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Obesity
Oxidative Stress and Dietary Antioxidants

Edited by

Amelia Marti del Moral

Department of Nutrition, Food Sciences and Physiology
School of Pharmacy and Nutrition, University of Navarra
IdiSNA, Navarra Institute for Health Research
Pamplona, Spain
Center of Biomedical Research in Physiopathology of Obesity and
Nutrition (CIBEROBN) Institute of Health Carlos III
Madrid, Spain

Concepción Marı́a Aguilera Garcı́a

Department of Biochemistry and Molecular Biology
Institute of Nutrition and Food Technology
Center of Biomedical Research, University of Granada
Granada, Spain
Center of Biomedical Research in Physiopathology of Obesity and
Nutrition (CIBEROBN) Institute of Health Carlos III
Madrid, Spain
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Contents

List of Contributors ix 5.3 MicroRNAs in Nonalcoholic Fatty

About the Editors xi Liver Disease 30
Preface xiii 6. Oxidative Stress and Epigenetic Changes
in Obesity-Related Diseases 31
1. Oxidative Stress and Inflammation 6.1 DNA Methylation and Oxidative
Stress 31
in Obesity and Metabolic Syndrome 6.2 DNA Methylation, Oxidative Stress,
Francisco J. Ruiz-Ojeda, Josune Olza, Ángel Gil and Metabolic Syndrome 31
and Concepción M. Aguilera 6.3 Histone Acetylation, Oxidative
Stress, and Metabolic Syndrome 32
1. Introduction 1 7. Oxidative Stress, Metabolic Diseases,
2. Oxidative Stress, Obesity, and Metabolic and Cancer 32
Syndrome 2 8. Conclusion 33
2.1 Biomarkers of Oxidative Stress 2 Glossary 33
2.2 Antioxidant Defense System 7 List of Acronyms and Abbreviations 34
3. Inflammation, Obesity, and Metabolic References 36
Syndrome 8
3.1 Biomarkers of Inflammation 9
3.2 Adipose Tissue and Antiinflammatory 3. Molecular Basis of Oxidative Stress
Proteins 12 and Inflammation
4. Conclusions and Future Perspectives 13
References 13 Maria D. Mesa-Garcia, Julio Plaza-Diaz
and Carolina Gomez-Llorente
2. Genetics of Oxidative Stress and 1. Introduction 41
Obesity-Related Diseases 17 2. Molecular Basis of Oxidative Stress 42
2.1 Free Radicals and Reactive Oxygen
Azahara I. Rupérez and Augusto Anguita-Ruiz Species 42
1. Introduction 17 2.2 Generation and Reactivity of Reactive
2. Gene Expression of Antioxidant Enzymes 18 Oxygen Species 42
3. Reactive Oxygen Species Response 2.3 Generation and Reactivity of
Mechanisms 19 Nitrogen-Derived Reactive Species 43
3.1 Peroxisome Proliferator-Activated 2.4 Molecular Cytotoxicity of Reactive
Receptor Gamma 20 Oxygen Species 44
3.2 PPARg Coactivator 1 Alpha 20 2.5 Reactive Oxygen Species Functions
3.3 Nuclear Factor (Erythroid-Derived 2)- in Cell Signaling 44
Like 2 20 2.6 Beneficial Effects of Reactive Oxygen
3.4 Forkhead Box O 21 Species 45
4. Genetic Variants 21 2.7 Antioxidant Cellular Defenses 46
4.1 Antioxidant Defense System Genes 22 3. Molecular Basis of Inflammation 49
4.2 Prooxidant Enzyme Genes 26 3.1 The Innate Immune System 51
4.3 Genetic Variants in Transcription 3.2 Adaptive Immune System 54
Factors 26 3.3 Microbiota and the Immune System 57
5. MicroRNAs 27 Glossary 58
5.1 MicroRNAs in Adipose Tissue 27 List of Acronyms and Abbreviations 58
5.2 MicroRNAs in Atherosclerosis 28 References 59

