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Asian Journal of Medical Sciences | Jan-Feb 2019 | Vol 10 | Issue 1 1
The impact of obesity on cardiovascular
disease risk factor
Arun Kumar
Professor and Head, Department of Biochemistry, Jagannath Gupta Institute of Medical Sciences, Buita, Budge Budge,
Kolkata-700137
ABSTRACT
REVIEW ARTICLE ASIAN JOURNAL OF MEDICAL SCIENCES
Submitted: 08‑10‑2018 Revised: 27‑11‑2018 Published: 01‑01‑2019
Obesity has emerged as the most potential cardiovascular risk factor and has raised concern among
public and their health related issues not only in developed but also in developing countries. The
Worldwide obesity occurrence has almost has gone three times since 1975. Research suggests
there are about 775 million obese people in the World including adult, children, and adolescents.
Nearly 50% of the children who are obese and overweight in Asia in are below 5 years. There
is a steep incline of childhood obesity when compared to 1971 which is not only in developed
countries but also in developing countries. A considerable amount of weight gain occurs during
the transition phase from adolescence to young adulthood. It is also suggested that those adults
who were obese in childhood also remained obese in their adulthood with a higher metabolic risk
than those who became obese in their adulthood. In India, the urban Indian female in the age
group of 30-45 years have emerged as an 〝at risk population” for cardiovascular diseases. To
understand how obesity can inuence cardiovascular function, it becomes immense important
to understand the changes which can take place in adipose tissue due to obesity. There are two
proposed concepts explaining the inammatory status of macrophage. The predominant cause
of insulin resistance is obesity. Epidemiological and research studies have indicated that the
pathogenesis of obesity-related metabolic dysfunction involves the development of a systemic,
low-grade inammatory state. It is becoming clear that targeting the pro-inammatory pathway
may provide a novel therapeutic approach to prevent insulin resistance, particularly in obesity-
induced insulin resistance. Some cost effective interventions that are feasible by all and can be
implemented even in low-resource settings includes - population-wide and individual, which are
recommended to be used in combination to reduce the greatest cardiovascular disease burden.
The sixth target in the Global NCD action plan is to reduce the prevalence of hypertension by
25%. Reducing the incidence of hypertension by implementing population-wide policies to
reduce behavioral risk factors. Reducing cigarette smoking, body weight, blood pressure, blood
cholesterol, and blood glucose all have a benecial impact on major biological cardiovascular risk
factors. A variety of lifestyle modications have been shown, in clinical trials, to lower blood
pressure, includes weight loss, physical activity, moderation of alcohol intake, increased fresh
fruit and vegetables and reduced saturated fat in the diet, reduction of dietary sodium intake, and
increased potassium intake. Also, trials of reduction of saturated fat and its partial replacement
by unsaturated fats have improved dyslipidaemia and lowered risk of cardiovascular events.
This initiative driven by the Ministry of Health and Family Welfare, State Governments, Indian
Council of Medical Research and the World Health Organization are remarkable. The Government
of India has adopted a national action plan for the prevention and control of non-communicable
diseases (NCDs) with specic targets to be achieved by 2025, including a 25% reduction in
overall mortality from cardiovascular diseases, a 25% relative reduction in the prevalence of
raised blood pressure and a 30% reduction in salt/sodium intake. In a nutshell increased BMI
values can predict the nature of obesity and its aftermaths in terms inammation and other
disease associated with obesity. It’s high time; we must realize it and keep an eye on health
status in order to live long and healthy life.
Key words: Body mass index; Waist to hip ratio; Cardiovascular risk; Global Prevalence;
Asian; Indian; Obesity; Obesity induced inamation; Preventional Strategies
Access this article online
Website:
http://nepjol.info/index.php/AJMS
DOI: 10.3126/ajms.v10i1.21294
E-ISSN: 2091-0576
P-ISSN: 2467-9100
Address for correspondence:
Dr. Arun Kumar, Professor and Head, Department of Biochemistry, Jagannath Gupta Institute of Medical Sciences, Buita, Budge Budge,
Kolkata‑700137 E-mail: arun732003@gmail.com Tel No: +91‑7584089886 © Copyright AJMS
Arun Kumar: Body mass Index indicator as cardiovascular risk
2 Asian Journal of Medical Sciences | Jan-Feb 2019 | Vol 10 | Issue 1
INTRODUCTION
BMI is the body mass divided by the square of the body
height, and is universally expressed in units of kg/m2,
resulting from mass in kilograms and height in metres.
The BMI basically indicates the quantity of tissue mass
viz, muscle, fat, and bone in a subject. Based on the
BMI values, the subjects are categorized as underweight,
normal weight, over-weight or obese. The widely
accepted categories based on the values are underweight;
<18.5 kg/m2, normal weight; 18.5-25 kg/m2, overweight- 25
to 30 kg/m2, obese->30 kg/m2. These cut-off values does
not necessarily indicates risks among all globally, as it is
observed that Asians especially Indians have higher risks
due to other compounding factors such as type 2 diabetes
and cardiovascular disease as an additive risk at BMIs lower
than the WHO cut-off point for overweight, 25 kg/m2.
Which is better indicator of risk: BMI or waist to hip
ratio?
As it is already established and widely accepted that
increased blood pressure, higher ratio of total cholesterol
to high-density lipoprotein are considered as standard
markers of risk for cardiovascular diseases. Evidence shows
that BMI; normal ≤25kg/m2 and waist-to-hip (W/H) ratio
measurements (normal: women ≤0.8, men≤ 0.9) may serve
as a better atherogenic prognosticators. Studies conducted
study among obese women, W/H ratio was considered as
better indicator of peer cardiac status than BMI.1 Waist
to hip ratio was not only signicantly connected to blood
pressure and total cholesterol/HDL-cholesterol but also to
triacylglycerols where as BMI was signicantly associated
to total cholesterol/HDL-cholesterol which is indicative
of better foreteller than depending on mere BMI values.2
In a case-control study conducted among a total of 26903
participants who presented with their rst myocardial
infarction (MI) within 24 hours of symptoms onset from
52 countries3 who were age/sex matched and with no
history of CVD. The researchers observed that though
BMI values were directly related to the risk of MI, but the
relation disappeared after adjustment of W/H ratio and
other risk factors.
Obesity as a risk factor for cardiovascular diseases
The term “risk factor” includes modiable life styles
and biochemical and physiological characteristics as well
as non modiable personal characteristics such as age,
gender and family history of early onset of cardiovascular
disease (CVD) found in healthy individuals, which are
independently related to the subsequent occurrence of
coronary heart Disease (CHD) (Figure 1). The effects of
risk factors in adults are additive i.e. the greater the number
of high risk factors present, the greater the risk of CVD.
Obesity has emerged as the most potential cardiovascular
risk factor and has raised concern among public and their
health related issues not only in developed but also in
developing countries.4 As per reports by World Health
Organization, more than 1400 million adults across the
globe were overweight in 2008, and obesity being the
most prevalent among more than 200 million men and
300 million women world-wide.5 Two-third of the world’s
population lives in countries where the most signicant
cause of death is due to obesity related illness.6 Being
overweight in adulthood increases the risk of cardiovascular
disease.
Obesity‒ global prevalence
The Worldwide obesity occurrence has almost has gone
three times since 1975. In 2016>1.9 billion adults >18 years
were overweight.7 Among them >650 million were obese.
Thirty-nine percent (39% of men and 40% of women)
of adults aged ≥18 years were overweight in 2016,
and overall about 13% of the world’s adult population
(11% men and 15% of women) were obese.8 Most of the
world’s population lives in countries where overweight and
obesity (Figure 2)are silent killers rather than underweight.9
Forty-one million children <5 years were overweight or
obese in 2016. Over 340 million children and adolescents
aged 5-19 were overweight or obese in 2016. Once was
once considered as the disease of the developed country,
but now it is also predominant in lower and middle income
countries, more in urban localization.7
Obesity among other countries
New research suggests there are about 775 million
obese people in the World including adult, children, and
adolescents.10 Research ndings suggest that there are
nearly 650 million obese adults on the planet and about
125 million obese children and adolescents in the entire
world according to a BMI values of >30.11 The most obese
countries are USA, China and India ranks third among the
list. More than 50 percent of the world’s 775 million obese
people live in just ten of these countries: United States,
China, India, Russia, Brazil, Mexico, Egypt, Germany,
Figure 1. Risk factors of cardiovascular disease
Arun Kumar: Body mass Index indicator as cardiovascular risk
Asian Journal of Medical Sciences | Jan-Feb 2019 | Vol 10 | Issue 1 3
Pakistan and Indonesia.11 The highest proportion of
the world’s obese people, 13 percent, live in the United
States.6 In Africa, there is almost 50% increased overweight
children since 2000. Nearly half of the children who were
obese and overweight in Asia in 2016 were below 5 years.
Obesity a major health threat among indians
In India, the urban Indian female in the age group of
30-45 years have emerged as an“at risk population” for
cardiovascular diseases.12 Ninety-ve percent of them are
overweight or obese. Cardiovascular diseases in women are
slowly on the rise and now considered as epidemic. Heart
ailments have replaced communicable diseases in both rural
and urban India. Indian urban women are at more risk today
than they were three years ago. The reasons for the high
cardiovascular diseases in women includes, an unhealthy
lifestyle, increased intake of food containing high trans fat,
cheese, sugar and salt.13 Inadequate physical exercise and
stressful life, dependence onalcohol and tobacco, untimely
dinners are the leading cause of increased abdominal
obesity and increased W/H ratio which is a major risk
factor for heart diseases.14
The largest groups of women at risk of cardiovascular
diseases are aged between 35 to 44 years.15 Low HDL-c
and high BMI are the most common harbingers of CVD.
Cardiovascular risk is as high amongst housewives as it is
amongst working professionals. The symptoms exhibited
by women are also different than those by men. Women
are less likely than men to have typical angina. They have
higher false positive rate in treadmill test. Heart disease in
women generally presents 10 years later than men but with
greater risk than men. These premature deaths from CVD
could be avoided if tobacco use, unhealthy diet, physical
inactivity and harmful use of alcohol are controlled.
Obesity among children in other countries
There is a steep incline of childhood obesity when
compared to 1971 which is not only in developed countries
but also in developing countries.16 The occurrence of
childhood obesity among Mediterranean countries
surpasses the Scandinavian countries; nonetheless, the
proportion of obese children is rising in both regions.
