Table Of ContentAdvances in Experimental Medicine and Biology 960
Ayse Basak Engin
Atilla Engin Editors
Obesity and
Lipotoxicity
Advances in Experimental Medicine
and Biology
Volume 960
Editorial Board
IRUN R. COHEN, The Weizmann Institute of Science, Rehovot, Israel
ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research, Orangeburg,
NY, USA
JOHN D. LAMBRIS, University of Pennsylvania, Philadelphia, PA, USA
RODOLFO PAOLETTI, University of Milan, Milan, Italy
More information about this series at http://www.springer.com/series/5584
Ayse Basak Engin • Atilla Engin
Editors
Obesity and Lipotoxicity
Editors
Ayse Basak Engin Atilla Engin
Faculty of Pharmacy Faculty of Medicine
Department of Toxicology Department of General Surgery
Gazi University Gazi University
Hipodrom, Ankara, Turkey Besevler, Ankara, Turkey
Mustafa Kemal Mah. 2137. Sok. 8/14
Cankaya, Ankara, Turkey
ISSN 0065-2598 ISSN 2214-8019 (electronic)
Advances in Experimental Medicine and Biology
ISBN 978-3-319-48380-1 ISBN 978-3-319-48382-5 (eBook)
DOI 10.1007/978-3-319-48382-5
Library of Congress Control Number: 2017934470
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Preface
Obesity and its associated diseases are a major and growing worldwide public
health problem of our century. Recent studies have suggested that obesity
prevalence is seriously increasing mostly due to depression- and anxiety-
related eating disorders, which may deeply affect quality of life.
Although behavioral improvements are aimed at promoting lifestyle
changes, multidisciplinary interventions should be based on biochemical and
immunological pathways. Either only conservative methods or only surgical
approaches have limited efficacy, in part due to the involvement of counter-
regulatory multiple metabolic pathways in obesity. Consequently, multidi-
mensional analysis of adipose tissue-derived signaling would provide greater
benefit. In this context, the book covers many critical and complex topics that
trigger obesity. We are aware that many subjects have not yet come to light
about obesity. Nevertheless, this book may encourage and further the research
of scientists and practitioners who are interested in obesity.
Hipodrom, Ankara, Turkey Ayse Basak Engin
Besevler, Ankara, Turkey Atilla Engin
v
Contents
1 The Definition and Prevalence of Obesity
and Metabolic Syndrome............................................................. 1
Atilla Engin
2 Circadian Rhythms in Diet-Induced Obesity ............................ 19
Atilla Engin
3 Eat and Death: Chronic Over-Eating ........................................ 53
Atilla Engin
4 Obesity, Persistent Organic Pollutants
and Related Health Problems ..................................................... 81
Loukia Vassilopoulou, Christos Psycharakis, Demetrios Petrakis,
John Tsiaoussis, and Aristides M. Tsatsakis
5 Human Protein Kinases and Obesity ......................................... 111
Atilla Engin
6 Fat Cell and Fatty Acid Turnover in Obesity ............................ 135
Atilla Engin
7 Adipose Tissue Function and Expandability
as Determinants of Lipotoxicity and the Metabolic
Syndrome ...................................................................................... 161
Stefania Carobbio, Vanessa Pellegrinelli, and Antonio Vidal-Puig
8 What Is Lipotoxicity? .................................................................. 197
Ayse Basak Engin
9 The Pathogenesis of Obesity-A ssociated Adipose
Tissue Inflammation .................................................................... 221
Atilla Engin
10 Microbiota and Lipotoxicity ....................................................... 247
Evren Doruk Engin
11 Endoplasmic Reticulum Stress and Obesity .............................. 261
Erkan Yilmaz
12 Insulin Resistance, Obesity and Lipotoxicity ............................ 277
Dilek Yazıcı and Havva Sezer
vii
viii Contents
13 Adipose Tissue Hypoxia in Obesity and Its Impact
on Preadipocytes and Macrophages: Hypoxia Hypothesis ...... 305
Atilla Engin
14 Adipocyte-Macrophage Cross-Talk in Obesity ......................... 327
Ayse Basak Engin
15 Endothelial Dysfunction in Obesity ............................................ 345
Atilla Engin
16 Diet-Induced Obesity and the Mechanism
of Leptin Resistance ..................................................................... 381
Atilla Engin
17 Influence of Antioxidants on Leptin Metabolism
