Research on Obesity Caused by Genetic Defects in Specific

Populations

Zhiru Li

University of Washington Seattle WA, Seattle, U.S.A.

Keywords: Obesity Leptin, MC4R, UCP, β3 Adrenergic Receptors, PPARγ.

Abstract:

Obesity is caused by several factors, including diet, exercise, and the environment. However, one critical

factor that many people ignore is genetic abnormality. People are aware of the fact that the amount of food

ingested, and the amount of energy exerted can impact the formation of fat. Thus, obesity can be induced by

mutations or diseases in genes involved in these three systems in our body. And it is necessary to study the

problem of obesity caused by genetic defects. This paper focuses on 5 genetic problems to find the obesity

problems and solutions caused by genetic variants. It is found that Leptin and MC4R genes can increase

appetite and lead to obesity. And UCP and beta-adrenergic receptor during energy expenditure may result in

reduced energy expenditure or hormonal instability in the body, both of which will contribute to obesity. The

PPARy gene is essential for fat storage, and a mutation in the gene can result in an inability to store fat, which

will eventually lead to significant bodily damage. By studying and compiling the literature, this research has

identified the problems that arise after each genetic variation and the corresponding solutions.

1 INTRODUCTION

Genetic defects and obesity have received much

attention in the study of genes and metabolism in

different populations. Therefore, this paper

investigates the causes and solutions of obesity in

people with different congenital genetic defects.

Many genes have been discussed separately in the

context of congenital genetic defects which cause

obesity. But there was no definite study. This paper

focuses on the category and the study of the obesity

problem caused by genetic defects and divides the

basic elements of fat production in humans into three

major categories. The three categories are food

intake, energy expenditure, and fat storage. In each

section, one or two genetic defects were found to

demonstrate that congenital defects in genes cause

obesity.

Meanwhile, this study summarizes and lists the

possible obesity problems and solutions separately,

demonstrating the root cause for understanding the

common genetic defects that cause obesity problems.

Therefore, this paper systematically summarizes the

essential congenital genes that cause obesity through

clinical cases and mouse experiments and provides

solutions to the genetic defects as well as future

therapeutic prospects. Also, this study will make it

easier and more straightforward for researchers in the

field of genetic variants and congenital genetic

defects to understand the problems.

2 FACTORS THAT INFLUENCE

OBESITY

Table 1 lists the five genes that are crucial in obesity,

as well as the function of each gene. The function

of genes and genetic defect problems will be explored

in the following section.

212

Li, Z.

Research on Obesity Caused by Genetic Defects in Speciﬁc Populations.

DOI: 10.5220/0011196200003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 212-219

ISBN: 978-989-758-595-1

Table 1: Gene with CLEARLY defined role in obesity (Gao 2014)

GENE WITH CLEARLY

DEFINED ROLE IN

OBESITY

GENE NAME Function

FOOD INTAKE

LEPTIN Regulation eating behavior

MELANOCORTIN 4

RECEPTOR

Receptors of neuropeptides

ENERGY EXPENDITURE

UNCOUPING PROTEIN 1 Proton transporter and thermogenesis

ΒETA 3 ADRENERGIC

RECEPTOR

Lipolysis and thermogenesis in adipose tissue

FAT SYNTHESIS AN

STORAGE

PEROXISOME

PROLIFERATOR-

ACTIVATED RECEPTOR-

GAMA

Master gene of lipogenesis and adipogenesis

2.1

Genetic Defect Problems

2.1.1 Food Intake Leptin

Food intake usually depends on our appetite and

satiety; many genes control appetite and satiety, the

first and foremost being the leptin gene. Adipocytes

generate the hormone leptin, and leptin is the crucial

factor for regulates food intake and energy balance.

(Chen 2005) The leptin receptor is a protein that

leptin binds to and activates. The leptin receptor

protein is located on the cell surface of numerous

organs and tissues in the body, including the

hypothalamus which is a component of the brain. The

primary role of the hypothalamus is to control hunger

and thirst and also to control the quality of sleep and

mood. In the hypothalamus, leptin is a very important

hormone. Leptin binds to its receptors, triggering a

cascade of chemical signals that alter appetite and aid

in the production of satiety. Leptin, produced by fat

cells, regulates biological behavior and metabolism

by binding to central nervous system receptors.

