The Association between FTO, MC4R Variants and Obesity in

Different Populations and the Possible Reasons

Hanyu Zhang

Academy of life science biology engineering, Henan University, Shandong, China

Keywords: FTO, Obesity, Different, Population, MC4R, Association.

Abstract: Obesity is one of the diseases which have bad effects on human health. The finding of obesity genes is a

breakthrough in the related area for sure. The association between obesity genes and obesity have certain

differences in different population which never be investigated systematically. FTO genes and MC4R genes

are common obesity genes. Furthermore, the paper concerning the roles of two genes in different

populations and their mechanisms are abundant. However, limits still exist, including the lack of detailed

researches on the interaction between two genes. There is less papers on whether other genes’effects cause

this phenomenon and how the genes’ interactions cause it. Topic and method: This paper aimes at exploring

the differences of FTO and MC4R’s functions in different populations. The author investigates it by looking

through papers and analysis and comparing. Results and conclusions: Two hypotheses to the topic are

proposed. Firstly, the reasons may be the genes’ differences or the influences from other genes. Secondly,

two possible influences from other genes are also mentioned, namely influence directly or indirectly. By

analysing the results of existing literature and research, both two possibilities, including one hypothesis that

the same genes have certain distinct features in different populations and another possibility that other genes

may make effects on it, tend to be reasonable and for the latter circumstance, the effects made by other

genes can be directly and indirectly.

1 INTRODUCTION

In recent years, with the improvement of life level,

the number of obese people increase a lot. Obesity

becomes one of the most severe diseases which

influence people's health. Obesity causes trouble to

people's life and every nations are eager to solve or

relieve obesity through doing research on obesity.

As varied obesity genes are found in turn, the

mechanism of obesity genes, the methods to cure

obesity become the focus of the researches. The

topic of this paper is to explore the differences of

obesity genes' functions among different populations

and the possible reasons, analyzing the differences

to find possible reasons to explain them. FTO genes

and MC4R genes are proven to be one of the most

significant obesity genes, which are related to

human obesity. However, after research on the

association between these two genes and obesity, the

author finds that two genes’ roles are different in

different people are varied, showing the degree of

functions, namely strong or poor, or even showing to

have opposite functions. Questions are got and

discussed. By looking through materials, two

hypothesis about this phenomenon are made and

then by analyzing papers, rationality of the two

hypothesis will be described,including whether the

genes themselves cause differences in different

populations or other genes’ influences lead these

kinds of differences; if the latter description is

correct, then, how the genes interact, directly or

indirectly. Moreover, it can be used as an example to

explore the differences of obesity genes among

different populations.

This research has certain meanings for

exploration of the differences of obesity genes in

different population and may direct the direction to

the further research to certain extent.

Zhang, H.

The Association between FTO, MC4R Variants and Obesity in Different Populations and the Possible Reasons.

DOI: 10.5220/0011371800003438

In Proceedings of the 1st International Conference on Health Big Data and Intelligent Healthcare (ICHIH 2022), pages 437-442

ISBN: 978-989-758-596-8

437

2 ASSOCIATION BETWEEN FTO

GENES AND OBESITY, MC4R

GENES AND OBESITY IN

DIFFERENT POPULATIONS

AND AN INTERESTING

PHENOMENON

FTO genes and MC4R genes all tend to have varied

influence in different populations. It is shown as the

reduction or increase of their functions or even

showed to have opposite effects which is interesting.

The two genes seemed to be able to influence each

other. Both FTO genes and MC4R genes are genes

related to obesity significantly. However, these two

genes are proven to have different effects in

different populations in recent researches. In specific

regions, researchers selected obese people and

healthy people in random. They used real-time

polymerase chain reaction to measure the prevalence

of FTO variants and MC4R variants in participants

and also took certain methods to measure related

obesity markers, including body wight, body mass

index, fat mass percentage, hip circumference, waist

circumference, waist-to-hip ratio and so on.

According to these data they collected, they built

linear regression analysis and other mathematical

models to analyze the relationship between these

variants and obesity. The results found that

polymorphisms in the first intronic region of the

FTO gene are associated with obesity-related

characteristics such as increased body weight, hip

circumference, and waist/hip circumference ratio in

European, Asian, African(Adeyemo 2010, Dina

2007, Tan 2008, Peeters 2008, Hess 2014).

However, actually, the associations between FTO

genes and obesity are very complex among people.