Childhood obesity observed the Middle East, Central
and Eastern Europe has the higher prevalence and Iran
tops the list of childhood prevalence countries.17 Among
developed countries, North America, Great Britain and
some South Western European Countries (Greece, Italy,
Malta, Portugal, Spain) the prevalence of overweight youth
(10-16 years) was > 15%. In Egypt and Cyprus, 14%
and 25% of 6-11 year old children were reported to be
overweight or obese. Obesity is increasingly being reported
from countries such as Taiwan and Saudi Arabia. In Saudi
Arabia, one in every six children aged 6 to 18 years old is
obese.18 The incidence of obesity at all ages is on the rise
in the developing countries including India. Reports from
South India validates 21.4% of boys and 18.5% of girls
aged between 12-14 years were overweight or obese.19
The prevalence of obesity among School children in India
has been reported between 5.74% and 8.82%.17During
last two decades, the prevalence of overweight among
children and adolescents havealmost doubled in USA and
tripled in Canada and Brazil.20It is observed from studies
that those overweight adolescent have a strong tendency
to become overweight in their adulthood and follow up
studies observed that these adolescent are more likely to
be affected by cardiovascular mortality.20
Epidemiology and global scenario of obesity
Obesity has reached epidemic proportions in the developed
countries harboring around 30-40% of obese adults and
children.21 World health organization has declared obesity
Figure 2. Global prevalence of obesity
Arun Kumar: Body mass Index indicator as cardiovascular risk
4 Asian Journal of Medical Sciences | Jan-Feb 2019 | Vol 10 | Issue 1
as one of the most neglected diseases. The 2002 World
Health Report lists overweight as the fth most serious
risk factor for both developed countries and developing
countries. According to the report of International Obesity
Task Force (IOTF), in the year 2000 about 10% (a total of
155 million) of the young people aged 5-17 years globally
were overweight; among whom 2-3% (30-45 million) were
obese, a further 22 million younger children are also affected
according to previous IOTF global estimates based on WHO
data for under ves.20It is predicted that the levels of obesity
will continue to rise unless action is taken now. WHO has
warned “the growth in the number of severely overweight
adults to double that of underweight during 1995-2025”
(WHO 1998).17 From existing data it has been projected
that by the year 2030 levels of obesity could be as high as
50-80% in the USA, between 30-40% in Australia, England
and Mauritius and over 20% in some developing countries.
Obesity among children
Over the past 30 year period, the world wide prevalence
of obesity in childhood has drastically increased. Globally
in 2010, around 43 million children <5 years were
over-weight. In a study comprising of children aged
1-17 years, overweightincreased the chances for pre-
hypertension by 50% and doubledor tripled the gures
in terms of hypertension, compared with normalweight
children.Hypercholesterolemia in childhood is common
in westernized countries with high rates of CHD.
Atherosclerosis embarks at the age of nine years, evidence
and supported by the study of cross sectional area of
common carotid artery wall and the mean intima thickness
of internal carotid arteries, which shows progressive
increase in thickness due to fat deposition from lean to obese
children. Autopsy studies have shown that early coronary
atherosclerosis often begin in childhood and adolescence.22
Further, hypercholesterolaemia in adolescents correlated
positively with changes in vasculature predictive of later
CVD.23There is a tendency to persistence in ranks (tracking)
for serum total and B-lipoprotein cholesterol with age.
A considerable amount of weight gain occurs during the
transition phase from adolescence to young adulthood.
It is also suggested that those adults who were obese in
childhood also remained obese in their adulthood with
a higher metabolic risk than those who became obese
in their adulthood.24It has been found that maternal
obesity is the most signicant predictor of obesity during
childhood.25 Thus the combination of having an obese
mother and an earlier onset of obesity translates into higher
BMI and weight at young adulthood. Risk parameters
for cardiovascular disease in childhood such as BMI,
cholesterol, blood pressure and triglyceride concentrations
have shown to be signicantly correlated with adult levels
over long term follow-up.
Childhood obesity causes increase in fasting insulin
concentration to almost 12 manifoldin obese children
aged 5 to 17 years.26 In addition, amounts of triglycerides,
totalcholesterol, low density lipoprotein cholesterol (LDL-
cholesterol), and high density lipoprotein-cholesterol
(HDL-cholesterol) are all more likely to be abnormal
in overweightchildren than in normal weight children.
Therefore, childhood health could greatly affect the risk
ofcardiovascular disease in adulthood.
Causes of obesity among children
The fundamental cause of obesity and overweight is an
energy imbalance between calories consumed and calories
expended. Studies have conrmed that there is a decline
in daily physical education classes in high school students
with some schools removing the period of physical
education from their time table, down trends in the number
of children walking or cycling to school, and increase in
sedentary lifestyles such as use of computers and mobiles
phone games which limits their physical activity and
outdoor games.
Obesity – major contributory factor for cardiovascular
diseases
As we gain additional fat in the body, it forms an additional
very active metabolic organ and these organs constantly
generate very harmful substances called as free radicals
or the active oxidant species.27 Excessive formation
of free radicals damages the cells and this process is
called as oxidative stress. Oxidative stress than triggers
an inammatory process which can affect the cells of
throughout the whole body as they circulate in the blood
stream. When trying to protect from these harmful
processes, the target cells become resistance to action of
insulin, which is also known as insulin resistance. If we are
constantly exposed to these free radicals in our modern life
style, such as high fat meals, inadequate sleep, stressful job,
lack of exercise, sedentary life style, smoking consequently
leads to low-grade chronic inammation can cause havoc in
our body.27 These chain reaction of free radical formation,
oxidative stress, insulin resistance and inammation is
an interactive destructive metabolic cycle whereby we
develops most of the diseases of life style namely diabetes,
hypertension, cardiovascular diseases and cancer.
An individual’s genetic make-up is one of the most
important probabilities of developing certain diseases,
including cardiovascular disease.The foundations of adult
health are predestined in early stages of their life, much
even before birth. It is most likely that poor young mothers
with low educational status are most likely to give birth to
low-birth-weight baby and less likely to breastfeed. These
low-birth-weights are usually associated with increased
risk of developing coronary heart disease, stroke and high
Arun Kumar: Body mass Index indicator as cardiovascular risk
Asian Journal of Medical Sciences | Jan-Feb 2019 | Vol 10 | Issue 1 5
blood pressure. Healthy life styles, good health-related
habits,exercise, are all learnt early in life by the nurture
and care of sensible peer and parents. Socioeconomic
group is another factor which plays a vital role in future
risk of CVD. Earlier research conducted has shown that
males between 20-64 years of age in semi- and unskilled
manual occupations have 3 folds higher risk of pre-mature
death due to CVD. Moreover, when improvements to
health do occur, the benets are unevenly distributed
within society. Demanding white color jobs and stressful
life is associated with CVD and depression being another
predictor of poor life expectancy among those who suffer
from cardiovascular diseases. High salt intake leading to
hypertension and consumption of saturated fat and trans-
fat furthermore increases the risk of CVD. Overweight and
obese are especially predisposed to develop CVD. Physical
activity of at least 150 minutes each week is estimated to
decrease the CVD risks by 30% further reducing the risk
of stroke and hypertension.Tobacco use in any form is
estimated to cause about 10% of cardiovascular disease
worldwide. Alcoholconsumption also increases the risk
of cardiovascular diseases. Diabetes is yet another major
risk factor and trigger for cardiovascular disease. Due to
urbanization the trend of people is towards unhealthy diets
and diverting from the good habits which causes serious
implications of obesity.