Leptin deficiency or resistance can lead to severe

obesity in humans.

Figure 1: Leptin Activity (Chuck 2021).

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213

This figure shows where leptin comes from and

how it works in the most basic way. Leptin is released

from adipose tissue, and the larger the number of

adipose tissues, the greater the amount of leptin

released, and vice versa. At the hypothalamic location

in the brain, leptin interacts with leptin receptors to

signal satiety. In other words, leptin acts in the

hypothalamus to control appetite based on fat storage

levels. According to the figure, as fat storage

increases, fat cells produce more leptin, which

suppresses hunger in the hypothalamus and causes

people to eat less. When people lose weight, their

leptin levels would drop, and their appetite would

returns. This graph depicts leptin activity in the

average individual. When a person has a congenital

leptin gene deficiency, fat cells do not release leptin

hormone, and leptin receptors in the hypothalamus do

not receive leptin hormone regardless of fatness, and

hence do not control appetite. Finally will lead to

severe obesity.

2.1.2 MC4R

In addition to the congenital deficiency of the leptin

gene, another gene that affects food intake leading to

obesity is the melanocortin-4 receptor gene (MC4R),

it is also considered to be the most common

monogenic form of obesity in humans (Chung 2012)

“MC4R is a single exon gene on chromosome

18q21.3. It encodes a G-protein coupled receptor

expressed mainly in the brain.” (Abdullah 2016) In

the hypothalamus, the melanocortin-4 receptor gene

(MC4R) is a key regulator of energy balance, food

intake, and body weight. (Doulla 2021) As mentioned

earlier, leptin acts mainly on neurons in the arcuate

nucleus of the hypothalamus and in the fasting state,

a decrease in leptin increases food intake by

stimulating agouti-related peptide (AgRP) neurons.

At the same time, leptin inhibits POMC neurons and

reduces the amount of alpha-MSH (melanocyte-

stimulating hormone), which normally inhibits food

intake. Second-order neurons with melanocortin-4

receptors (MC4R) synthesize and integrate these

signals.

The main clinical features of MC4R deficiency

are hyperphagia, increased appetite, and impaired

satiety. Adults with MC4R deficiency had

significantly lower blood pressure and a decreased

risk of hypertension than those of same age and

weight. (Melanocortin 2021) The heart rate and

sympathetic tone values are generally lower in

patients with MC4R deficiency. Patients with MC4R

deficiency have difficulty achieving weight loss

because people tend to be less responsive to diet and

exercise.

Complete deletion of MC4R also occurs and it is

similar to the symptoms of MC4R deficiency.

Abdullah, S and Reginold, W etc. reported a 4.5-year-

old child with a complete deletion of one copy of

MC4R. The young child presented obesity, tall

stature, overall developmental delays, and sexual

equality. (Abdullah 2016) The report also states that

the child weighed 7 pounds 4 ounces at birth and had

poor growth until 15 months of age when he began to

gain weight rapidly. He had gained a lot of weight by

the time he was 18 months old owing to his regular

overeating.

2.2 Energy Expenditure

2.2.1 UCP1

Human energy consumption depends on many factors

such as gender, age, and weight. A huge part of the

factors related to energy expenditure that leads to

obesity is due to the brown adipose tissue (BAT)

(Pravednikova 2020) and the uncoupling protein

(UCP) that are mainly found in the mitochondria of

brown cell tissues. Therefore, the study of the UCP

family can be of great help to the causes of obesity.

Uncoupling protein 1(CUP1) is a mitochondrial

membrane protein involved in brown adipocyte

adaptive thermogenesis. UCP1 is the only component

that is capable of transporting protons across the inner

membrane of mitochondria in brown adipocytes. In

this mechanism, UCP1 acts as a proton carrier that is

activated by free fatty acids, producing a shunt

between respiratory chain complexes and ATP

synthase. When UCP1 is active, the uncoupling

process results in a futile cycle and the loss of

oxidative energy as heat.

