozygote genotype carriers(Reference Hosseini-Esfahani, Koochakpoor and Daneshpour36). Med Diet adherence can be useful for the prevention or treatment of obesity phenotypes in subjects with FTO risk alleles(Reference Hosseini-Esfahani, Koochakpoor and Daneshpour36).

Weight gain in obese patients is influenced by the frequency of various FTO gene polymorphisms. Obese patients were remarkably associated with FTO (rs9939609) AA genotype compared with non-obese patients, not only the frequencies of rare FTO alleles (A) in obese patients were conspicuously higher than those in non-obese controls, but also the frequencies of (TA + AA) genotype in obese patients were also significantly higher than those in non-obese controls(Reference Ali, Diab and Elsaid37). Similarly, SNP rs9939609 A allele carrier subjects (AT/AA) who had dramatically higher BMI (P = 0·001) and fat mass index (P = 0·002) compared with SNP rs9939609 TT homozygote carriers and carriers of T allele in SNP rs10163409 had a higher risk of central obesity than carriers of AA genotype of SNP rs10163409 in the Turkish population(Reference Isgin-Atici, Alsulami and Turan-Demirci38). The total fat content of rs9939609 AA genotype individuals was higher in Turkey(Reference Agagunduz and Gezmen-Karadag39). The higher is the frequency of AA genotype in SNP rs9939609 A/T, the more is the obese individual in population.

FTO polymorphisms have genetic difference among obese population according to the difference of sex, ethnic group and region. Women carrying the minor allele of rs9930506 variant have a significant increase in BMI by year, which indicates that rs9930506 exhibited positive interactions with age and BMI in a sex-dependent manner(Reference Saldana-Alvarez, Salas-Martinez and Garcia-Ortiz40). Male carrying FTO (rs8050136) risk A allele would even lose more weight than non-carriers after exercise intervention but not in females(Reference Wang, Yang and Wang41). The FTO SNP rs1421085 is a genetic factor associated with obesity in Mayan school-aged children, and FTO SNP rs1421085 and rs9939609 affect genetic susceptibility for obesity only in girls; however, SNP rs8057044 is associated with overweight status only in boys(Reference González-Herrera, Zavala-Castro and Ayala-Cáceres42). The FTO rs1558902 and rs1421085 variations had robustly effected on obesity in women, and overweight may be regulated by different genetic patterns depending on sex(Reference Sobalska-Kwapis, Suchanecka and Slomka43). FTO contributed to obesity susceptibility in Caucasian, Chinese, African American and Hispanic population(Reference Tan, Zhu and He44). FTO rs9939609 A allele and rs1421085 C risk allele increased the risk of obese in Balinese(Reference Bressler, Kao and Pankow45), and the FTO variant rs1421085 CT genotype was associated to raise the risk of overweight/obesity (BMI ≥ 25 kg/m2 for overweight and BMI ≥ 30 kg/m2 for obesity) to 1·583 times in Pakistani individuals(Reference Newfield, Graves and Newbury46). The severe obesity in Brazilian population was strongly related to FTO rs9939609 allele (A)(Reference Da Fonseca, Abreu and Zembrzuski47).

FTO and polycystic ovary syndrome

PCOS is a common endocrine and metabolic disorder in women of childbearing age, which is characterised by polycystic ovary, hypomenorrhea or amenorrhea, clinical or biochemical hyperandrogenism and insulin resistance. Due to the majority of patients with PCOS is obese, it is reasonable to assume that FTO gene might play a central role in the pathogenesis of PCOS.

FTO polymorphisms are closely related to the risk of PCOS, in which rs9939609 is the most important factor, followed by rs1421085, rs17817449, rs8050136, rs8060136, rs1588413, etc. Li et al. (Reference Li, Wu and You48) and Yuan et al. (Reference Yuan, Zhu and Wang49) demonstrated that FTO rs9939609 risk allele A was associated with PCOS in obese Chinese women. The association was influenced by BMI, while the connection was weakened after the adjustment for BMI. FTO risk allele A was associated with measurements of IR traits and weight gain; however, the obesity risk allele A of the FTO variant rs9939609 was lower frequency in polycystic ovary patients than that in PCOS patients without polycystic ovary(Reference Tan, Scherag and Janssen50). FTO polymorphisms were associated with PCOS susceptibility, and both the FTO polymorphisms and PCOS susceptibility were observably related with BMI. The A allele of rs9939609 variation in FTO gene was associated with PCOS susceptibility in Chinese population, possibly because of its influence on BMI(Reference Yan, Hong and Gu51). Likewise, the A risk allele of SNP rs9939609 has been indicated to increase the susceptibility to PCOS(Reference Beyazit, Hiz and Turkon52). The G/G genotype (rs1421085), the C/C genotype (rs17817449) and the A/A genotype (rs8050136) variations of FTO gene were associated with PCOS susceptibility, hyperandrogenemia and a higher BMI in young Korean women, which suggests that these results might be caused by obesity(Reference Song, Lee and Oh53). In contrast, neither FTO rs9939609 (T/A) and FTO rs8050136 (A/C) nor its haplotypes were associated with PCOS in Brazilian women(Reference Ramos and Spritzer54).