v
vi Contents

4. Inflammation and Oxidative Stress in 5.2 Metabolic Agonists 103

Adipose Tissue: Nutritional Regulation 5.3 Genetics Profile 104
6. Conclusions 105
Leyre Martı´nez-Fernández, Marta Fernández- List of Acronyms and Abbreviations 106
Galilea, Elisa Felix-Soriano, Xavier Escoté, Pedro References 107
González-Muniesa and Marı´a J. Moreno-Aliaga
1. Introduction 63
6. Obesity and Nonalcoholic Fatty Liver
2. White, Brown, and Beige Adipose Tissue: Disease: Role of Oxidative Stress
Physiological Roles 63
M. Vanessa Bullón-Vela, Itziar Abete, J. Alfredo
2.1 White Adipose Tissue 63
Martı´nez and M. Angeles Zulet
2.2 Brown Adipose Tissue 65
2.3 Beige Adipose Tissue 66 1. Introduction 111
3. Inflammation and Oxidative Stress 2. Definition 111
in Adipose Tissue in Obesity 66 3. Prevalence and Trends 113
4. Nutritional Regulation of Inflammation 3.1 Ethnicity, Gender, and Age 113
and Oxidative Stress in Obesity 70 4. Risk Factors Associated With
4.1 n-3 Polyunsaturated Fatty Acids 70 Nonalcoholic Fatty Liver Disease 113
4.2 a-Lipoic Acid: Antioxidant Properties 4.1 Obesity 113
and Beyond 77 4.2 Insulin Resistance 115
5. Conclusions and Future Perspectives 82 4.3 Dyslipidemias 116
List of Acronyms and Abbreviations 82 4.4 Metabolic Syndrome 117
Acknowledgments 84 5. Pathogenesis: The Hits Hypothesis 117
References 84 5.1 First Hit: Lipid Accumulation in
Hepatocytes 117
5.2 Second Hit: Oxidative Stress 120
5. Vascular Damage in Metabolic 6. Diagnosis 122
Disorders: Role of Oxidative Stress 6.1 Liver Biopsy 122
6.2 Noninvasive Techniques 122
Álvaro Pejenaute and Guillermo Zalba Goñi 7. Dietary Treatment 125
1. Metabolic Syndrome 93 8. Conclusions 127
1.1 Definition and Classification 93 Glossary 127
1.2 Epidemiology and Clinical List of Abbreviations 127
Repercussion 95 References 128
2. Oxidative Stress 95
2.1 Introduction 95 7. Kidney Damage in Obese Subjects:
2.2 Cellular Consequences of Oxidative Stress and Inflammation
Pathological Reactive Oxygen
Species Production 96 Elia Escasany, Adriana Izquierdo-Lahuerta and
2.3 Oxidative Stress and Cardiovascular Gema Medina-Gómez
and Metabolic Disease 97 1. Introduction 135
2.4 Enzymatic Sources of Superoxide 2. Physiological State of the Kidney: From
Anion 97 Normal Function to Changes During
3. Nicotinamide Adenine Dinucleotide Disease 136
Phosphate Oxidases 98 3. The Adipose Tissue Expandability
3.1 Nicotinamide Adenine Dinucleotide Hypothesis and Renal Lipotoxicity 136
Phosphate Oxidases Localization 99 4. Mechanisms of Action Underlying the
3.2 Nicotinamide Adenine Dinucleotide Pathological Renal Effects of Obesity 137
Phosphate Oxidase Regulation 100 4.1 The Role of Adipokines and
4. Phagocytic Nicotinamide Adenine Proinflammatory Factors From
Dinucleotide Phosphate Oxidase Adipose Tissue in Renal Injury 137
and Metabolic Disorders 100 4.2 Lipid Accumulation Promotes
4.1 Arterial Hypertension 101 Changes in Renal Lipid Metabolism 138
4.2 Metabolic Syndrome 101 4.3 Inflammation and Oxidative Stress
4.3 Atherosclerosis 102 Relationship in Kidney Disease 141
5. Regulation of Phagocytic Nicotinamide 4.4 Endoplasmic Reticulum Stress Is Also
Adenine Dinucleotide Phosphate Oxidase Associated With Renal Lipotoxicity 142
in Metabolic Disorders 103 4.5 Oxidative Stress and Autophagy in
5.1 Humoral Agonists 103 the Context of Renal Lipotoxicity 142
 Contents vii