and its Role in the Pathogenesis of Obesity ............................... 399
Harald Mangge, Christian Ciardi, Kathrin Becker,
Barbara Strasser, Dietmar Fuchs, and Johanna M. Gostner
18 Adiponectin-Resistance in Obesity ............................................. 415
Atilla Engin
19 Non-Alcoholic Fatty Liver Disease ............................................. 443
Atilla Engin
20 Lipotoxicity-Related Hematological Disorders in Obesity ....... 469
Ibrahim Celalettin Haznedaroglu and Umit Yavuz Malkan
21 MicroRNA and Adipogenesis ...................................................... 489
Ayse Basak Engin
22 The Interactions Between Kynurenine, Folate, Methionine
and Pteridine Pathways in Obesity ............................................ 511
Ayse Basak Engin and Atilla Engin
23 Eligibility and Success Criteria for Bariatric/Metabolic
Surgery .......................................................................................... 529
Manuel F. Landecho, Víctor Valentí, Rafael Moncada,
and Gema Frühbeck
24 Does Bariatric Surgery Improve Obesity
Associated Comorbid Conditions ............................................... 545
Atilla Engin
25 Obesity-associated Breast Cancer: Analysis of risk factors ....... 571
Atilla Engin
26 Lipotoxicity in Obesity: Benefit of Olive Oil ............................. 607
Saad Elias, Sbeit Wisam, Arraf Luai, Barhoum Massad,
and Assy Nimer
Index ...................................................................................................... 619
1
The Definition and Prevalence
of Obesity and Metabolic
Syndrome
Atilla Engin
Abstract
Increase in prevalence of obesity has become a worldwide major health problem
in adults, as well as among children and adolescents. Furthermore, total adipos-
ity and truncal subcutaneous fat accumulation during adolescence are positively
and independently associated with atherosclerosis at adult ages. Centrally accu-
mulation of body fat is associated with insulin resistance, whereas distribution
of body fat in a peripheral pattern is metabolically less important. Obesity is
associated with a large decrease in life expectancy. The effect of extreme obesity
on mortality is greater among younger than older adults. In this respect, obesity
is also associated with increased risk of several cancer types. However, up to
30% of obese patients are metabolically healthy with insulin sensitivity similar
to healthy normal weight individuals, lower visceral fat content, and lower
intima media thickness of the carotid artery than the majority of metabolically
“unhealthy” obese patients.
Abdominal obesity is the most frequently observed component of met-
abolic syndrome. The metabolic syndrome; clustering of abdominal obe-
sity, dyslipidemia, hyperglycemia and hypertension, is a major public
health challenge. The average prevalence of metabolic syndrome is 31%,
and is associated with a two-fold increase in the risk of coronary heart
disease, cerebrovascular disease, and a 1.5-fold increase in the risk of all-
cause mortality.
Keywords
Metabolic syndrome • Body mass index • Metabolically healthy obese •
Insulin resistance • Obesity-paradox • Prevalence of obesity
A. Engin, M.D., Ph.D. (*)
Faculty of Medicine, Department of General Surgery,
Gazi University, Besevler, Ankara, Turkey
Mustafa Kemal Mah. 2137. Sok. 8/14, 06520,
Cankaya, Ankara, Turkey
e-mail: [email protected]
© Springer International Publishing AG 2017 1
A.B. Engin, A. Engin (eds.), Obesity and Lipotoxicity, Advances in Experimental
Medicine and Biology 960, DOI 10.1007/978-3-319-48382-5_1
2 A. Engin
1 Introduction including waist circumference (WC) and central
and peripheral fat mass, have also been used, but
Increasing prevalence of obesity is a worldwide currently BMI is continued to be used for the
health concern because excess weight gain causes classification of obesity. However, BMI does not
an increased risk for several diseases, most nota- give a precise idea about the body composition
bly cardiovascular diseases, diabetes, and cancers which affects the health risks of excess weight
(Wang et al. 2011). The global food system drivers such as the proportion of body weight which con-
interact with local environmental and genetic fac- sists of fat or the distribution of fat. These dis-
tors to create a wide variation in obesity preva- crepancies will be discussed in later sections.