Theoretically, UCP1 deficiency should lead to a

decrease in fat burning capacity and then lead to

obesity. Kozak, L’s articles8 have proposed

experiments with mice because brown adipose tissue

is the primary source of heat supply in mice, and there

is little brown adipose tissue in adults that

corresponds to that of mice. Interestingly, it has been

shown from mouse experiments that UCP1

deficiency causes mice to be forced to use other

thermogenic, metabolic systems, so UCP1 deficiency

does not cause obesity in mice. In other words, UCP1

deficiency is not the leading cause of congenital

obesity in children or people. (Kozak 2005) However,

mice that lack UCP1 were more likely to develop fat

accumulation with age than normal mice in the

experiment. This experiment also proves that people

with UCP1 deficiency are more likely to develop

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obesity as they age than the general population.

(Kontani 2005)

2.2.2 Beta 3-Adrenergic Receptors

β3 adrenergic receptors (β3-AR) are found on the cell

surface of both white and brown adipocytes and are

involved in lipolysis and thermogenesis. In humans,

β3-ARs are widely expressed in brown adipose

tissue, while white adipose tissue has few or no

receptors. The relationship between β3-ARs and

UCP1 is inextricably linked in terms of heat

production. Uncoupling protein -1 is primarily

responsible for the thermogenic activity of brown

adipose tissue. Hypothermia stimulates Ucp1 gene

expression via the sympathetic nervous system and -

adrenergic receptors. (Razzoli 2018)

Variants or absence of β3-ARs can lead to obesity

or less energy expenditure. (Clément 1970) Most of

the β3-ARs mutations are mutations in the Trp64Arg

of the β3-ARs, which can lead to an increased

probability of weight gain, insulin resistance, or

dyslipidemia, as well as a lower-body metabolic rate.

Defects in 3-adrenergic receptor binding, signaling,

or regulatory processes in obese people with such

mutations may result in reduced lipolytic reactions in

adipose tissue, aggravating obesity.

2.3 Fat Synthesis

The previous two parts examined the effect of genes

on appetite and thermogenesis on obesity, starting

from food intake and energy expenditure

respectively. The main direction of this paragraph is

about the relationship between fat storage and

production and obesity. (Lazar 2004)

In adipogenesis, peroxisome proliferator-

activated receptors γ are the primary regulators of

adipogenesis. The most abundant expression of

PPAR is found in adipose tissue, and two different

PPARγ isoforms, PPARγ1 and PPARγ2, have been

identified. Cells are also found in other organs, such

as breast, colon, liver, and vascular cells. The

expression of the PPARγ2 isoform appears to be

entirely adipocyte specific.(Stienstra 2007)

Adipogenesis is dependent on PPAR, and PPAR

target genes regulate adipocyte differentiation, lipid

storage, and glucose metabolism. In the liver, PPARγ

is able to balance triglycerides and helps contribute to

steatosis. At the same time, PPARγ in the liver

protects other tissues from triglyceride accumulation

and insulin resistance. In addition to this, PPARγ is

also involved in managing inflammatory responses

and has been shown to reverse macrophage

infiltration and thus reduce inflammatory gene

expression.

Therefore, PPARγ plays an essential role in our

bodies. When there is a deficiency or variation of

such an important gene, the body can suffer serious

consequences. This issue was confirmed in mouse

experiments, where mice's previous adipose-specific

knockdown of the PPARγ gene did not show a

dramatic phenotype in vivo. However, a specific

mouse type, Adipoq-Cre mice, was used to drive

adipose-specific recombination during the

experiments. At 3 months of age, there is little visible

brown and white adipose tissue, according to reports.

As a result, mice appeared to have hugely enlarged

pancreatic islets, massive fatty liver, and dramatically

increased blood glucose and serum insulin levels with

extreme insulin resistance. (Wang 2003) All of which

are major complications of obesity and common

pathophysiological bases for the development of

metabolic disorders and other chronic diseases in

obese populations.

3 TREATMENTS

3.1 Congenital Leptin Deficiency

(Leptin Injection)

Congenital leptin deficiency is a specific condition

that causes obesity and is relatively simple to treat.