4.6 Oxidative Stress and Renal Fibrosis 143 2.11 Leukemia Inhibitory Factor 168
4.7 Overactivation of RenineAngiotensin 2.12 Brain-Derived Neurotrophic Factor 168
Aldosterone System in Obesity 143 2.13 C1QTNF5/Myonectin 168
5. Obesity as Independent Risk Factor 2.14 Pigment Epithelium-Derived
for Renal Disease: Obesity-Related Factor 169
Glomerulopathy 143 2.15 Osteocrin/Musclin 169
6. Obesity Complications in Kidney 2.16 Ceramides 169
Disease 145 2.17 Infiltrated Immune Cells 169
6.1 Insulin Resistance in the 3. Role of Inflammation-Related Factors
Development of Renal Disease 145 in the Development of Obesity-
6.2 Diabesity and Diabetic Nephropathy 145 Associated Skeletal Muscle Insulin
6.3 Cardiovascular Risk in Chronic Resistance 170
Kidney Disease Patients 147 4. Oxidative Stress Markers in Skeletal
6.4 Obesity and Renal Cancer 147 Muscle in Obesity 172
7. Oxidative Stress and Inflammation 4.1 Thiobarbituric Acid Reactive
as Biomarkers for Renal Disease Substances 172
During Obesity 148 4.2 8-Isoprostane 173
7.1 Lipid Peroxidation 148 4.3 Glutathione and Glutathione
7.2 Protein Oxidation 148 Peroxidase Activity 173
7.3 Nucleic Acid Oxidation 149 4.4 Superoxide Dismutase 174
7.4 Antioxidants 149 4.5 4-Hydroxynonenal 175
7.5 Hydrogen Sulfide 149 4.6 Protein Carbonylation 175
7.6 Glutathionyl Hemoglobin 149 4.7 Superoxide Anion 175
7.7 Asymmetric Dimethyl Arginine 150 4.8 Catalase 175
7.8 Kynurenine Pathway 150 4.9 Peroxiredoxins 176
7.9 Inflammation Markers 150 4.10 Thioredoxins 176
8. Therapies in Obesity-Related Kidney 5. Role of Oxidative Stress Factors in the
Disease 150 Development of Obesity-Associated
8.1 Weight Loss: Dietary Food Restriction Skeletal Muscle Insulin Resistance 176
and Bariatric Surgery 150 6. Effect of Aging on Inflammation and
8.2 Peroxisome Proliferator-Activated Oxidative Stress in Skeletal Muscle 177
Receptor Agonists as Therapy 151 7. Effect of Proinflammatory and Oxidative
8.3 Antioxidant Therapies 152 Stress Factors on the Development of
8.4 Antiinflammatory Therapy 154 Sarcopenic Obesity 177
8.5 Dialysis 154 8. Therapeutic Effect of Diet on
9. Conclusion 155 Inflammation and Oxidative Stress in
Glossary 155 Skeletal Muscle in Obesity 178
List of Acronyms and Abbreviations 156 8.1 Reduce Saturated Fats and Transfats
References 157 From Diet 178
8.2 Omega-3 Fatty Acids 178
8. Inflammatory and Oxidative Stress 8.3 Increase the Amount of Fruits and
Vegetables in Diet 179
Markers in Skeletal Muscle of Obese 8.4 Increase Foods Rich in Antioxidants 179
Subjects 9. Role of Exercise in the Regulation of
Inflammation and Oxidative Stress
Victoria Catalán, Gema Frühbeck and
in Skeletal Muscle in Obesity 179
Javier Gómez-Ambrosi
10. Conclusions 180
1. Introduction 163 List of Acronyms and Abbreviations 181
2. Inflammatory Markers in Skeletal Acknowledgments 182
Muscle in Obesity 164 References 182
2.1 Tumor Necrosis Factor-a 164
2.2 Interleukin-6 166 9. Evaluation of Oxidative Stress in
2.3 Interleukin-15 166
2.4 Interleukin-8 166
Humans: A Critical Point of View
2.5 Interleukin-10 166 Josep A. Tur, Antoni Sureda and Antoni Pons
2.6 Fibroblast Growth Factor 21 167
2.7 Irisin 167 1. Blood Cells Give Information on
2.8 Monocyte Chemotactic Protein-1 167 Antioxidant Endogenous Status 191
2.9 Myostatin 167 2. Blood Cells Give Information on
2.10 Calprotectin 168 Eicosanoid Levels 192
viii Contents

3. Blood Cells Are Useful to Define 5. Classification of Polyphenols 215

Antioxidant Exogenous (Vitamin) 5.1 Nonflavonoids 215
Status 193 5.2 Flavonoids 221
4. Conclusions 194 6. Conclusion 229
References 194 Glossary 230
List of Acronyms and Abbreviations 230
10. Benefits of Selenium, Magnesium, References 231
and Zinc in Obesity and Metabolic
Syndrome 12. Aging, Telomere Integrity, and
Antioxidant Food
Paulina López-López, Loreto Rojas-Sobarzo
and Miguel Arredondo-Olguı´n Ana Ojeda-Rodriguez, Lydia Morell-Azanza,
Lucia Alonso-Pedrero and Amelia Marti del Moral
1. Introduction 197
2. Selenium 198 1. Aging and Cellular Senescence 241
2.1 Requirements and Absorption 198 2. Oxidative Stress and Aging 242
2.2 Selenoproteins 199 3. Telomeres as Markers of Biological Age 243
2.3 Role of Selenium in Metabolic 4. Telomere Integrity in Human Studies 244
Syndrome and Obesity 201 5. Precision Nutrition for Telomere
3. Magnesium 202 Integrity 245
3.1 Requirements and Absorption 202 5.1 Nutrients 245
3.2 Role of Magnesium in Metabolic 5.2 Fat Intake 254
Syndrome and Obesity 203 5.3 Foods and Beverages 255
3.3 Magnesium and Inflammation 203 5.4 Dietary Patterns 256
3.4 Magnesium Consumption: Clinical 6. Conclusions 256
and Prospective Trials 204 List of Abbreviations 257
3.5 Magnesium Supplementation 204 Acknowledgments 257
4. Zinc 204 References 257
4.1 Requirements and Absorption 205
4.2 Role of Zinc in Metabolic Syndrome 13. Antioxidant Supplements in Obesity
and Obesity 205 and Metabolic Syndrome: Angels
4.3 The Role of Zinc as an Antioxidant 206
5. Concluding Remarks 206 or Demons 263
List of Abbreviations 207 Rafael A. Casuso and Jesús R. Huertas
References 208
1. Introduction 263
2. Oxygen, Reactive Oxygen Species,
11. Polyphenols in Obesity and and Oxidative Stress 263
3. Obesity and Diabetes “Pandemic” 266
Metabolic Syndrome 213 4. Reactive Oxygen Species Production,
Belén Pastor-Villaescusa, Estefania Sanchez Mitochondria, and Adaptation 267
Rodriguez and Oscar D. Rangel-Huerta 5. Insulin Resistance, Diabetes, and
Reactive Oxygen Species 268
1. Obesity and Metabolic Syndrome 213 6. Cancer and Antioxidants 272
2. Oxidative Stress and Antioxidant 7. Mediterranean Diet and Obesity 273
Defense 213 8. Conclusions 273
2.1 Oxidative Stress and Metabolic List of Acronyms and Abbreviations 274
Syndrome 214 References 274
3. Exogenous Antioxidants 214
4. Polyphenols 214 Index 277
List of Contributors

