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Obesity Leads to Elevated Level of Circulating Cell-Free DNA
Al-Hatamleh MAI1, Tengku MA2, Alshajrawi OM1, Ilyas MN1, Rao SKsup>2, Majid L3, Zubaidi AB1, Nordin Bin Simbak1 and Atif AB1*
1Faculty of Medicine, Universiti Sultan Zainal Abidin, Kuala Terengganu, Malaysia
2Institute for Community (Health) Development, Universiti Sultan ZainalAbidin, Malaysia
3Department of Chemical Pathology, CMH Quetta, Pakistan
Submission: June 06, 218; Published: September 20, 2018
*Corresponding author: Atif Amin Baig, Faculty of Medicine, Universiti Sultan Zainal Abidin, Kuala Terengganu, Malaysia.
How to cite this article: Al-Hatamleh MAI, Tengku MA, Alshajrawi OM, Ilyas MN, Rao SK, Majid L, Zubaidi AB, Nordin B S, Atif AB. DNA Replication. Curr Trends Biomedical Eng & Biosci. 2018; 16(4): 555944. DOI:10.19080/CTBEB.2018.16.555944.
With the steadily growing number of studies in the issues related to obesity research, it is proven, that obesity might be related to wide number of body disorders, some of these disorders have been already studied and investigated, and some still needed more investigations, which has opened new horizons to unlimite hypotheses about involvement of obesity in many physiological disorders. In the current opinion, we hypothesized to the conclusion that there is a correlation between obesity severity and elevated cfDNA levels in the circulation. This correlation is based on free radicals and oxidative stress hypothesis of cellular and molecular damage in cell injury, which in turn leads to a disorder in the whole body and enhances the inflammatory status.
Abbrevations: WHO: World Health Organization; NIH: National Institutes of Health; BMI: Body Mass Index; LEPR: Leptin Receptor; LEP: Leptin; POMC: Pro-Opiomelanocortin; MC4R: Melanocortin-4 Receptor; SNP: Single-Nucleotide Polymorphisms; ROS: Reactive Oxygen Species
It is clear to the medical community the importance and impact of the various types of obesity on a wide range of diseases and physical disorders and requires more research and investigation in any relationship suspected between obesity and other disorders. This review emphasizes a new opinion and summarises the current state of knowledge about the impact of obesity on level of cell-free DNA in circulation, which has been used recently as a new and significant biomarker for some illness and inflammatory disorders.
Obesity has received significant attention as a complex health hazard. Obesity is defined as a status of excessive fat accumulation in adipose tissue which is resulting in health is impairment . The National Institutes of health (NIH) and The World Health Organization (WHO) have used Body Mass Index (BMI) which is the most widely used measure of obesity due to its low cost and simplicity. BMI is defined as the weight in kilograms divided by the height in meters squared, according to BMI overweight means as a BMI between 25.0 and 29.9 kg/m2; and obesity as a BMI greater than 30.0 kg/m2 [2,3].
The most common methods used as reference measures of body composition especially for research purposes include single-cut imaging of the abdomen using computed tomography scan or magnetic resonance imaging, densitometry, and dual- energy X-ray absorptiometry. However, increasing evidence indicates that abdominal obesity is also useful beside total body fat, and it is independent predictor of several cancer and cardiovascular-related outcomes in addition to other illnesses . Some of the commonly used measures of abdominal obesity are hip circumference, waist circumference, and waist-to-hip ratio [2,3].
Obesity is a complex, multifactorial, and one of the greatest public health epidemics of the 21st century . The prevalence of obesity is rising globally, with about 2 billion adults worldwide currently classified as being overweight or obese . However, estimates of its prevalence are still insufficient for all countries, and the available data are not comparable or uniformly accurate . If secular trends continue, by 2030 an estimated 20% will be obese and another 38% of the world’s adult population will be overweight . In the USA, based on earlier secular trends point, by 2030 an estimated 85% of adults will be obese or overweight . Whereas in most developed countries growth, trends in overall obesity seem to have levelled off , but still morbid obesity in many of these countries continues to rise, including among children. Furthermore, obesity prevalence in most developing countries continues to trend upwards toward US levels .
Environmental factors are seeming to be major contributors
to the obesity. It is certain that obesity evolves when there is
an imbalance between increase energy intake and decrease
energy expenditure. Evidence supports the contribution of
both excess energy intake and decreased energy expenditure
in the obesity epidemic [10-12]. On the other hand, it is known
that single gene mutations are associate with rare forms of
monogenic obesity (leptin receptor (LEPR), leptin (LEP),
pro-opiomelanocortin (POMC), and melanocortin-4 receptor
(MC4R)) . However, there is growing evidence that singlenucleotide
polymorphisms (SNP) or common genetic variants
may play an important role in the obesity. These SNPs have some
effects on an individual susceptibility to obesity, but due to their
high frequencies, if involved in lipogenic pathways, may be able
to have a wide contribution to obesity in the population .
Besides, nutrigentics plays a vital role . The methods used
for analysis these mutations are limited and there is a need to
work with a cos-effective method [16,17] and to consider any
particular method as a prominent bimolecular tool for obesity
and its severity.
It has been reported that obesity is associated with chronic
systemic inflammation in adipose tissue. This condition is
affected by the activation of the innate immune system in adipose
tissue that enhances oxidative stress and pro-inflammatory
status, affecting a systemic acute-phase response. Various
chronic diseases are also the result of obesity (e.g., diabetes
mellitus, metabolic syndrome, cancers, and cardiovascular and
liver diseases) and associated with oxidative stress . So, it
has been hypothesized that inflammation of adipose tissue in
obese patients plays a significant role in the pathogenesis of
obesity-related disorders .
