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.
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
2022 by SCITEPRESS Science and Technology Publications, Lda. All rights reserved
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.
ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare
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
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
ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare
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.
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
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
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
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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ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare