The Mechanobiology of Obesity and Related Diseases (Studies in Mechanobiology, Tissue Engineering and Biomaterials Book 16)

This volume describes the state-of-knowledge in the study of the relationships between mechanical loading states in tissues and common pathophysiologies related to increase in mass of adipose tissues and/or hyperglycemia which eventually lead to obesity, diabetes, insulin resistance, hyperlipidemia, metabolic inflammations, certain types of cancer and other related diseases. There appears to be an interaction between the loading states in tissues and cells and these chronic conditions, as well as with factors such as age, gender and genetics of the individual. Bioengineering has made key contributions to this research field in providing technologies for cell biomechanics experimentation, microscopy and image processing, tissue engineering and multi-scale, multi-physics computational modeling. Topics at the frontier of this field of study include: the continuous monitoring of cell growth, proliferation and differentiation in response to mechanical factors such as stiffness of the extracellular matrix (ECM) and mechanical loads transferred through the ECM; mechanically-activated signaling pathways and molecular mechanisms; effects of different loading regimes and mechanical environments on differentiation fates of mesenchymal stem cells (MSCs) into myogenic and osteogenic versus adipogenic lineages; the interactions between nutrition and mechanotransduction; cell morphology, focal adhesion patterns and cytoskeletal remodeling changes in adipogenesis; activation of receptors related to diabetes by mechanical forces; brown and white adipose plasticity and its regulation by mechanical factors. Preface 6 Contents 9 Part IFrom Tissues to Cells 11 180 Mechanical Behavior and Properties of Adipose Tissue 12 Abstract 12 1...Introduction 12 2...Linear Visco-elastic Behavior at Small Strains 13 3...Temporal Property Changes in Tests of Long Duration 14 4...Large Strain Behavior of Adipose Tissue 15 5...Consequences for Biomechanical Studies 17 References 17 170 Mathematical Models of Adipose Tissue Dynamics 19 Abstract 19 1...Adipose Cells 19 2...Bimodal Size Distribution 21 3...Bayesian Inference 22 4...Adipose Tissue Dynamics 25 4.1 Recruitment of New Adipose Cells 26 4.2 Size-Dependent Growth/Shrinkage 26 4.3 Size Fluctuations and Lipid Turnover 27 4.4 Cell Death 27 4.5 Cell Turnover 28 5...Adipose Tissue Development 29 5.1 Parallel Tempering as a Model Selection Method 29 6...Adipose Cell Dynamics and Body Composition 32 7...Summary and Discussion 39 References 40 169 Mechanical Stretching and Signaling Pathways in Adipogenesis 43 Abstract 43 1...Introduction 44 2...Effects of Mechanical Stimuli on Adipocyte Differentiation 45 3...Mechanotransduction that Affects Adipogenesis 48 3.1 Mechanosensing Molecules 48 3.2 Cellular Mechanical Properties and Cytoskeletal Controls 48 3.3 Extracellular Matrix--Integrin Interaction 49 3.4 Rho--Rho-Kinase Pathway 52 3.5 Dual Effects of ERK in the Stretch-Induced Response on Adipogenesis 52 3.6 Cyclooxygenase Pathway 54 3.7 Wnt Signal 55 3.8 Tension-Induced/Inhibited Proteins Pathway 56 4...Possible Pharmacological Intervention 57 5...In Vivo Application of Mechanical Stimuli to Adipose Tissues 61 6...Concluding Remarks 61 Competing financial interests 63 References 63 173 Role of Mechanical Stimulations in Directing Mesenchymal Stem Cell Adipogenesis 71 Abstract 71 1...Introduction 72 2...Mechanical Control of Stem Cell Adipogenesis 73 2.1 Effects of Mechanical Stretch 73 2.2 Effects of Compression 80 2.3 Effects of Fluid Shear 82 3...Control by Substrate Cues 85 4...Perspective 89 References 92 176 The Vicious Cycle of Estrogen Consumption and Obesity: The Role of Mechanotransduction 96 Abstract 96 