Factors including races, regions where they live and

so on may affect it. There is a research showing that

FTO genes have no apparent relationship with

obesity in Egypt (Abdelmajed 2017), though this

gene is shown to be related to some factors related to

obesity, like LDL. For Portugal, FTO genes are

associated with obesity significantly, as it is related

to many characteristics including BMI (Albuquerque

2013). At the same time, though the participants are

from the same population, some differences of

FTO's effects for obesity exist in females and males

or in different age ranges.

Taking China as an example, some research

concluded that FTO broad variant rs9939609 are

linked with weight, BMI, waist-to-height ratio and

fat(Wang 2012). This theory have differences in

different sex, as this bond is stronger in girls than in

boys. Whereas, the research-based on Egypt, the

association between obesity and FTO genes is

strongest in children aged 11. These differences may

be led by the errors in sample selection, standard and

data-analysis methods. Still, they are too little to be

taken into considerations. Excluding these errors,

from this phenomenon, a hypothesis is put forward.

It may be because the influence from some special

genes only play roles in certain populations or have

different degree of activity on FTO genes or FTO

genes themselves do play different roles in different

populations. There is a research by Ningombam

SS(Ningombam 2021), which can be cited as an

evidence to justify the first hypothesis. In India

Liangmai and Mizo tribes, rs17782313, a variant of

MC4R, reduces the risk for people suffer from

obesity which is very special and the FTO variants

rs9939609 can increase the risk. However, if people

have MC4R and FTO variants simultaneously, the

extent of risks increased by FTO variants will be

decreased to some degree. Theoretically, as an

important obesity gene, MC4R genes are thought as

a regulator working in hypothalamus to maintain

physical homeostasis, control food intake and

weight(Farooqi 2008). Its variants are justified to

have close relationship with obesity in varied

populations including Chinese(Wang 2017),

German(Vogel 2011), Brazilian(Fernandes 2015),

European-American and African-American(Grant

2009) and it does increase the risk of getting obesity

through certain pathways. Contrasted by these data,

the condition in India written above is very special

and totally different from that, it can be guessed that

obese genes have different expression in different

people caused by other obese genes’ roles.

Nevertheless, this hypothesis needs more evidences

to increase its persuasion. In the following content,

mechanism will be investigated in order to explore

whether this hypothesis is accurate.

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438

Figure 1: Genetic interaction results between FTO rs9939609, MC4R rs17782313, ACE I/D rs4646994 and MTHFR C677T

rs1801133 for somatometric and dyslipidaemia variables using generalized multifactor dimensionality reduction (GMDR).

It comes from the paper of Somorjit.(Inandiklioğlu 2021).

Figure 2: Distribution of polymorphisms of melanocortin-4 receptor and fat mass and obesity-associated genes between

obese patient group and control group.This table is derived from paper written by Nihal (Inandiklioğlu 2021).

The Association between FTO, MC4R Variants and Obesity in Different Populations and the Possible Reasons

439

3 EXPLORING THE FUNCTION

BETWEEN OBESITY GENES

FROM THEIR MECHANISM

In 2019, Luca A.Lotta etc did research and found

that there are 9 MC4R variants among 61 kinds of

variants are connected to their activities and this

kind of variations can make people reduce eating.

This finding can work as an evidence for the first

hypothesis which can explain that rs17782313

shows the function of obesity suppression in Indian

tribes while in other districts, it increases the risk of

suffering obesity. What is more, it proves that if the

same variant' activity changes, it may cause changes

in their functions. For hypothesis two, two possible

situations exist. One is that two or more genes all

work independently and different roles added up to

have a general final results. Two is that genes’

functions and pathways are similar, opposite or

crossing, then same functions or opposite functions

are added up or counteract which lead to the final

results. Put these concepts into the analysis of the

Indian tribes' phenomenon and it shows to have two

possibilities. Namely, the pathways of FTO to play

roles are opposite to MC4R’s and then MC4R genes

suppress the functions of FTO genes; or these two

genes function through unrelated pathways but their

direct functions are opposite completely, so MC4R

genes can suppress FTO genes, for example, FTO

may suppress the appetite while MC4R lead a good

appetite or their direct effects have no associations

but these effects can lead opposite results for

obesity, for example, FTO can suppress appetite

while MC4R can suppress the release of insulin and

finally they have the opposite function to the

possibilities of suffering obesity. Through the

research, the mechanisms of FTO are below:

Under high-fat diet, FTO can influence the

distributions of fat. Also, FTO can reduce glucose

tolerance and influence leptin resistance. In

2015,Y.C.Tung etc found that WT mice given a

HFD gained more visceral epididymal fat than

subcutaneous fat(Tung 2015). But variant mice have

opposite tendency. Moreover, its binding partner is

NFкB’s transcriptional coactivator, which can

influence signaling pathway of NFкB to make

effects on leptin.