Mechanism of obesity induced cardiovascular diseases
To understand how obesity can inuence cardiovascular
function, it becomes immense important to understand
the changes which can take place in adipose tissue due
to obesity. When we consume high calorie diet it causes
expansion of adipose tissue due to increase in the number
of adipocytes which is mediated by proliferation of
adipogenic progenitors.28This increase in adipocytes can
result in an increase in adipocyte size affecting the normal
metabolic functions of adipose tissue. In case of advanced
stage of obesity, these hypertrophied adipocytes may
undergo some necrotic or apoptotic changes contributing
to the generation of inammatory cells, macrophages
and cellular dysfunction of adipose tissue.29 Other
cells surrounding the adipocytes namely lymphoctyes,
macrophages, broblasts and vascular cells also plays an
important role in manipulating the functional status of
adipose tissue.30 The increased macrophages around the
adipocytes lead to higher macrophage-to-adipocyte ratio.
This can further cause systematic inammation along with
insulin resistance.
There are two proposed concepts explaining the
inammatory status of macrophage, namely M1/M2.
(Figure 3) Macrophages that accumulate in adipose tissue
due to inammation process in obese organisms usually
expresses genes associated with M1-like or classically
activated phenotype. On the other hand, macrophages
accumulated in adipose tissue of lean organism tend to
express genes associated with M2-like or alternatively
activated phenotype.31
M1-like macrophages are usually associated with
inammation and tissue destruction due to production of
tumor necrosis factor (TNF)α, it also expresses inducible
nitric oxide synthase (iNOS) and produce high levels
of reactive oxygen and nitrogen intermediates.32On the
contrary, M2-like macrophages are basically inclined
towards wound healing, angiogenesis and resolution of
inammation due to expression of anti-inammatory
cytokines, namely interleukin (IL)-10, and the enzyme
arginase-1 which inhibits iNOS activity.33 It is thought that
M1-like macrophages supports insulin resistance, whereas
M2-like macrophages protect against obesity-induced
insulin resistance.34
Another distinguishing feature of adipose tissue from
obese organism is the presence of crown-like structures in
histological sections.35Thesecrowns like structures represent
macrophages around dead or dying adipocytes. Subjects
lacking these crowns like structures in histological sections
have better metabolic control, diminished expression of
inammatory gene and reduced cardiovascular risk than
those who display such in histological sections.
The T cells in adipose tissue regulate the phenotypic
feature of macrophage which is inuenced by the grade
of obesity in individuals.36CD4+ regulatory T cells and
TH 2-polarized cells which are predominant in the
adipose tissue of lean mice, regulates the adipose tissue
functions and insulin sensitivity.37On the other hand, in
obese state, the accumulation of CD8+ effector T cells
and CD4+ TH1 cells in the adipose tissue generates TH1
signals which initiate the recruitment and activation of
Figure 3. Complement regulating macrophage in inammatory process
Arun Kumar: Body mass Index indicator as cardiovascular risk
6 Asian Journal of Medical Sciences | Jan-Feb 2019 | Vol 10 | Issue 1
macrophages, perpetuate the pro-inammatory cascade
that is associated with insulin resistance.38 Thus, what is
observed that the balance of TH1- and TH2-type signalare
mainly inuenced by obesity, which directly or indirectly
influence macrophage recruitment and phenotype in
adipose tissue, thereby generating either a pathogenic
or a protective environment. Similarly, B cells also play a
pivotal role in obesity-induced adipose tissue inammation,
promoting the T cell and macrophage activation and thus
contributing to insulin resistance.39Neutrophil inltration
and activation also contributes to adipose tissue dysfunction
through the action of neutrophil elastase. Research studies
reported the role of eosinophils in adipose tissue to
promote alternative activation of macrophages and glucose
tolerance through the production of the TH2 cytokine
IL-4.40 Therefore, the status of immune cells in adipose
tissue is an area of thrust for research which needs to be
further validated and investigated for better understanding
of the complex relationship between inammation and
metabolism.
The phenotypic changes in adipose tissue due to obesity are
presumed to induce vascular endothelial cell activation and
recruitment of inammatory cells. It can be justied that
obesity promotes a vicious cycle of endothelial activation
and tissue inammation that contributes to adipose tissue
dysfunction. Supporting this fact, studies shows that
endothelial cells expresses cellular adhesion molecules
such as P-selectin, E-selectin, and intercellular adhesion
molecule 1 (ICAM-1).41Administration of anti-ICAM-1
antibody can be used as a tool to prevent leukocyte-
endothelium interactions and macrophage inltration into
adipose tissue. In addition, adipose tissue inammation also
causes endothelial cell activation through inammatory
adipokines such as TNFα, which could contribute to
obesity-associated cardiovascular disease.
Obesity induced Insulin resistance
The pancreas is a glandular organ of the digestive system
and has dual functions, both exocrine and endocrine.