Daily subcutaneous injections of recombinant human

leptin have been shown to be effective in treating

congenital leptin deficiency, resulting in persistent

beneficial effects on weight reduction, reduced

hunger, normal pubertal development, and

hyperinsulinemia, according to theoretical and

clinical instances.

During the treatment process, some

considerations need to be taken into account. Before

the injection may be administered, the patient must

first be clinically examined for an endocrine,

sympathetic, and immunological function to confirm

that they are normal. There are examples of clinical

use of recombinant methionyl human leptin (r-metHu

Leptin, Amylin Pharmaceuticals, San Diego, USA).

In addition to this leptin, injections need to be

administered at low physiological doses and need to

mimic the normal circadian rhythm of leptin, usually

starting at 6 pm. (Paz-Filho 2009) This article

confirmed that the body composition, food intake and

energy expenditure, lipid and glucose metabolism,

sympathetic tone, and gonadal, adrenal, somatic, and

thyroid functions are all affected by treatment.

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Somatic and thyroid functions. The article also

mentions other conditions affected by leptin include

obesity, steatosis syndrome, diabetes, hypothalamic

amenorrhea, and anorexia nervosa. (Paz-Filho 2010)

Figure 2: The effect of leptin treatment in adults (Licinio 2021)

These three graphs were produced by Julio

Licinio, Sinan Caglayan et al. for three leptin-

deficient adults treated with r-metHuLeptin injections

for 18 months. In Figure A, it can be seen that all three

patients had significant weight loss. During the

treatment process, the three patients lost weight

without any dietary changes or additional daily

activities. Figure B shows the energy intake of the

three patients. It shows a relationship between weight

loss and energy intake. R-metHuLeptin injections

suppressed their appetite and allowed them to lose

weight by reducing their energy intake. All three

individuals had significant weight loss after 18

months of treatment. Patient A, for instance, lost

more than half of his initial body weight. These

graphs reveal that leptin injections can effectively

cure patients with congenital leptin deficiency.

3.2

MC4R Deficiency (Bariatric

Surgery or Injections of

Liraglutide)

MC4R gene mutations, also called MC4R deficiency,

are divided into homozygous and heterozygous

mutations. There are corresponding treatments for

both mutations; Obesity is linked to heterozygous

MC4R mutations in a dominantly inherited manner.

MC4R deficiency affects around 2-5 percent of obese

children, 1% of obese adults, and about 1/500 of the

general population, making it the most prevalent

single-gene cause of obesity. (Melanocortin 2021)

The treatment for MC4R heterozygous mutations is

bariatric surgery, called Roux-en-Y-bypass surgery.

The size of the upper stomach will be reduced to a

tiny pouch roughly the size of an egg with this

operation. This will result in weight loss, however, in

those who have homozygous mutations, this

procedure may not be beneficial. The treatment for

patients with homozygous mutations is injections of

liraglutide, a GLP-1 receptor agonist that causes

weight loss by reducing appetite. The example of

obese people with the pathogenic MC4R mutation

treatment resulted in an average weight loss of 6.8 kg.

(Iepsen 2018) Overall fat, waist circumference,

fasting, and postprandial glucose concentration were

all decreased in a comparable way. As a result,

liraglutide might be an effective therapy for obesity's

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most frequent homogenous mutation.

Figure 3: Results of liraglutide treatment for 14 people during 16 weeks (Iepsen 2018).

This graph is a comparison graph of 14 people

treated with liraglutide for 16 weeks done by Eva W.

Iepsen, Jinyi Zhang, et al. The graph shows the

comparison of fat mass, lean body mass, liver mass,

and muscle fat. There is a significant decrease in fat

mass in both MC4R deficient and controlled groups.

In addition, lean body mass and liver mass also

decreased. This fully demonstrates that liraglutide

treatment is helpful in MC4R deficient group. It is a

very good treatment option.

3.3

UCP Deficiency (Rosiglitazone)

UCP deficiency is not a direct cause of obesity in

people, but UCP deficiency can make that group of

people more susceptible to obesity. Moreover, UCP is

involved in the thermogenesis of brown fat which

helps burn fat. If UCP is deficient, the body will be

forced to use other thermogenic systems, which is one

less way to help the body burn fat and is another form

of obesity causing factor. Thus, the way to treat UCP

deficiency is to take rosiglitazone (Rosi), which is a

PPAR gamma agonist, usually in the form of a pill. It

can be taken with or without meals at regular times.