lence between populations. Epidemiologically, in Nevertheless, BMI is now the internationally
low-income countries, obesity mostly affects mid- accepted standard method used by researchers
dle-aged adults, whereas in high-income countries and the others dealing with human health, in spite
it affects both sexes and all ages (Swinburn et al. of its alternatives. According to BMI; individuals
2011). On the other hand, increased obesity rates are allocated to five different categories as 18.5–
lead to a large health and economic burden in all 24.9 kg/m2: normal range, 25.0–29.9 kg/m2:
countries (Rtveladze et al. 2014). According to overweight, 30.0–34.9 kg/m2: class 1-obesity,
Keaver et al. overweight and obesity are proposed 35.0–39.9 kg/m2: class 2-obesity, equal or greater
to reach levels of 89% and 85% in males and 40 kg/m2: class 3-obesity. Morbid obesity is con-
females, respectively by 2030. This will result in sidered to be grade 3 obesity or grade 2 obesity
an increase in the obesity-related prevalence of plus significant obesity-related co-morbidities
coronary heart disease (CHD) by 97%, cancers by (Ashwell et al. 2014; Dixon et al. 2011). In the
61% and type 2 diabetes by 21%. Thereupon, the past 33 years, 1769 studies from 104 different
direct healthcare costs will increase significantly. centers indicated that the established health risks
A 5% reduction in population body mass index and substantial increase in prevalence of obesity
(BMI) levels by 2030 is estimated to result in has become a major worldwide health problem.
€495 million decrease in the expenditures in obe- The proportion of adults with a BMI of 25 kg/m2
sity-related direct healthcare over 20 years (Keaver or greater increased between 1980 and 2013 from
et al. 2013). Additionally, after adjustment for sig- 28.8% (95% Uncertainty intervals (UI): 28.4–
nificant maternal and sociodemographic charac- 29.3) to 36.9% (36.3–37.4) in men, and from
teristics, healthcare costs of children with obesity 29.8% (29.3–30.2) to 38.0% (37.5–38.5) in
are 1.62 times higher than those of children with women (Ng et al. 2014). Moreover, population-
healthy weight (Hayes et al. 2016). Cost-effective based studies in different countries showed that
strategies targeted at reducing the prevalence of obesity will continue to be a serious health-risk in
obesity during the early years of life can signifi- future. Between 1985 and 2011, the prevalence
cantly reduce both healthcare and non-healthcare of adult obesity in Canada increased from 6.1%
costs over the lifetime (Sonntag et al. 2016). In this to 18.3%. Furthermore, since 1985, the preva-
respect, the obesity related disease burden on lence of obesity in classes 1, 2 and 3 increased
health care expenses should be evaluated with the from 5.1% to 13.1%, from 0.8% to 3.6%, and
epidemiological data considering whether the from 0.3% to 1.6%, respectively. It has been pre-
obese population is metabolically healthy or not. dicted that, by 2019, the prevalence of obesity in
classes 1, 2 and 3 will increase to 14.8%, 4.4%
and 2.0%, respectively (Twells et al. 2014). By
2 Definition and Prevalence 2030, in the USA up to 86% of adults will be
of Obesity overweight or obese (Ginter and Simko 2014). In
Australia, approximately 63% of adults were
Obesity is usually classified by BMI. It is calcu- overweight and obese in between the years 2011–
lated as body weight in kilograms divided by the 2012. The proportion of the Australian popula-
height in meters squared (kg/m2). Other methods, tion who are overweight and obese is expected to
1 The Definition and Prevalence of Obesity and Metabolic Syndrome 3
increase to approximately 66% in 2017 (Sassi 25.7% (Pérez-Farinós et al. 2013). The WHO
et al. 2009; Statistics 2012). Regional Office for Europe analyzed 168,832
On the other hand the prevalence of over- children from 12 countries in the context of WHO
weight and obesity among children and adoles- European Childhood Obesity Surveillance
cents has also increased worldwide (Ebbeling Initiative (COSI). Indeed, COSI routinely mea-
et al. 2002; Lissau et al. 2004). Thirty-nine arti- sures overweight and obesity prevalence of
cles and one national health report that were primary- school children aged 6–9 years.