Itziar Abete, Department of Nutrition, Food Science and Victoria Catalán, Clínica Universidad de Navarra, Pam-
Physiology, Faculty of Pharmacy and Nutrition, plona, Spain; Centro de Investigación Biomédica en
University of Navarra, Pamplona, Spain; Biomedical Red-Fisiopatología de la Obesidad y Nutrición
Research Centre Network in Physiopathology of Obe- (CIBEROBN), Instituto de Salud Carlos III, Pamplona,
sity and Nutrition (CIBERobn), ISCIII, Madrid, Spain Spain; Instituto de Investigación Sanitaria de Navarra
Concepción M. Aguilera, University of Granada, Gran- (IdiSNA), Pamplona, Spain
ada, Spain; IBS (Instituto de Investigación Biosanitaria Elia Escasany, Universidad Rey Juan Carlos, Madrid,
de Granada), Granada, Spain; CIBERobn (Centro de Spain
Investigación Biomédica en Red, Fisiopatología de la Xavier Escoté, Centre for Nutrition Research, University
obesidad y nutrición), Carlos III Health Institute, of Navarra, Pamplona, Spain
Madrid, Spain
Elisa Felix-Soriano, Centre for Nutrition Research, Uni-
J. Alfredo Martínez, Department of Nutrition, Food versity of Navarra, Pamplona, Spain
Science and Physiology, Faculty of Pharmacy and
Nutrition, University of Navarra, Pamplona, Spain; Marta Fernández-Galilea, Centre for Nutrition Research,
Biomedical Research Centre Network in Physiopathol- University of Navarra, Pamplona, Spain; Center for
ogy of Obesity and Nutrition (CIBERobn), ISCIII, Applied Medical Research, University of Navarra,
Madrid, Spain; Navarra Institute for Health Research Pamplona, Spain
(IdiSNA), Pamplona, Spain Gema Frühbeck, Clínica Universidad de Navarra, Pam-
Lucia Alonso-Pedrero, University of Navarra, Pamplona, plona, Spain; Centro de Investigación Biomédica en
Spain; IdiSNA (Instituto de Investigación Sanitaria de Red-Fisiopatología de la Obesidad y Nutrición
Navarra), Pamplona, Spain (CIBEROBN), Instituto de Salud Carlos III, Pamplona,
Spain; Instituto de Investigación Sanitaria de Navarra
M. Angeles Zulet, Department of Nutrition, Food Science (IdiSNA), Pamplona, Spain
and Physiology, Faculty of Pharmacy and Nutrition,
University of Navarra, Pamplona, Spain; Biomedical Ángel Gil, University of Granada, Granada, Spain; IBS
Research Centre Network in Physiopathology of Obe- (Instituto de Investigación Biosanitaria de Granada),
sity and Nutrition (CIBERobn), ISCIII, Madrid, Spain; Granada, Spain; CIBERobn (Centro de Investigación
Navarra Institute for Health Research (IdiSNA), Pam- Biomédica en Red, Fisiopatología de la obesidad y
plona, Spain nutrición), Carlos III Health Institute, Madrid, Spain
Augusto Anguita-Ruiz, University of Granada, Granada, Javier Gómez-Ambrosi, Clínica Universidad de Navarra,
Spain Pamplona, Spain; Centro de Investigación Biomédica
en Red-Fisiopatología de la Obesidad y Nutrición
Miguel Arredondo-Olguín, Universidad de Chile, San- (CIBEROBN), Instituto de Salud Carlos III, Pamplona,
tiago, Chile Spain; Instituto de Investigación Sanitaria de Navarra
M. Vanessa Bullón-Vela, Department of Nutrition, Food (IdiSNA), Pamplona, Spain
Science and Physiology, Faculty of Pharmacy and Carolina Gomez-Llorente, University of Granada, Gran-
Nutrition, University of Navarra, Pamplona, Spain ada, Spain
Rafael A. Casuso, University of Granada, Granada, Spain