1...Introduction 96 2...Development and Structure of Adipose Tissue 97 3...Distribution of Adipose Tissues in Obesity 98 4...Pathophysiology of Adipose Tissue 99 5...Estrogen and Adipose Tissues 99 5.1 Estrogen Consumption 99 5.2 Estrogen Production in Adipose Tissues 100 5.3 The Influence of Estrogen on Proliferation and Differentiation of Adipocytes 100 6...Mechanotransduction in Adipocytes 102 7...Mechanical Properties of Adipose Tissues 103 8...Mechanical Properties of Adipocytes 103 9...Closure 105 Acknowledgements 106 References 106 172 Extracellular Matrix Remodeling and Mechanical Stresses as Modulators of Adipose Tissue Metabolism and Inflammation 111 Abstract 111 1...Introduction 112 2...Adipose Cellular Hypertrophy and ECM Changes 113 3...Tissue Stiffening Leads to Metabolic Stress and Inflammation 115 4...Pathways Activated by Mechanical Stimuli 116 5...Mechanical Influences 118 5.1 Substrate-Mediated Influences 118 5.2 Applied Mechanical Loading 120 6...Concluding Remarks 123 References 124 Part IIThe Biomechanics and Mechanobiologyin Comorbidities of Obesity 129 174 The Impact of Obesity and Weight Loss on Gait in Adults 130 Abstract 130 1...Introduction 131 2...Normal Gait Cycle 132 2.1 Gait Phases 132 2.2 Methods of Gait Analysis 134 3...Spatio-Temporal Variables and Joint Kinematics in the Obese 134 3.1 Spatio-Temporal Variables 134 3.2 Gait Kinematics 138 4...Gait Kinetics in the Obese 141 4.1 Ground Reaction Forces 141 4.2 Ankle, Knee, and Hip Joint Moments 141 4.3 Impulsive Loading Measurements 143 5...Effects of Weight Loss on Gait 145 5.1 Diet and Exercise 145 5.1.1 Knee Osteoarthritis 146 5.2 Bariatric Surgery 147 6...Summary and Conclusions 148 Acknowledgments 149 References 149 175 Excessive Weight Bearing Compromises Foot Structure and Function Across the Lifespan 153 Abstract 153 1...Introduction 154 2...Development of the Foot 154 3...Normal Foot Structure and Function 156 4...Effects of Excessive Body Mass on Foot Structure and Function 158 4.1 Infants/Preschool (2--5 years) 159 4.1.1 Effects of Obesity in Young Children on Foot Structure 159 4.1.2 Effects of Obesity in Young Children on Gait and Plantar Pressures 160 4.2 School-Aged Children (6--18 years) 161 4.2.1 Effects of Obesity in Children on Foot Structure 161 4.2.2 Effects of Obesity in Children on Gait and Plantar Pressures 164 4.2.3 Effects of Obesity in Children on Foot Pain and Plantar Pressures 165 4.3 Adults (18--60 years) 167 4.3.1 Effects of Obesity in Adults on Foot Structure 168 4.3.2 Effects of Obesity in Adults on Foot Pain 169 4.3.3 Effects of Obesity in Adults on Plantar Heel Pain 170 4.3.4 Effects of Obesity in Adults on Plantar Pressures 171 4.4 Older Adults ( greaterthan 60 years) 173 4.4.1 Effects of Obesity in Older Adults on Foot Structure 174 4.4.2 Effects of Obesity in Older Adults on Plantar Pressures 175 4.4.3 Effects of Obesity in Older Adults on Foot Pain 175 5...Summary and Conclusions 177 Acknowledgments 177 References 177 178 Obesity, Osteoarthritis and Aging: The Biomechanical Links 184 Abstract 184 1...Introduction 185 2...Obesity and Joint Loading 186 3...Obesity and Inflammation 189 3.1 Systemic Versus Local Factors 189 3.2 Interaction of Biomechanics and Inflammation 191 4...Redox Signaling and Oxidative Stress in the Obese Joint 193 4.1 Reactive Oxygen Species, Metabolism, and Mechanical Loading 193 4.2 Antioxidants and Oxidative Stress 195 5...Summary and Conclusions 197 References 198 177 Impaired Neutrophil Mechanoregulation by Fluid Flow: A Potential Contributing Factor for Microvascular Dysfunction in Obesity 205 Abstract 205 1...Introduction 205 2...Chronic Neutrophil Activity and the Microcirculation in Obesity 206 2.1 Obesity and Chronic Inflammation 207 2.2 Obesity and Hypertension 208 2.3 Obesity and Hypercholesterolemia 208 