undertaken to consideration; in 16 of the 23 According to COSI data, the prevalence of obe-
countries with national representative data using sity ranged from 6.0% to 26.6% among boys and
the International Obesity Task Force (IOTF) cut- from 4.6% to 17.3% among girls. Consequently,
off, over-weight and obesity prevalence were overweight among 6–9-year-old children is iden-
found to be higher than 20%, five countries tified as a serious public health concern
showed prevalence above 30%, and only in two (Wijnhoven et al. 2013). BMI is correlated with
countries prevalence was lower than 10%. Data visceral adipose tissue (VAT) in pediatric popula-
from the National Health and Nutrition tions. Furthermore, BMI may also be converted
Examination Survey 2009–10 (NHANES) indi- to BMI percentiles by using Centers for Disease
cated a prevalence of overweight and obesity Control and Prevention (CDC) growth charts.
among 4111 adolescents aged 12 through 19 BMI percentile is a sensible and useful tool for
years of 15.2% and 18.4%, respectively (Bibiloni the prediction of VAT mass, fat mass and cardio-
et al., 2013). IOTF versus BMI cut-offs are vascular disease (CVD) risk in children and ado-
widely used to assess the prevalence of child lescents (Harrington et al. 2013). In a series of
overweight, obesity and thinness. IOTF defines 14,493 children, increasing waist-to-height ratio
the revised international child cut-offs and they (WHtR) was significantly associated with
are available corresponding to the following BMI increased cardiometabolic risk in overweight and
cut-offs at 18 years. 16 kg/m2: thinness grade 3, obese subjects. Obese subjects with WHtR higher
17 kg/m2: thinness grade 2, 18.5 kg/m2: thinness than 0.6 should undergo a further cardiometa-
grade 1, 23 kg/m2: overweight (unofficial Asian bolic risk assessment (Khoury et al. 2013).
cut-off), 25 kg/m2: overweight, 27 kg/m2: obesity However, in 3–5 years old overweight/obese
(unofficial Asian cut-off), 30 kg/m2: obesity, 35 children, WHtR is not found to be superior to
kg/m2: morbid obesity (Cole and Lobstein 2012). WC or BMI in estimating body fat percentage
The prevalence has increased substantially in (BF%) and cardiometabolic risk (Sijtsma et al.
children and adolescents in developed countries; 2014). Regardless of weight and length at birth,
23.8% (BMI; 22.9–24.7) of boys and 22.6% the correlation of higher BMI at preschool age
(BMI; 21.7–23.6) of girls were overweight or with the ratio of weight gain per cm gain in height
obese in 2013. The prevalence of overweight and may be a better indicator of risk for overweight
obesity has also increased in children and adoles- and obesity (Nascimento et al. 2011). Actually,
cents in developing countries, from 8.1% (min; overweight children often become overweight
7.7–max; 8.6) to 12.9% (min; 12.3–max; 13.5) adolescents and adults later. A child or adolescent
for boys and from 8.4% (min; 8.1–max; 8.8) to with a high BMI percentile may have a high risk
13.4% (min; 13.0–max; 13.9) for girls during the of being overweight or obese at 35 years of age,
same time period (Ng et al. 2014). In an another and this risk increases with age (Guo et al. 2002).
European country, Spain, the prevalence of over- Furthermore in men, total adiposity and truncal
weight and obesity in children was determined subcutaneous fat accumulation during adoles-
by using Spanish reference tables (SPART), cence, are positively and independently associ-
IOTF reference values, and The World Health ated with atherosclerosis at age 36 (Ferreira et al.
Organization (WHO) growth standards. The 2004). Indeed, accumulation of body fat centrally
average prevalence of overweight in boys ranged is associated with insulin resistance (IR), whereas
from 14.1% to 26.7%, and in girls from 13.8% to distribution of body fat in a peripheral pattern is