ix
x List of Contributors

Pedro González-Muniesa, Centre for Nutrition Research, Azahara I. Rupérez, University of Zaragoza, Zaragoza,
University of Navarra, Pamplona, Spain; CIBERobn, Spain
Institute of Health Carlos III, Madrid, Spain; IdiSNA, Estefania Sanchez Rodriguez, University of Granada,
Navarra Institute for Health Research, Pamplona, Spain Granada, Spain
Jesús R. Huertas, University of Granada, Granada, Spain Antoni Sureda, University of the Balearic Islands &
Adriana Izquierdo-Lahuerta, Universidad Rey Juan CIBEROBN, Palma de Mallorca, Spain
Carlos, Madrid, Spain Josep A. Tur, University of the Balearic Islands &
Paulina López-López, Universidad de Chile, Santiago, CIBEROBN, Palma de Mallorca, Spain
Chile Guillermo Zalba Goñi, University of Navarra, Pamplona,
Amelia Marti del Moral, University of Navarra, Pam- Spain; IdiSNA, Navarra Institute for Health Research,
plona, Spain; IdiSNA (Instituto de Investigación Sani- Pamplona, Spain
taria de Navarra), Pamplona, Spain; CIBERobn (Centro
de Investigación Biomédica en Red, Fisiopatología de
la obesidad y nutrición), Carlos III Health Institute,
Madrid, Spain
Leyre Martínez-Fernández, Centre for Nutrition
Research, University of Navarra, Pamplona, Spain
Gema Medina-Gómez, Universidad Rey Juan Carlos,
Madrid, Spain
Maria D. Mesa-Garcia, University of Granada, Granada,
Spain
Lydia Morell-Azanza, University of Navarra, Pamplona,
Spain; IdiSNA (Instituto de Investigación Sanitaria de
Navarra), Pamplona, Spain
María J. Moreno-Aliaga, Centre for Nutrition Research,
University of Navarra, Pamplona, Spain; CIBERobn,
Institute of Health Carlos III, Madrid, Spain; IdiSNA,
Navarra Institute for Health Research, Pamplona, Spain
Ana Ojeda-Rodriguez, University of Navarra, Pamplona,
Spain; IdiSNA (Instituto de Investigación Sanitaria de
Navarra), Pamplona, Spain
Josune Olza, University of Granada, Granada, Spain; IBS
(Instituto de Investigación Biosanitaria de Granada),
Granada, Spain; CIBERobn (Centro de Investigación
Biomédica en Red, Fisiopatología de la obesidad y
nutrición), Carlos III Health Institute, Madrid, Spain
Belén Pastor-Villaescusa, University of Granada, Gran-
ada, Spain
Álvaro Pejenaute, University of Navarra, Pamplona, Spain
Julio Plaza-Diaz, University of Granada, Granada, Spain
Antoni Pons, University of the Balearic Islands &
CIBEROBN, Palma de Mallorca, Spain
Oscar D. Rangel-Huerta, University of Oslo, Oslo,
Norway
Loreto Rojas-Sobarzo, Pontificia Universidad Católica de
Chile, Santiago, Chile
Francisco J. Ruiz-Ojeda, University of Granada, Granada,
Spain
About the Editors

Amelia Marti del Moral is Professor of Physiology at the Department of Food Science and Physiology of the University
of Navarra. She is the director of the Navarra Study Group for Childhood Obesity (GENOI) and the Children Obesity
Group of the Spanish Society of Obesity. She has published more than 250 scientific articles with a factor H of 42. She has
supervised 15 doctoral theses which have received both national (Royal Academy of Doctors) and international (Ibero-
American Academy of Pharmacy, Best Thesis Award of the European Society of Obesity) prizes. Her research has
been honored with the Silver Medal of the British Nutrition Society, the Merck & Daphne Award, and the Be Alsajara
Award for Excellence, among other awards. In 2017 she edited Telomeres, Diet and Human Disease: Advances and
Therapeutic Opportunities, published by CRC Press.
Concepción M. Aguilera is a Professor in the Department of Biochemistry and Molecular Biology at the University of
Granada in Spain. She leads the research on childhood obesity as a member of the Research Excellence Group BIONIT.
Currently she is leading various projects in genetics, particularly on the evaluation of genetic and epigenetic markers and
their association with obesity and prepubertal metabolic changes related to early onset of metabolic syndrome. Professor
Aguilera has published more than 75 scientific articles and supervised ten PhD theses. Currently she is secretary of the
Institute of Nutrition and Food Technology at the University of Granada and the Iberomerican Nutrition Foundation, an
institution supported by the International Union of Nutritional Sciences, and secretary of the Spanish Society of Nutrition.

xi
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Preface

This volume contains 13 contributions from a panel of experts, ranging from basic science to relevant clinical work
concerning the role of oxidative stress and antioxidants in obesity.
Oxidative stress is a feature of obesity or weight-related metabolic syndrome which centers on or around molecular and
cellular processes. Although a dysfunction in energy balance is the central feature of these conditions, oxidative stress can
also arise from nutritional imbalance over a spectrum of time frames before the onset of obesity or weight-related metabolic
syndrome. The major aim of the present book is to provide an in-depth review of our current knowledge on oxidative stress
and human obesity, and examine the role of antioxidants in obesity and associated comorbidities. It also points to future
directions in research on oxidative stress damage, telomere length as a marker of oxidative stress, and/or antioxidant
supplementation.
The first part of the volume (Chapters 1e8) focuses on the effect of inflammation and oxidative stress on the human
body, specifically covering damage to adipose tissue, vascular endothelia, liver, kidney, and skeletal muscle of obese
subjects. In Chapters 1 and 2 a general overview of the relationship between obesity and oxidative stress and the evidence
on the genetic basis of these conditions are presented.
A review of the evidence on the potentially therapeutic usage of natural antioxidants for obesity-related disease is
presented in the second part of this volume (Chapters 9e13), ranging from vitamin C and selenium to polyphenols and
antioxidant food. The last chapter offers a critical view on antioxidant supplements as angels or demons.
There is a fundamental need to understand the processes inherent in the oxidative stress in subjects who are obese.
The text is intended to furnish the reader with a general view of the state of the art in this novel area of research. We will
be satisfied if the multidisciplinary nature of these proceedings informs and stimulates readers. It is our hope that the
volume will encourage further research and understanding of all aspects of this intriguing and complex field of “obesity,
oxidative stress, and antioxidants.”
The editors express their gratitude to the authors of the chapters, and to Elsevier for having made possible the
publication of this volume.

xiii
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Chapter 1

Oxidative Stress and Inflammation

in Obesity and Metabolic Syndrome
Francisco J. Ruiz-Ojeda1, Josune Olza1, 2, 3, Ángel Gil1, 2, 3 and Concepción M. Aguilera1, 2, 3
1
University of Granada, Granada, Spain; 2IBS (Instituto de Investigación Biosanitaria de Granada), Granada, Spain; 3CIBERobn (Centro de
Investigación Biomédica en Red, Fisiopatología de la obesidad y nutrición), Carlos III Health Institute, Madrid, Spain

1. INTRODUCTION
Obesity is a worldwide public health problem that has been increasing in the last decades. According to the World Health
Organization, obesity and overweight are defined as “abnormal or excessive fat accumulation that may impair health.”
Increased consumption of highly caloric foods, without an equal increase in energy expenditure, mainly by physical ac-
tivity, leads to an unhealthy increase in weight; decreased levels of physical activity will result in an energy imbalance and
will lead to weight gain. Worldwide obesity has more than doubled since 1980. In 2014, more than 1.9 billion adults
18 years and older were overweight, and of these over 600 million were obese. Thus 30% of adults aged 18 years and over
were overweight in 2014 and 13% were obese. In addition, 41 million children under the age of five were overweight or
obese in 2014. Thus the problem is twice as important than in the 1980s, and about 13% of the population is estimated to
be obese [1].
Obesity is a well-known risk factor for insulin resistance (IR) and the development of type 2 diabetes (T2D). Diabetes is
associated with complications such as cardiovascular diseases (CVDs), nonalcoholic fatty liver disease (NAFLD), reti-
nopathy, angiopathy, and nephropathy, which consequently lead to higher mortality risks. Obesity-associated diabetes is
hence a major public health problem, and paucity of available medication against IR requires the validation of new
therapeutic targets [2]. Deaths from CVD and diabetes accounted for approximately 65% of all deaths, and general
adiposity and mainly abdominal adiposity are associated with increased risk of death for all these disorders. Adiposity is
also associated with a state of low-grade chronic inflammation, with increased tumor necrosis factor (TNF)-a and inter-
leukin (IL)-6 releases, which interfere with adipose cell differentiation and the action pattern of adiponectin and leptin until
the adipose tissue (AT) begins to be dysfunctional. Accordingly, the subjects present IR and hyperinsulinemia, probably
the first step of a dysfunctional metabolic system. Subsequent to central obesity, IR, hyperglycemia, hypertriglyceridemia,
hypoalphalipoproteinemia, hypertension, and fatty liver are grouped in the so-called metabolic syndrome (MetS) [3]. With
regard to MetS, overnutrition leads to Kuppfer cell activation, chronic inflammation, hepatic steatosis, and eventual
steatohepatitis and cirrhosis. Similarly, in the vascular intima, overnutrition-induced hyperlipidemia leads to oxidized low-
density lipoprotein (LDL) formation and uptake in macrophages leading to foam cell formation and vascular inflammation.
The cross-talk between metabolism and inflammation is also demonstrated by immunomodulatory corticosteroids that also
have strong effects on host protein and carbohydrate metabolism [4].
In subjects with MetS an energy balance is critical to maintain a healthy body weight, mainly limiting high energy
density foods. The first factor to be avoided in the prevention of MetS is obesity; the percentage of fat in the diet has
traditionally been associated with the development of obesity. However, it is well established that the type of fat consumed
could be more decisive than the total amount of fat consumed when we only look at changes in body composition and
distribution of AT. Additionally, IR is a feature of MetS and is associated with other components of the syndrome. The
beneficial impact of fat quality on insulin sensitivity (IS) was not seen in individuals with a high fat intake (>37% of
energy). Other dietary factors that can influence various components of MetS, like postprandial glycemic and insulin