Some researches find that FTO can control

mitochondrial content and fat metabolism by

moderating N6-methyladenosine(m6A) levels in

hepatic cells which can be known from the figure 3

below(Kang 2018).

Figure 3: N6-methyladenosine(m6A) levels in hepatic cells.

FTO regulates hepatic lipid metabolism by

altering the methylation state of genes that are

involved in fatty acid oxidation, lipolysis and de

novo lipogenesis. FTO also regulates hepatic lipid

metabolism by altering the activity of transcription

factors. Increased FTo expression and/or activity

causes a reduction of m6A levels and reduces CPT1,

LIPE and ATGL mRNA expression, leading to

reduced fatty acid oxidation and lipolysis. It also

causes an increase in ATF4 expression, which then

stimulates expression of lipogenic genes, leading to

increased de novo lipogenesis in the liver. Reduced

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FTO expression and/or activity causes the opposite

effect. FTO: Fat mass and obesity-associated, m6A:

N6-methyladenosine, CPT1: Carnitine

palmitoyltransferase 1, LIPE: Hormone sensitive

lipase, ATGL: Adipose triglyceride lipase, ACC1:

Acetyl-CoA carboxylase 1, FASN: Fatty acid

synthase, SCD: Stearoyl-CoA desaturase,

MOGAT1: Monoacylglycerol O-acyltransferase 1,

ATF4: Activating transcription factor4. Red arrow:

Stimulation. Blue arrow: Inhibition.

This is an open access article distributed under

the Creative Commons Attribution License, which

permits unrestricted use, distribution, and

reproduction in any medium, provided the original

work is properly cited

Under the moderation of metabolic signal, FTO

encodes FTO protein and change FTO protein level

can influence glucose and lipid metabolism.

However, MC4R genes are at the end of appetite

regulation mediated by leptin and can encode MC4R

receptor. When α−MSH combines with MC4R

receptor in hypothalamus, the appetite will be

suppressed. In addition, MC4R genes also take part

in the regulation of leptin sensitive and glucose

steady state.

From two genes' mechanisms, the two all

participate in the regulation of leptin which means

the first possibility is right. FTO genes are related to

glucose tolerance while MC4R can regulate insulin

and glucose state which are not the same but all

influence glucose metabolism and obesity. It caters

to the second possibility. Therefore, the hypothesis

two is reasonable.

4 CONCLUSIONS

Through certain methods, the fact that some obesity

genes have differences in different populations are

judged. The fact is found that MC4R genes variant

rs17782313 plays an opposite role in Liangmai and

Mizo tribes in India, compared with other

countries.The results of the two hypotheses are as

follows.

In terms of the first hypothesis showed as

resonable possibility , the author found some MC4R

variants change activities, which do have an

opposite result to those common variants,

suppressing obesity. Hence, the reason for the

differences of MC4R functions in Indian tribes may

be related to the discrepancy of genes' activity. The

second hypothesis is proved to be right. In Indian

tribes, when FTO genes and MC4R genes exist

together, FTO's acceleration to obesity is suppressed

by MC4R genes, which prove the rationalities for

hypothesis.

For the mechanism of two genes, two

possibilities are put forward: their mechanisms are

related; their mechanisms are opposite or the same

or crossing. Taking MC4R genes and FTO genes as

examples, according to the researches, it is found

that both genes have relationship with leptin which

prove the rationalities of possibility one. What is

more, their roles in moderating glucose have

differences, FTO genes can change glucose

tolerance while MC4R can moderate insulin and

glucose state which support possibility two. After

research and discussion, the author finds that obesity

genes do not work independently but are related and

interact. The differences of genes in different

population do lead to different results of obesity

genes.

ACKNOWLEDGMENTS

Thanks for the paper provided by many researchers.

Thanks for the instruction of Professor Murray and

teacher Yvonne, Max, Sherry, Li Nuo etc. And

thanks for my parents and my brother, as they

provide a peaceful and comfortable environment

during my writing paper. Without them, it will be

hard for me to finish this paper.

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