Classically they have endocrine role related to blood
glucose maintenance via secretion of insulin and other
hormone and an exocrine role related to secretion of
digestive substances involved in digestion process. Insulin
is an anabolic hormone that promotes glucose uptake via
Insulin dependent receptor, glycogenesis, lipogenesis and
protein synthesis of skeletal muscles and fat tissue through
the tyrosine kinase receptor pathway. Insulin maintains
the blood glucose homeostasis and counteracts glucagon,
epinephrine, glucocorticoids and growth hormone. So when
insulin resistance occurs due to obesity and inammation,
it disrupts all insulin-mediated signaling pathways resulting
in systemic hyperglycemia along with other metabolic
symptoms like hypertension and hyperlipidemia.
To understand insulin resistance, we need to clarify
molecular mechanisms of insulin signaling. At the
molecular level, insulin binds to the cell surface insulin
receptor that exists as a α2β2 heterodimer. Following the
binding of insulin the tyrosine kinase domain of β subunits
autophosphorylates and activates its intrinsic kinase activity
to proximal substrates such as insulin receptor substrate
(IRS)42 family (IRS1-IRS4), Insulin sensitivity and secretion
are reciprocally regulated, thus in case of insulin resistance
we observe there is a increased insulin secretion to maintain
normal blood glucose and lipid homeostasis. Several
mediators are thought to be involved in passing a signal to
the pancreatic beta cells to respond to insulin resistance,
failure of those signals or inadequate adaptability results
in inappropriate insulin levels resulting to complications
of insulin resistance.
The potential signal mediators are glucose, free fatty acids,
fat derived hormones (adiponectin) and gut hormone
glucagon like peptide-1 (GLP-1). GLP-1 is an incretin
hormone that is supposed to stimulate insulin secretion,
causes beta cell mitosis while inhibiting apoptosis, inhibits
glucagon secretion, delay gastric emptying and overall anti-
diabetic affects.43
The predominant cause of insulin resistance is obesity. It is
associated with decreased number of receptors and post-
receptor failure to activate tyrosine kinase. Due to insulin
resistance there is an associated risk of cardiovascular
disease and endothelial dysfunction.
The adipokine concept
Adipokines are a family of hormones and cytokines with
both pro- and anti-inammatory effect that are secreted
by adipose tissue. These includes TNH-α and IL-6 (pro-
inammatory), leptin and adiponectin. Epidemiological
and research studies have indicated that the pathogenesis
of obesity-related metabolic dysfunction involves the
development of a systemic, low-grade inflammatory
state.44An excess of pro-inflammatory adipokines is
hypothesized to explain the metabolic syndrome that
accompanies obesity. Additionally several cell types with the
myocardium express adipokines resulting in both autocrine
and paracrine inuences. Since TNF-α and IL-6 inhibit
adiponectin production, decreased circulating adiponectin
is associated with left ventricular hypertrophy, suggesting
that adiponectin might be cardioprotective.45The degree
of obesity could be presumed by the proportional increase
in pro-inammatory maker C-reactive protein and IL-6
which are predictive of development of type 2 diabetes.
In contrast, weight loss leads to decreased levels of CRP
and IL-6. These ndings strongly suggest that obesity is
highly associated with chronic low-grade inammation, and
it is believed that this obesity-linked inammatory state is
Arun Kumar: Body mass Index indicator as cardiovascular risk
Asian Journal of Medical Sciences | Jan-Feb 2019 | Vol 10 | Issue 1 7
due to changes in the expression of cytokines by adipose
tissue (Figure 4).46
Adipose tissue is mainly found in visceral and subcutaneous
depots, it is also widely dispersed throughout the body.
Other depot sites that might be a potential risk for
cardiovascular disease include epicardial, perivascular,
and pulmonary adipose tissue. The levels of adipokine
production determine the adipose tissue depots it generally
favor the production of pro-inammatory adipokines
regardless of depot site location. Interestingly, studies in
mice suggest that aging irrespective of diet-induced obesity
also induces the expression of proinammatory adipokines,
such as TNFα and IL-6 in visceral adipose tissue.47
Most adipokines which are identied till date are pro-
inammatory and they are upregulated in the obese state.
Under conditions of obesity, these adipokines function
to promote metabolic and cardiovascular diseases. Pro-
inflammatory adipokines include TNFα leptin, IL-6,
resistin, RBP4, lipocalin 2, IL-18, ANGPTL2, and others.
In this regard, it is very important to testify whether
the increase in cardiovascular disease associated with an
adipokine imbalance is due to a paracrine mechanism via
local release of pro-inammatory factors from epicardial
or perivascular adipose tissue, or an endocrine mechanism
that is reected by an increase in serum adipokine levels.
Pro-inflammatory adipokine: TNFα, leptin, interleukin-6
Adipose tissue is not only an energy storage organ but also
an active endocrine tissue producing various biologically
active proteins known as adipokines. Adipokines
contributes to pathogenesis of obesity linked metabolic
syndrome and cardiovascular complications. Omentin, a
novel adipokine is a protein expressed and secreted from
visceral but not subcutaneous adipose tissue that increases
insulin sensitivity in adipocytes. Visceral and subcutaneous
adipose tissue part from white adipose tissue, synthesizes
unique adipokines which are mediators of inammation
and insulin resistance in obese human and rodents.48
Research on this line was sparked by the discovery of
adipsin, TNF-α, andleptin which are bonade adipokines.