Obesity. https://doi.org/10.1016/B978-0-12-812504-5.00001-5 1
Copyright © 2018 Elsevier Inc. All rights reserved.
2 Obesity

levels, triacylglycerols (TAGs) and high-density lipoprotein (HDL) cholesterol levels, weight regulation and body
composition, as well as fatty liver, are the glycemic load and the excess of fructose, and amount of dietary fiber content of
food eaten. The increased levels of TAG associated with hypoalphalipoproteinemia are a feature of IR and MetS, and
increase cardiovascular risk regardless of LDL cholesterol levels [3,4].
AT is the main organ for energy storage, but also AT itself can be seen as an endocrine organ that plays a critical role in
immune homeostasis. In healthy people, AT represents about 20% of the body mass in men and about 30% in women. In
obesity, it expands tremendously and may constitute more than 50% of the body mass in morbidly obese individuals. AT
produces and releases a variety of adipokines and cytokines, including leptin, adiponectin, resistin, and visfatin, as well as
TNF-a and IL-6, among others [5]. Proinflammatory molecules produced by AT have been implicated as active partici-
pants in the development of metabolic disease. Furthermore, AT macrophages (ATMs) are prominent sources of proin-
flammatory cytokines, which can block insulin action in AT, skeletal muscle, and liver autocrine/paracrine signaling and
cause systemic IR via endocrine signaling, providing a potential link between inflammation and IR [6].

2. OXIDATIVE STRESS, OBESITY, AND METABOLIC SYNDROME

Another critical factor that is involved in the pathogenesis of metabolic diseases is oxidative stress. Oxidative stress is a
state of imbalance between the oxidative and antioxidative systems of cells and tissues, resulting in the production of
excessive oxidative free radicals and reactive oxygen species (ROS) [7] caused either by exposure to damaging agents, or
limited capabilities of endogenous antioxidant systems [8]. The components of the MetS as well as their comorbidities lead
to the progression of prooxidative status contributing to the damage of biomolecules that are highly reactive and can
stimulate cell and tissue dysfunctions, leading to the development of metabolic diseases [7]. High levels of circulating
glucose and lipids can result in excessive energy substrates for metabolic pathways in adipose and nonadipose cells,
increasing the production of ROS; if ROS are not well controlled, they can damage proteins, lipids, sugars, and DNA [8,9].
It is well known that mitochondria are the most critical sites for ROS production, because an excess supply of electrons
to the electron transport chain can produce very high levels of ROS [10]. In addition to the range of pathologies that it can
cause, this increase in ROS production can also damage the mitochondria, affecting the cellular redox signaling, indicating
that this organelle can be an important target in the treatment of those pathologies [11].
A large quantity of epidemiological as well as in vivo and in vitro studies have suggested that obesity and redox
alteration are interconnected through mutual mechanisms. It is hypothesized that oxidative stress is one of the links be-
tween fat accumulation-derived alterations and the appearance of a cluster of health problems including adipokine secretion
alteration, inflammation, and IR (Fig. 1.1).
ROS have been involved in the adipogenesis (proliferation and differentiation) process, indicating its participation in
the development of metabolic diseases through various mechanisms including chronic adipocyte inflammation, fatty acid
oxidation, overconsumption of oxygen and accumulation of cellular damage, diet, and mitochondrial activity. Obesity
can cause oxidative stress through the activation of intracellular pathways such as nicotinamide adenine dinucleotide
phosphate (NADPH) oxidase (NOX), oxidative phosphorylation in mitochondria, glycoxidation, protein kinase C, and
polyol [12]; it can also deregulate the synthesis of adipokines such as adiponectin, visfatin, resistin, leptin, plasminogen
activator inhibitor-1 (PAI-1), and TNF-a and IL-6. Both TNF-a and IL-6 increase the activity of NOX and the pro-
duction of superoxide anions [13]. Indeed it seems that obesity is the connection between oxidative stress and
inflammation although it is not easy to confirm which one antecedes the other. It has also been observed that oxidative
stress controls food intake and body weight by upholding some effects on hypothalamic neurons with impact on satiety
and hunger [14].
Different studies in obese subjects have reported low levels of antioxidant molecules, oxidized-LDL (ox-LDL) and
thiobarbituric acid reactive substances (TBARSs) as well as increased activities of antioxidant enzymes [13]. Additionally,
high levels of protein oxidation have been correlated with the presence of AT, IR, and inflammation [15].