Adipose tissue is a storage organ required for energy
homeostasis. Adipose tissue is composed of adipocytes primarily
and contains other cells (e.g. pre-adipocytes, endothelial,
fibroblasts, fibroblastic and immune cells) , secreting
hormones and cytokines (adipocytokines or adipokines) which
exercise autocrine, endocrine, and paracrine action on the
whole body. In pathological and, even more, in physiological
conditions, adipokines also induce the production of reactive
oxygen species (ROS), generating oxidative stress and, in turn, a
major, irregular output of other adipokines . Oxidative stress
and pro-inflammatory processes are strongly associated [22,23].
Upon activation, many immune cells produce free radicals, and,
in the same way, the synthesis of ROS enhances the inflammatory
Oxidative stress is also considered as a measure of unbalance
between the production of free radicals and antioxidant defences
[24-26]. Oxidative stress has been involved in response to stress
and the pathogenesis of psychiatric and neurologic diseases
[27-29]. Mostly, the main cause of oxidative stress has been a
production of free radicals. Free radicals are chemical species
which contain an odd number of electrons in last electronic
layer . This state of electrons of the last layer that grant high
reactivity to these molecules or atoms . ROS often generated
by mitochondria, in addition to other sources of ROS, such as
NADPH oxidase (NOX) enzymes; they are a group of membrane
proteins with a known function to generate ROS. These enzymes
are working as a transmembrane electron transport chain by
using cytoplasmic NADPH as an electron granter to O2 molecule
to generate superoxide anion in the lumen of intracellular
organelles or the extracellular space. Superoxide anion is mostly
considered the essential product of the electron transfer, also to
generate other ROS in particular hydrogen peroxide [32,33].
The researchers have identified a total of seven NOX genes:
NOX1 to 5 and DUOX1 and 2. The better-described isoform
NOX2 needs interaction with another trans-membrane protein,
p22phox, in addition to the cytosolic subunits, p40phox,
p47phox, p67phox, and with one of the small Rho GTP-binding
proteins, Rac1 or 2. On the other hand, other NOX isoforms
have a different mechanism of activation and require p22phox
for activity. NOX3 and NOX1 enzymes require interaction with
cytosolic subunits, NOXO1 and NOXA1, and with Rac1 or 2 .
NOX4 seems to be constitutively active; NOX5 and DUOX enzymes
are often regulated by increased intracellular Ca2+ . It is
worth mentioning that ROS generated by NOX enzymes can
directly impact cellular functions; by encourage the oxidation of
proteins, then their functional and structural changes . From
this particular issue we suggested that increases oxidative stress
which is enhances the inflammatory status, subsequently causes
damage and destruction of cells which is increasing cell-free
DNA in circulation.
In 1948, Mandel and Metais discovered the presence of cellfree
DNA (cfDNA) in blood plasma . This discovery was not
attracted great attention in the medical scientific community
until 1994; when the importance of cfDNA was explored in the
study of mutated RAS gene fragments in the circulation of cancer
patients [36,37]. Understanding the mechanisms of generation
of cfDNA is important for conclusion its role in pathology and
biology and speeding the translation of analyses to clinical
practice. Despite the apparent of cfDNA in blood circulation
and other bio-fluids, the exposition of its origin has only been a
partial triumph [36,37].
Mostly, cfDNA are found as double-stranded molecules with
molecular weights in the wide range of 0.18 kB to 21 kB [38,39].
Various possible sources and cognate mechanisms have been
detected. Firstly, it was supposed that cfDNA enters the blood
following the cells lysis on the interface between a tumour and
blood circulation only. Since it was reported in patients that the
concentration of cfDNA in their blood is higher than could be accounted for by the mass of cells present, this hypothesis has
been abandoned . The exact mechanism of releasing cfDNA
into the blood circulation is still unknown, several researchers
have suggested that in either healthy or diseased individual’s
cfDNA is predominantly haematopoietic origin [41,42]. They
also demonstrated that under normal conditions, cfDNA is
released from apoptotic rather than necrotic processes. It
should be emphasized on the role of a dynamic balance between
processes of cellular DNA secretion/release and mechanisms
of DNA degradation and clearance in the keep of the existing
level of cfDNA in human blood [43,44]. The cfDNA is composed
of both genomic DNA (gDNA) and mitochondrial DNA (mtDNA)
. The concentration of cfDNA has been assessed previously
by quantitative PCR (such as TaqMan and SYBR Green) or by
different fluorescence-based methods (such as, ultraviolet (UV)
spectrometry and PicoGreen staining) .
Based on the above discussion, increased oxidative stress,
which might result in enhancing inflammatory status and result
in cell damage can therefore proposed to rise in circulation of
cfDNA. Therefore, various metabolic diseases also can have high
chances of high cfDNA level in circulation according to hypothesis
of related cfDNA with oxidative stress. The significant disorders
might be associated with cfDNA are mertabolic diseases high
oxidative stress, for example, obesity and diabetes [47-49].
Studies are required in future to look into the effect of severity
of metabolomics stress and oxidative stress on cfDNA .
Looking at the cited literature, we hypothesized to the
conclusion that there is a correlation between the obesity and
elevated cfDNA levels. This correlation based on free radicals
and oxidative stress hypothesis of cellular molecules damage
and cell injury which in turn leads to a disorder in the whole
body, but it still needs to more study and investigation.