TNF-α is key mediator and regulator of mammalian
immune response in healthy organism and in diseased
state. It was identied in the beginning as an endotoxin-
induced serum factor that mediates tumor necrosis
and cancer cachexia.49 TNF-α is mostly expressed in
monocytes and macrophages which are converted to their
active form by TNF-α converting enzyme. TNF-α is a
typical pro-inammatory cytokine found to be elevated
in obese humans and rodents suggesting its contribution
to insulin resistance.50 Experimental evidences using cell
lines treatment with TNF- α induces insulin resistance,
and neutralization of TNF-α in obese enhances insulin
sensitivity thus proving its role in inducing insulin
resistance.51 TNF-α enhances the phosphorylation of IRS
on Ser-307 residues that causes suppression of insulin-
induced IRS1 tyrosine phosphorylation and activation
of downstream targets.52 Although TNF-α levels in the
circulation is positively correlated with insulin resistance in
other species, its clinical effects of TNF-α in human is still
controversial. Short-term administration drugs blocking
TNF-α in obese T2D patients suppresses inammation but
when the dosage is increased it does not shows improved
insulin sensitivity. In contrast, long-term treatment of
TNF-α blocking reagent in obese patients with severe
inammatory diseases improves insulin sensitivity.53 TNF-α
also suppresses the expression of phosphodiesterase 3B
(PDE3B) and perilipin. As PDE3B reduces cAMP after
insulin stimulation, and perilipin regulates the access of
hormone-sensitive lipase in adipocytes, TNF-α induces
lipolysis in adipocytes to release free fatty acid. Free fatty
acid in turn binds to TLR4, and pro-inammatory factors
are expressed through NF-KB activation.53
Leptin
This is derived from the Greek meaning thin, the hormone
which is responsible for energy expenditure. This is
predominantly synthesized by adipose cells that balances
energy by inhibiting hunger which are regulated by the
hormone ghrelin also known as hunger hormone. Both
hormones act on receptors present in the arcuate nucleus of
the hypothalamus to regulate appetite in order to achieve
energy homeostasis. In obesity, there is a decreased sensitivity
to leptin, resulting in an inability to detect satiety despite
high energy stores and high levels of leptin.54Although the
fat storage is the primary function of leptin, it plays a role
in other physiological processes. The Ob(Lep) gene (Ob
for obese, Lep for leptin) is located on chromosome 7 in
humans. Any mutation in Leptin gene can cause extreme
obesity in infancy with hyperphagia. Leptin is produced
primarily in the adipocytes of white adipose tissue and
Figure 4. Signaling in inammatory process due to obesity
Arun Kumar: Body mass Index indicator as cardiovascular risk
8 Asian Journal of Medical Sciences | Jan-Feb 2019 | Vol 10 | Issue 1
also by brown adipose tissue, placenta, ovaries, skeletal
muscle, stomach, mammary epithelial cells, bone marrow,
gastric chief cells. The levels of leptin are inuenced by
the inammatory markers and are involved in regulation
of inammatory response specically to adipose-derived
inammatory cytokines.55 Chronically elevated leptin levels
are associated with obesity, overeating, and inammation-
related diseases, including hypertension, metabolic
syndrome, and cardiovascular disease.56Mutation of Obese
gene increases food intake and obesity resulting in T2D.
Importantly, exogenous administration of leptin to Lepob/
Lepob mice reduces obesity and restores insulin sensitivity.57
However, in circulation when leptin levels are increased in
obese rodents and humans it suggests of leptin resistance.
Leptin resistance has been reported as mediated by impaired
leptin transport in blood brain barrier.58Obesity-induced
chronic inammation also induces leptin resistance through
the activation of TLR4, JNK, and IKKβ.59The structure
of leptin is similar to pro-inammatory helical cytokines
including IL-2, IL-6, and granulocyte-colony stimulating
factor (G-CSF), and leptin induces inammatory responses
through leptin receptor b (LepRb)and its proximal Janus
kinase 2 (JAK2) and signal transducer and activator
of transcription 3 (STAT3) signaling pathway. Leptin
activates monocytes and macrophages to produce pro-
inammatory IL-6, TNF-α, and IL-12 and stimulates the
production of CCL2 and vascular endothelial growth
factor in human hepatic stellate cells. TNF-α and LPSalso
stimulate the expression of leptin and leptin receptor.
Leptin also enhances the production of pro-inammatory
Th1 cytokines whereas suppresses the production of anti-
inammatory Th2 cytokines such as IL-4 in CD4+ T cells.60
Interleukin-6
Interleukin-6 is a cytokine which is not only involved
in inammation and infection responses but also in the
regulation of metabolic, regenerative, and neural processes.
In classicsignaling interleukin-6 stimulates target cells via
a membrane bound interleukin-6 receptor, which upon
ligand binding associates with the signaling receptor protein
gp130. Gp130 dimerizes, leading to the activation of
Janus kinases and subsequent phosphorylation of tyrosine
residues within the cytoplasmic portion of gp130.The
cytokine interleukin-6 (IL-6) exhibits both pro- and anti-
inammatory properties. Only few cells express the IL-6
receptor and respond to IL-6 (classic signaling), all cells
can be stimulated via a soluble IL-6 receptor since gp130 is
ubiquitously expressed. They are elevated in most, if not all,
inammatory states and have been recognized as potential
targets of therapeutic intervention. The role of IL-6 in
obesity and insulin resistance still remains controversial.
IL-6 is expressed in adipose tissue and is well correlated with
degree of obesity in humans.61 Peripheral administration of
IL-6 interrupts insulin signaling due to enhance expression
of SOCS3 in hepatocytes suggesting that obesity-induced
IL-6 expression mediates insulin resistance.53 On the
contrary, IL-6 decient mice demonstrate mature-onset
obesity and hepatic inammation, and IL-6 administration
reverses insulin resistance.62As central administration of
IL-6 enhances energy expenditure and decreases obesity,
IL-6 can also inuence obesity and insulin sensitivity
through a central nervous system mechanism. Thus the role
IL-6 in obesity and insulin resistance likely depends upon
the specic sites of expression that is integrated with other
adipokine/cytokine factors in a systems integrated manner.