2.1 Biomarkers of Oxidative Stress

The direct quantification of ROS is a valuable biomarker that can reflect the disease process [8]; however, their mea-
surement in biological systems has been complex given their short half-life and instability, which makes it a significant
challenge to perform an accurate assessment of these species [16]. For this reason, different methods have been developed
for measuring stable markers that reflect a systemic or tissue-specific oxidative stress [17].
Lipids, proteins, and DNA are the most common molecules that are modified when ROS levels increase in the or-
ganism. These modifications can have a direct effect on the function of target molecules or can just reflect a local degree of
 Oxidative Stress and Inflammation in Obesity Chapter | 1 3

FIGURE 1.1 Oxidative stress and inflammation in the context of obesity. Obesity is associated with a high energy intake, which increases glycemia
and circulating FFA. These increase ROS in the cells due to the overactivation of mitochondrial electron transport chain and the endoplasmic reticulum.
The obesity associated fat accumulation leads to inflammation, hypertrophied adipocytes, and hypoxia. Moreover, oxidative stress worsens inflammation
and alters adipokine secretion. Many of these phenomens activate the monocyte infiltration in adipose tissue that worsens the inflammatory processes.
Hypoxia also increases glucose uptake and thus mitochondrial function, further contributing to ROS production. Through these mechanisms, ROS
contribute to the development of insulin resistance, systemic oxidative stress, and endothelial damage. FFA, free fatty-acids; IL-6, interleukin 6; NADPH,
nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species; TNFa, tumor necrosis factor alpha.

oxidative stress; these modifications influence the clinical applicability of markers because the functional significance or
the causal role of oxidative modifications on biological functions is essential for the validity of a biomarker. Thus it is
important to take this into account when choosing a valid biomarker, the type of sample, and the characteristics of the
individual under investigation. Table 1.1 summarizes the main biomarkers of oxidative stress studied in human obesity and
MetS.

2.1.1 Lipid Oxidation Products

Lipid oxidation end product determination is an extensively used marker of oxidative stress. Cell membranes are sus-
ceptible to lipid peroxidation due to the presence of polyunsaturated fatty acids (PUFAs) that make them highly susceptible
to oxidative damage in the presence of ROS or free radicals [18]. Enzymatic reactions, which oxidize arachidonic acid
(AA) into prostaglandins, prostacyclin, thromboxane, and leukotrienes, can also produce lipids peroxidation through the
activity of lipooxygenase and cyclooxygenase (COX) [8]. Primary products of lipid peroxidation are unstable hydroper-
oxides that decompose to various secondary products, among which are stabile aldehydes, malondialdehyde (MDA), and
4-hydroxynonenal (HNE) [19]. These last compounds represent the most investigated end products of lipid oxidation [20]
together with F2-isoprostane 15(S)-8-iso-prostaglandin F2a (15(S)-8-iso-PGF2a) [21].

2.1.1.1 Malondialdehyde, Alkenals, and Alkadienes Enclose Thiobarbituric Acid Reactive Substances
Although TBARS is the oldest methodology to determine these products, it is still widely used. This methodology has been
criticized for its low sensitivity and selectivity since several MDA-unrelated species from biological samples can react with
TBA, and some artifactual generation of MDA during the assay has been raised [22]. In the last few years, several in-
novations have been introduced to improve the specificity of the test and to reduce known bias. The combination of
spectrophotometric and fluorometric technologies with high-performance liquid chromatography (HPLC) has increased the
sensitivity of the test, and more recently gas chromatography coupled with mass spectroscopy (GCeMS)-based methods
have been developed [17]. These methods have been demonstrated to be specific and more sensitive than the batch TBARS
assays. Much evidence has been published in patients with metabolic diseases where plasma MDA and TBARS have been
positively correlated with obesity in clinical studies [23]. It has also been shown that plasma glucose and insulin levels are
positively associated with MDA levels in patients with T2D and IR compared with healthy volunteers [21]. Likewise,
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