This drug was shown to be used in the treatment of

UCP because, in primary cultures of brown

adipocytes, rosiglitazone has an "exogenous" effect

and induces p44/p42 and p38 mitogen-activated

protein kinase (p38MAPK) activation. The latter is

involved in the expression of the UCP-1 gene. Thus,

the action of Rosi can lead to a high increase in

transcriptional activity on the UCP-1 enhancer,

leading to thermogenic effects. (Teruel 2002)

Ultimately it will help patients to stimulate

thermogenesis and fat oxidation in humans.

3.4

Beta 3-Adrenergic Receptors

Mutation (Mirabegron)

People with mutations in the beta3-adrenergic

receptor gene (Trp64Arg) typically develop non-

insulin-dependent diabetes with a low metabolic rate,

as well as increased body weight. Treatment is with

Mirabegron, a beta3-AR agonist that effectively

activates BAT. It will enhance glucose homeostasis

and treat several of the underlying mechanisms of

insulin resistance, such as insulin sensitivity and

secretion, while also improving adipose tissue and

inflammation. Mirabegron begins to work within a

few hours but may take several weeks to reach full

effect. (Finlin 2020)

3.5

PPARγ (Thiazolidinediones)

PPARγ is expressed predominantly in fat and very

low in the liver and muscle. PPARγ deficiency leads

to severe lipoatrophy, insulin resistance, and other

associated metabolic disorders. In addition to its

effects on obesity, PPARγ has a major impact on hair

formation, breast growth, and increased bone mass.

Thus, PPARγ is an important regulator of the

development and function of these adipose-

containing tissues. The treatment of PPARγ is with

thiazolidinediones (TZD). TZD is a synthetic ligand

for PPARγ. PPAR improves glucose and lipid

absorption, boosts glucose oxidation, decreases free

fatty acid concentrations, and reduces insulin

resistance via activating numerous genes in tissues.

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Among the studied genetic defects that cause

obesity, congenital leptin deficiency is the least

frequent one, and it occurs in childhood. MC4R is the

most common genetic defect that causes obesity, and

its treatment is more straightforward than other

genes. One method is bariatric surgery, and the other

is liraglutide injections, which act as an appetite

suppressant. UCP deficiency does not lead to direct

obesity. Still, the study of mice have shown that UCP

deficiency can lead to a higher risk of future obesity

than in the general population. Both β3-AR and

PPARγ genes are critical, and deficiency is associated

with obesity and metabolic problems. In particular

the master gene PPARγ can cause problems in many-

body functions. β3-AR is treated with Mirabegron.

Mirabegron is an agonist of β3-AR itself, and PPARγ

is somewhat similar to β3-AR, but is treated with

Thiazolidinedione, which is a PPARγ agonist, is also

used to stimulate PPARγ to treat obesity. Although

TZD is beneficial for obesity and insulin resistance,

some studies have shown that the use of TZD, the

synthetic ligand of PPARγ, leads to bone-crunching,

which allows for higher fracture rates. Rosiglitazone

inhibits osteoblast differentiation and activates

osteoclast differentiation, leading to bone loss due to

reduced bone formation and increased bone

resorption. (Wei 2011) Therefore, more researches

are needed to find better solutions to the problem of

PPARγ deficiency.

4 CONCLUSIONS

This paper mainly focuses on the causes and possible

solutions of obesity caused by genes and metabolism

in populations with different genetic defects. And

also, this study has successfully summarized and

concluded the effects of each gene congenital or

mutation and the corresponding treatment options.

However, during the research process, it was found

that some genes, such as the UCP1 gene defect, do

not respond significantly in human bodies but are

inferred from experiments in mice, and further

clinical studies are needed in the future. Also, most of

the treatments found in this study were

pharmacological, and the PPARγ treatment drug

Thiazolidinediones had significant side effects,

which needs to be further investigated in the future

treatment of PPARγ gene defects.

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