Adiponectin: The anti-inflammatory adipokine
Adiponectin are expressed by adipocytes exhibiting potent
anti-inammatory properties. Due to the overwhelming
expressions of pro-inammatory factors namely TNF-α,
IL-6, ROS, the expression of adiponectin in adipocytes
are suppressed and decreased in obese rodents and
humans.63In contrast PPARγ antagonists stimulate the
expression of adiponectin in adipocytes. Adiponectin
activates AMP-dependent protein kinase (AMPK)
through its receptors, ADIPOR1/2, to accelerate fatty
acid oxidation and glucose uptake in muscle and to
suppress gluconeogenesis in liver.64Experiment evidence
by administering exogenous adiponectin in transgenic mice
results in improved insulin sensitivity whereas adiponectin
decient mice develop high fat diet induced inammation
and insulin resistance.65Adiponectin inhibits LPS-induced
TNF-α production in macrophages through inhibition
of NF-κB activation and stimulate the production of
anti-inammatory IL-10.66Adiponectin also promotes the
differentiation of anti-inammatory M2 macrophages and
modulates T cells activation and inammatory function of
NK cells.67Adiponectin receptors are upregulated on the
surface of human T cells after stimulation by antigen and
it mediates apoptosis of antigen specic T cells resulting
in the suppression of antigen specic T cells expansion.
Furthermore adiponectin suppresses TLR-mediated IFN-γ
production in NK cells without affecting in cytotoxicity of
NK cells.68 Thus adiponectin can also delays and suppress
the development of atherosclerosis, fatty liver diseases, and
liver brosis. Low serum levels of adiponectin have been
associated with coronary artery disease, hypertension, left
ventricular hypertrophy, and a greater risk of myocardial
infarction.69 Numerous experimental studies have shown
that adiponectin exerts protective actions on cardiovascular
cell types including vascular endothelial cells, smooth
muscle cells, and cardiac myocytes, and adiponectin-
decient mice display worse outcomes in various models
of cardiovascular disease.70 Importantly, mouse models of
adiponectin-deciency display normal body and fat mass
and normal metabolic parameters when fed a normal chow
diet. Thus, the cardiovascular actions of adiponectin can be
studied independently of its metabolic regulatory effects.
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Asian Journal of Medical Sciences | Jan-Feb 2019 | Vol 10 | Issue 1 9
As discussed, Obesity increases the inammatory markers
which causes insulin resistance in human, although
observed that approximately 20% of the obese population
remains fully insulin sensitive and metabolically normal
regardless of inammation. Though research evidence
supportinammation a prime cause of insulin resistance,
still it is unclear what is the initiation factor(s) which is
responsible for impulse of the inflammatory cascade.
Research studies assumes that adipocyte released chemokines
such as CCL2 is responsible for the initiation of pro-
inammatory macrophage inltration.53 However, we now
know that inltration of macrophages is a late step in the
adipose tissue inammatory process and the earliest events
is the inltration of neutrophils. Whether or not neutrophil
recruitment/activation in adipose tissue is the initiator of
the inammatory cascade and/or the signals responsible for
neutrophil recruitment remain undetermined.
Though reports from enormous research have been
published but still the queries remain unresolved in the
mechanism/s by which adipose tissue inammation results
in liver and skeletal muscle insulin resistance. Several studies
have also observed the local liver and skeletal muscle
expression of pro-inammatory cytokines and activation
of inammatory cells. Whether this results from systemic
inammation emanating from adipose tissue or is due to
a local release of pro-inammatory chemokines/cytokines
has yet to be established. Moreover, whether this accounts
for the hepatic and skeletal muscle insulin resistance or
results from alterations in central signaling and/or systemic
factors is area that needs further study.
It is becoming clear that targeting the pro-inammatory
pathway may provide a novel therapeutic approach to
prevent insulin resistance, particularly in obesity-induced
insulin resistance. In summary, adipose tissue has multiple
integrative functions serving as energy storage organ that
can provide fuel for energy production in times of external
nutrient shortage. However, over the past two decades
adipocytes have become established as bonadeprofessional
endocrine cells that integrate whole body energy status with
eating behavior, energy expenditure, and insulin sensitivity.
Moreover, adipose tissue has become a central node for
driving local and systemic sterile inammation that is a key
element in obesity-induced insulin resistance. Although
many adipokines have been identied and well studied,
the identication and functional studies of new adipokines
and their control of integrative physiologic responses are
essential to understand pathophysiological mechanisms of
obesity-induced metabolic diseases.
Goals to decrease the premature deaths due to CVD
Some cost effective interventions that are feasible by all
and can be implemented even in low-resource settings
includes - population-wide and individual, which are
recommended to be used in combination to reduce the
greatest cardiovascular disease burden.Examples of
population-wide interventions that can be implemented
to reduce CVDs include- Comprehensive tobacco
control policies which can be implemented at the level
of governance, mass campaigning and advertisements in
television and radio regarding the effects of high fat diet in
health, promoting cycling and walking to enhance physical
activity, provide healthy meals in schools to children,
funded by government, planning and documentation
of guidelines to educate mass regarding the aftermath
of obesity in various disease. At the individual level, for
prevention of rst heart attacks and strokes, individual
health-care interventions need to be targeted to those at
high total cardiovascular risk or those with single risk factor
levels above traditional thresholds, such as hypertension
and hypercholesterolemia. The former approach is more
cost-effective than the latter and has the potential to
substantially reduce cardiovascular events. This approach is
feasible in primary care in low-resource settings, including
by non-physician health workers.
For secondary prevention of cardiovascular disease in
those with established disease, including diabetes, treatment
with the following medications is necessary: aspirin, beta-
blockers, angiotensin-converting enzyme inhibitors, statins.
The benets of these interventions are largely independent,
but when used together with smoking cessation, nearly 75%
of recurrent vascular events may be prevented. Currently
there are major gaps in the implementation of these
interventions particularly at the primary health care level.In
addition costly surgical operations are sometimes required
to treat CVDs. They include: coronary artery bypass,
balloon angioplasty, valve repair and replacement, heart
transplantation, articial heart operations. Medical devices
are required to treat some CVDs. Such devices include
pacemakers, prosthetic valves, and patches for closing holes
in the heart.Under the leadership of the WHO, all Member
States (194 countries) agreed in 2013 on global mechanisms
to reduce the avoidable NCD burden including a “Global
action plan for the prevention and control of NCDs 2013-
2020”.71This plan aims to reduce the number of premature
deaths from NCDs by 25% by 2025 through nine voluntary
global targets. Two of the global targets directly focus on
preventing and controlling CVDs.