3...Neutrophils and Their Rheological Influence on the Microcirculation 209 3.1 The Neutrophils and Their Activation State 209 3.2 The Impact of Neutrophil Activation on Microvascular Blood Flow 212 4...The Shear Stress Regulation of the Neutrophil 214 4.1 The Shear Stress Environment of the Neutrophil 215 4.2 Neutrophil Responses to Fluid Shear Stress 216 4.3 Neutrophil Mechanosensitivity to Shear Stress 218 4.4 Influence of the Neutrophil Shear Responses on the Microcirculation 221 5...Impaired Neutrophil Shear Response and Microvascular Dysfunction in Obesity 222 6...Concluding Remarks 225 References 225 179 Mechanotransduction and the Myogenic Response in Diabetes 235 Abstract 235 1...Introduction 236 2...Myogenic Control of Blood Flow: Physiological Relevance 237 3...Current Understanding of the Cellular Mechanisms Underlying Myogenic Vasoconstriction 238 3.1 Sensed Variables 238 3.2 Membrane Depolarization 240 3.2.1 Mechanically-Activated Ion Channels 240 3.2.2 G-proteins and Membrane Located Effectors 245 3.2.3 Extracellular Matrix: Integrin Interactions 246 3.3 Ca2+ Mobilization 247 3.4 Activation of Protein Kinases 248 3.4.1 Myosin Light Chain Kinase and Myosin Phosphatase 248 3.4.2 Protein Kinase C 249 3.4.3 Sphingosine Kinase 249 3.4.4 Tyrosine Phosphorylation 250 4...Impact of Diabetes on Myogenic Signaling 250 4.1 Experimental Animal Studies: Insulin Resistance; Type 1 and 2 Diabetes Models 254 4.1.1 Insulin Resistance 254 4.1.2 Type 1 Diabetes Models 254 4.1.3 Type 2 Diabetes Models 255 Mouse Models of Type 2 Diabetes 255 Rat Models of Type 2 Diabetes 255 4.2 Human Studies 256 5...Mechanisms Impacting Vessel Mechanical Function in Diabetes 257 5.1 Extracellular Matrix Protein Glycation 257 5.2 Protein Deposition 260 5.3 Stiffening of the Vessel Wall 260 5.4 Alterations in Contractile Mechanisms Impacting Arteriolar Myogenic Signaling 262 6...Concluding Remarks and Future Directions 262 Acknowledgments 263 References 263 171 Role of Adipose Cells in Tumor Microenvironment 273 Abstract 273 1...Introduction 274 1.1 Obesity and Tumor Microenvironment 274 1.2 Cells Composing Adipose Tissue 274 2...Functions of WAT-Derived Cells in Tumor Microenvironment 276 2.1 Adipokines and Cancer 276 2.2 Adipose Cell Role in Tumor Immunomodulation 280 2.3 Adipose Cell Role in Tumor Vascularization 281 2.4 Adipose Cell Role in Tumor Matrix Remodeling 282 2.5 Adipose Cell Role in Tumor Metabolism 283 2.6 Other Molecular Mechanisms Mediating Adipose Cell-Driven Cancer Progression 284 3...Potential Mechanisms of Adipose Cell Trafficking to Tumors 285 4...Modeling Adipose Cell Role in Tumor Microenvironment 286 5...Summary and Conclusions 288 References 289 AuthorIndex 297 Front Matter....Pages i-x Mechanical Behavior and Properties of Adipose Tissue....Pages 3-9 Mathematical Models of Adipose Tissue Dynamics....Pages 11-34 Mechanical Stretching and Signaling Pathways in Adipogenesis....Pages 35-62 Role of Mechanical Stimulations in Directing Mesenchymal Stem Cell Adipogenesis....Pages 63-87 The Vicious Cycle of Estrogen Consumption and Obesity: The Role of Mechanotransduction....Pages 89-103 Extracellular Matrix Remodeling and Mechanical Stresses as Modulators of Adipose Tissue Metabolism and Inflammation....Pages 105-122 The Impact of Obesity and Weight Loss on Gait in Adults....Pages 125-147 Excessive Weight Bearing Compromises Foot Structure and Function Across the Lifespan....Pages 149-179 Obesity, Osteoarthritis and Aging: The Biomechanical Links....Pages 181-201 Impaired Neutrophil Mechanoregulation by Fluid Flow: A Potential Contributing Factor for Microvascular Dysfunction in Obesity....Pages 203-232 Mechanotransduction and the Myogenic Response in Diabetes....Pages 233-270 Role of Adipose Cells in Tumor Microenvironment....Pages 271-294 Back Matter....Pages 295-296