FTO gene variation rs9939609 is associated with metabolic disorders of PCOS in different ethnic populations. A study firstly provided the evidence that FTO genes were associated with metabolic syndrome, which is also a characteristic of PCO, especially impacted on impaired glucose tolerance in Caucasian women(Reference Attaoua, Ait El Mkadem and Radian55). The FTO rs9939609 was associated with hyperandrogenism and the metabolic manifestations of PCOS in women of Sri Lankan origin. The A risk allele of SNP rs9939609 has been shown to increase the susceptibility to PCOS, and serum adiponectin and leptin were independent markers of PCOS diagnosis, which depended on BMI status(Reference Branavan, Wijesundera and Chandrasekaran56). The risk alleles of both rs9939609 (TA/AA) and rs8050136 (AA/AC) in FTO gene were proposed to be associated with higher fasting glucose levels in Brazilian women(Reference Xu, Ye and Zhang57). FTO genes played a strong role in PCOS through their effects on obesity or metabolic complications in Central European populations(Reference Duan, Yang and Wang58). FTO polymorphisms were closely associated with the metabolic syndrome of PCOS patients, which is always shown as the higher fasting glucose levels and impaired glucose tolerance.

In conclusion, both FTO polymorphisms raise the risk of obesity in PCOS, and these vital polymorphisms are closely associated with BMI, metabolic syndrome, hyperandrogenemia, impaired glucose tolerance, lipid metabolism disorder, etc., in PCOS.

FTO and cancer

Cancer prevalence is increasing worldwide. The occurrence and development of cancer are closely related to many factors, such as environments, heredity, living habits, and diets. FTO is a demethylase which connects with cancer. There are many cancers which are induced by obesity, including breast cancer(Reference Xu, Ye and Zhang57), HCC(Reference Li, Zhu and Shi21), oesophageal cancer(Reference Zhang, Wan and Zhang59), etc. Interestingly, FTO gene has been reported to be closely associated with cancer. Not only the FTO polymorphisms are associated with the risk of cancer and DNA demethylation, but also FTO proteins regulate those specific mechanisms of carcinosis, and FTO glycosidases seem to play a major role in cancer by regulating the expression of FTO. Thus, FTO has been demonstrated to cause a variety of cancers, such as bladder, liver and breast cancer, and there are different pathological mechanisms for different cancers.

Overexpression of FTO protein promotes proliferation in cancer cells, while down-regulation of FTO protein inhibits proliferation in cancer cells. FTO expression was apparently increased in oral squamous cell carcinomas cell lines and tissues, and high expression of FTO was closely correlated with poor prognosis(Reference Zhao, Kong and Zhong60). FTO protein was up-regulated in HCC tissues and cells(Reference Li, Zhu and Shi21). In addition, the m6A levels in HCC cells were increased when FTO protein was silenced, and FTO protein as an oncogene might regulate mRNA demethylation in HCC tumorigenesis(Reference Li, Zhu and Shi21). The ability of migration was distinctly increased after enhancing FTO protein expression in human endometrial cancer cells (KLE)(Reference Yang, Shao and Guo61). In contrast, cell migration was tremendously decreased after silencing FTO protein expression in KLE cells(Reference Su, Dong and Li62). Meanwhile, FTO protein was closely related with the occurrence and development of endometrial cancer(Reference Zhang, Wan and Zhang59). FTO protein was overexpressed in transmissible endometrial cancer cells, which promoted migration and invasion of endometrial cancer cells in vivo and in vitro (Reference Zhang, Wan and Zhang59) (Fig. 1(a)). FTO protein was up-regulated in ovarian cancer tissues compared with non-cancerous ovarian tissues, which clearly improved the viability and autophagy but reduced apoptosis of ovarian cancer cells(Reference Zhao, Kong and Zhong60). However, FTO protein expression was down-regulated, which promoted tumour growth and metastasis and negatively correlated with poor survival in lung adenocarcinoma patients(Reference Chen, Chen and Guan63). Those researches revealed that up-regulated FTO protein expression in majority tumour cells promotes proliferation and differentiation of cancer cells, but the FTO protein overexpression inhibits the growth of cancer cells in some cancers, which demonstrated that the pathogenic mechanisms mediated by FTO were evidently different in cancers.

Different FTO protein signalling pathways for each type of cancer may provide new targets for cancer therapy. The carcinogenic activity of FTO/MIR-181B-3P/ARL5B signalling pathway promoted invasion and migration of breast cancer cells(Reference Xu, Ye and Zhang57). FTO protein enhanced ARL5B expression, while miR-181b-3p inhibited ARL5B expression(Reference Xu, Ye and Zhang57) (Fig. 1(b)). The 2-hydroxyglutarate (2HG) inhibited the proliferation/survival of FTO protein high-expression cancer cells by targeting the FTO/m6A/MYC/CEBPA signalling pathway(Reference Su, Dong and Li62). FTO protein was the direct target of R-2-hydroxyglutarate (R-2HG) and the main mediator of R-2HG-induced growth inhibition in leukemic cells(Reference Su, Dong and Li62). The down-regulation of FTO protein expression obviously increased m6A levels in a large number of genes of mRNA in key pathways, especially in metabolic pathway genes such as MYC (Reference Yang, Shao and Guo61). The level of m6A on MYC mRNA was increased to recruit YTHDF1 binding and enhance glycolysis, tumour cell proliferation and tumorigenesis(Reference Yang, Shao and Guo61). As such, the down-regulation of FTO protein expression is negatively correlated with survival rates of lung adenocarcinoma patients, which may promote tumour growth and metastasis.

FTO and diabetes

T2DM is a common polygenic disease and complex metabolic disease, which is caused by many genetic factors, environment, obesity and epigenetic regulation and accompanied by co-morbidity. Obesity is a major risk factor for the development of type 2 diabetes, and FTO polymorphisms are not only associated with obesity but also a main cause of type 2 diabetes.

FTO polymorphisms are differently expressed in various populations, and the different alleles of FTO cause diabetes. The SNP on the first intron of FTO gene was associated with T2DM(Reference Ghafarian-Alipour, Ziaee and Ashoori64). FTO rs9939609 gene variation is the predictor of T2DM in the future, which would use to further study the predictive model of T2DM in Vietnam(Reference Binh, Linh and Chung65). The FTO gene rs9940128 A/G polymorphism was investigated to be associated with type 2 diabetes in North Indians(Reference Naaz, Kumar and Choudhury66). The allele A at the rs9939609 locus is highly associated with type 2 diabetes in South Asian Indians(Reference Rees, Islam and Hydrie67), and the association with type 2 diabetes was still significant after adjusting BMI, waist circumference and other body measurement variables. The FTO rs9939609 polymorphism was associated with a family history of diabetes in the northeastern Iranian population(Reference Khoshi, Bajestani and Shakeri68). Not only FTO variants were related with type 2 diabetes, but also some variants were robustly connected with hormones and androgens in obese women in Iran(Reference Ghafarian-Alipour, Ziaee and Ashoori64). The FTO rs141115189, rs9926289 and rs9939609 polymorphisms were apparently associated with T2DM in the general population. The FTO rs9939609 A allele was associated with an increased risk of diabetes and obesity in White people, and only the rs1421085 C allele was found to be protective against diabetes in African Americans(Reference Bressler, Kao and Pankow45). In the same way, the homozygosity or heterozygosity of the T allele in FTO rs9939609 had a protective effect, decreasing T2DM risk by inheriting collectively with C/C for the PPARγ rs1801282 and C/C for melanocortin 4 receptor (MC4R) rs2229616 or C/C for PPARγ rs1801282 and C/T MC4R rs2229616(Reference Bakhashab, Filimban and Altall69). However, when the AA genotype of FTO rs9939609 was combined with CC genotype in PPARγ rs1801282 or CC MC4R rs2229616 genotype, it had a positive effect on the development of T2DM(Reference Bakhashab, Filimban and Altall69). Diabetics differently affected BMI in different races or regions, which may have a certain relationship with age. The FTO variation changed the risk of type 2 diabetes and increased the weight before adulthood of patients in Ahvaz, in which BMI also played an indispensable role(Reference Alipour, Rostami and Parastouei70). The studies of Indians in South Asia(Reference Yajnik, Janipalli and Bhaskar71) and Karachi in Pakistan(Reference Fawwad, Siddiqui and Basit72) demonstrated that the population with the minor allele A at the rs9939609 were predisposed to type 2 diabetes, and the variation may influence on BMI. However, FTO rs8050136 had no association with T2DM in Saudi people(Reference Yousuf, Kannu and Youssouf73). In sum, FTO gene can increase the risk of T2DM in different ages, races and regions. Next studies should be conducted according to the different influencing factors. Some research results were not completely consistent between FTO SNP and diabetes, and a large sample research is very necessary in multiple centres in the future.