Global action plan for the prevention and control of
NCDs 2013-2020
The sixth target in the Global NCD action plan is to reduce
the prevalence of hypertension by 25%.71Raised blood
pressure is one of the leading risk factor for cardiovascular
disease. The global prevalence of hypertension in adults
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10 Asian Journal of Medical Sciences | Jan-Feb 2019 | Vol 10 | Issue 1
aged ≥18 years is around 24.1% in men and 20.1% in
women in 2015.72The number of adults with raised blood
pressure increased from 594 million in 1975 to 1.13 billion
in 2015, with the increase largely in low- and middle-income
countries.73
Reducing the incidence of hypertension by implementing
population-wide policies to reduce behavioral risk factors,
including harmful use of alcohol, physical inactivity,
overweight, obesity and high salt intake, is essential to
attaining this target. A total-risk approach needs to be
adopted for early detection and cost-effective management
of hypertension in order to prevent heart attacks, strokes
and other complications.
The eighth target in the Global NCD action plan states at
least 50% of eligible people should receive drug therapy and
counseling to prevent heart attacks and strokes.74 Prevention
of heart attacks and strokes through a total cardiovascular
risk approach is more cost-effective than treatment
decisions based on individual risk factor thresholds only and
should be part of the basic benets package for pursuing
universal health coverage. Achieving this target will require
strengthening key health system components, including
health-care financing to ensure access to basic health
technologies and essential NCD medicines.
In 2015, countries set their national targets and measure
progress on the 2010 baselines reported in the “Global
status report on noncommunicable diseases 2014”.
Treatment and prevention
There is little controversy over the benets to cardiovascular
health of not smoking, eating awell balanced diet,
maintaining mental well-being, taking regular exercise
and keeping active, asdemonstrated in large cohort
studies. These health behaviors also play an etiological
role in othernon-communicable diseases, such as cancer,
respiratory disease, diabetes, osteoporosis and liverdisease,
which makes interventions to promote them potentially
very cost-effective. However, there is considerable
uncertainty about the best ways of helping people at high
CVD risk to modify their behavior.
Reducing cigarette smoking, body weight, blood pressure,
blood cholesterol, and blood glucose all have a benecial
impact on major biological cardiovascular risk factors.
Behaviors such as stopping smoking, taking regular physical
activity and eating a healthy diet promote health andhave
no known harmful effects. They also improve the sense
of well-being and are usually lessexpensive to the health
care system than drug treatments, which may also have
adverse effects. A variety of lifestyle modications have
been shown, in clinical trials, to lower blood pressure. These
include weight loss in the overweight, physical activity,
moderationof alcohol intake, increased fresh fruit and
vegetables and reduced saturated fat in thediet, reduction
of dietary sodium intake, and increased potassium intake.
Itis important to recognize, however, that most of the trials
of lifestyle modication have been ofshort duration, which
are unlikely to be feasible in routineprimary care in many
countries. Still, the evidence supports the notion that it
is possible to modify health behaviors and reduce blood
pressure. More encouragingly, randomized trials, involving
aprogram of weight reduction, dietary manipulation and
physical activity, reduced the incidenceof type 2 diabetes
among people at high risk of developing it. Also, trials of
reductionof saturated fat and its partial replacement by
unsaturated fats have improved dyslipidaemia and lowered
risk of cardiovascular events.
Appropriatepolicies might address: agricultural subsidies for
fruits and vegetables; food pricing and availability;labeling
of food; public transport; pedestrian- and cyclist-friendly
road planning; schoolhealth education; and tobacco
control measures, including prohibition of advertising and
pricecontrol. The overall objective should be to make it
easy for the population to make healthy choicesrelated to
diet, physical activity and avoidance of tobacco.
Strategies adopted by Indian government against CVD
This initiative driven by the Ministry of Health and
Family Welfare, State Governments, Indian Council of
Medical Research and the World Health Organization.
The Government of India has adopted a national action
plan for the prevention and control of non-communicable
diseases (NCDs) with specic targets to be achieved by
2025, including a 25% reduction in overall mortality from
cardiovascular diseases, a 25% relative reduction in the
prevalence of raised blood pressure and a 30% reduction in
salt/sodium intake. The funds will support costs associated
with stafng, implementing and maintaining the India
Hypertension Management Initiative. This structure helps
patients receive the full benet of the initiative, by ensuring
the resources needed to control blood pressure are in
place. Most of the costs are borne by state governments
themselves, which pay the primary care staff, procure
drugs and blood pressure monitors, and have overall
responsibility for the program. The additional inputs will
demonstrate their benet, and that state governments may
in the coming years decide to expand the program so that all
patients in India can benet from this life-saving treatment.
In a nutshell increased BMI values can predict the nature
of obesity and its aftermaths in terms inammation and
other disease associated with obesity. It’s high time; we
must realize it and keep an eye on health status in order to
live long and healthy life.
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Asian Journal of Medical Sciences | Jan-Feb 2019 | Vol 10 | Issue 1 11
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Authors Contribution:
AK- Concept,design,Literaturesearch,Manuscriptpreparation,criticalrevisionofthemanuscript,nalapproval.
Work attributed to: Department of Biochemistry, Jagannath Gupta Institute of Medical Sciences, Buita, Budge Budge, Kolkata, India
Orcid ID:
Dr. Arun Kumar‑ https://orcid.org/0000‑0002‑8800‑0296
Source of Funding: None, Conict of Interest: None.