Diabetes can also cause a variety of complications, including diabetic nephropathy, CVD, high blood pressure and depression, etc. The T2DM patients with inflammation had an increased risk of arteriosclerosis. The inflammatory state of T2DM patients played a stronger role in developing arteriosclerosis problems than the influence on CVD by obesity(Reference Alipour, Rostami and Parastouei70). The C allele of FTO gene polymorphism rs7204609 contributed to genetic predisposition of chronic kidney disease(Reference Marchetti, Balbino and Hermsdorff74). Chronic kidney disease patients with central obesity, hypertension, high proteinuria and diabetes are more common than patients with chronic kidney disease alone. Taira’s study for the first time identified the association between the G/A alleles of rs56094641 in FTO and susceptibility to diabetic nephropathy in T2DM patients in Japan(Reference Taira, Imamura and Takahashi75). Moreover, the results suggested that cognitive decline and dementia could be prevented by controlling blood sugar and depression. FTO promoted inflammatory response to stimulate the pathogenesis of diabetic kidney disease through the FTO/SOCS1/JAK-STAT axis, and FTO expression evidently decreased in the diabetic kidney disease tissue; thus, FTO overexpression can obviously reduce kidney inflammation(Reference Sun, Geng and Zhao76).

Conclusions

Many studies have proved the relationship between FTO and obesity. The obesity is affected not only by FTO gene but also by individuals eating habits. FTO SNP are also closely related to the increase of PCOS risk. However, the susceptibility of PCOS will also be related to BMI. Different regions, races and sexes have different genetic patterns of FTO. There are different sensitivities to BMI, and the complications of diabetes are related to FTO alleles among diabetic patients in Caucasians and South Asian Indians. The relationship of FTO gene with cancer shows that FTO overexpression can promote the proliferation of numerous cancer cells. On the contrary, it can inhibit the proliferation of cancer cells by down-regulating FTO expression and up-regulating mRNA and protein levels of m6A-related genes in other cancers (Fig. 2).

There are still limitations in studies. The scale of research objects is relatively small, and large-scale researches are needed to confirm the association and difference between FTO SNP and various races with regions. Secondly, the regulation mechanism of FTO gene is still obscure, and it is necessary for further researches to focus on the regulation mechanism of FTO as well as its polymorphisms on obesity. The current researches may help to understand the potential role of FTO polymorphism variation in different population of races and regions. However, in order to find the potential mechanisms of FTO-induced diseases, further researches should closely pay attention to the mechanism of tumorigenesis and other diseases in FTO risk alleles.

In a word, FTO gene may help to define the susceptibility of obesity or other metabolic complications in PCOS high-risk population through its association with metabolic syndrome and its components to provide a predictive genetic marker. The role of FTO in the development of cancers is to provide potential targets for the diagnosis, prognosis and treatment of various cancers. A comparative study of FTO between different races and regions, including functional genomics and epigenetics analysis, may be helpful to understand the key mechanism mediated by FTO gene of obesity and obesity-related diseases.

Acknowledgements

The authors thank all participants in this study.

This work was supported by grants from Natural Science Foundation of Hunan Province of China (#2021JJ30598, 2021JJ30593, #2020JJ4536) and China Scholarship Council Grant (#CSC201708430228).

D. Y., Y. L. and X. L. contributed to the conception of the study and wrote the manuscript; D. T., Y. X. and C. Z. contributed significantly to analysis and manuscript preparation; J. L., S. L., J. Z. and Y. N. performed the draws; H. L. and C. P. helped perform the analysis with constructive discussions.

The authors declare no competing interests.

Footnotes

These authors contributed equally to this work.

References

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Figure 0

Fig. 1. FTO overexpression promotes tumorigenesis via different signal pathways by Figdraw (www.figdraw.com). (a) Enhancing the expression of FTO in human endometrial cancer cells (KLE) and the m6A of HOXB13 mRNA decreases to activate the WNT signalling pathway so that the ability of migration and invasion was significantly increased. (b) FTO upregulates ARL5B by inhibiting miR-181b-3p. The carcinogenic activity of FTO/MIR-181B-3P/ARL5B signalling pathway promotes invasion and migration in breast cancer cells. (c) FTO overexpression downregulates the m6A of GNAO1 mRNA to increase the HCC cells level and HCC tumorigenesis. HCC, HCC, hepatocellular carcinoma.

Figure 1

Fig. 2. The relationships between FTO SNP and obesity with its diseases. PCOS, polycystic ovary syndrome; T2DM, type 2 diabetes mellitus.