Obesity is one of the largest medical epidemics our society faces today. There are over forty obesity-associated diseases that affect nearly every organ system in the body, including Type 2 Diabetes (T2D) and Non-Alcoholic Fatty Liver Disease (NAFLD). Insulin resistance is one of the hallmark characteristics underlying metabolic diseases, and mitochondrial dysfunction is believed to be a central player in this phenomenon, yet our understanding of the specific molecular mechanisms that serve as cause and consequence of defective mitochondria remain complex and elusive despite significant attention. In the studies presented in this dissertation, liver tissue isolated from a rat model of obesity-induced NAFLD and human subject-derived skeletal muscle cells revealed two distinct mechanisms by which mitochondrial dynamics may play a key role in regulating the progression of insulin resistance and cellular bioenergetics in obesity-related metabolic diseases. First, we found that markers of mitochondrial fusion and biogenesis are upregulated in the liver of obese Sprague-Dawley rats following gastric bypass surgery, and expression of a specific fusion marker, namely mitofusin 1, is associated with reductions in body weight and improved insulin sensitivity. Utilizing human primary skeletal muscle cells isolated from percutaneous needle biopsy, we found that metformin treatment in vitro upregulates glycolytic pathways, suppresses mitochondrial respiration, and activates a specific protein of mitochondrial fission. Together, the work presented here describes mitochondrial mechanisms related to insulin resistance in two obesity models and major metabolic tissues.

Mitochondria in Obesity and Type 2 Diabetes: Comprehensive Review on Mitochondrial Functioning and Involvement in Metabolic Diseases synthesizes discoveries from laboratories around the world, enhancing our understanding of the involvement of mitochondria in the etiology of diseases, such as obesity and type 2 diabetes. Chapters illustrate and provide an overview of key concepts on topics such as the role of mitochondria in adipose tissue, cancer, cardiovascular comorbidities, skeletal muscle, the liver, kidney, and more. This book is a must-have reference for students and educational teams in biology, physiology and medicine, and researchers. Synthesizes actual knowledge on mitochondrial function Provides an integrated vision of each tissue in the etiology of obesity and type 2 diabetes Identifies the interactive networks that involve alteration in mitochondrial mass and function in disease progression Highlights the role played by mitochondria in the prevention and treatment of obesity and type 2 diabetes

Methods in Toxicology, Volume 2: Mitochondrial Dysfunction provides a source of methods, techniques, and experimental approaches for studying the role of abnormal mitochondrial function in cell injury. The book discusses the methods for the preparation and basic functional assessment of mitochondria from liver, kidney, muscle, and brain; the methods for assessing mitochondrial dysfunction in vivo and in intact organs; and the structural aspects of mitochondrial dysfunction are addressed. The text also describes chemical detoxification and metabolism as well as specific metabolic reactions that are especially important targets or indicators of damage. The methods for measurement of alterations in fatty acid and phospholipid metabolism and for the analysis and manipulation of oxidative injury and antioxidant systems are also considered. The book further tackles additional methods on mitochondrial energetics and transport processes; approaches for assessing impaired function of mitochondria; and genetic and developmental aspects of mitochondrial disease and toxicology. The text also looks into mitochondrial DNA synthesis, covalent binding to mitochondrial DNA, DNA repair, and mitochondrial dysfunction in the context of developing individuals and cellular differentiation. Microbiologists, toxicologists, biochemists, and molecular pharmacologists will find the book invaluable.

Obesity and type 2 diabetes are modern epidemics, closely associated with the development of insulin resistance. While lipid induced mitochondrial dysfunction plays an important role in skeletal muscle insulin resistance, it is unclear whether a similar etiology is responsible for hepatic insulin resistance. The purpose of this thesis is to investigate whether impaired mitochondrial function plays a role in hepatic insulin resistance, and if so, whether it is a cause or consequence of insulin resistance. I further put forth the hypothesis that increased fat delivery either by diet or by genetic defect results in elevated hepatic triglyceride storage, induction of hepatic TCA cycle flux and poorly controlled gluconeogenesis in the insulin resistant liver. In order determine in vivo hepatic metabolism, we first developed a stable isotope tracer method to estimate hepatic fat oxidation and integrated it with other standard techniques to measure hepatic glucose production. These methods were used to determine in vivo hepatic mitochondrial pathways in a diet induced obese and diabetic mouse model and in a severe genetic model of diabetes (ZDF rats). Additionally, a pharmacological intervention in ZDF rats was used as an attempt to correct the dysfunctional metabolic pathways. The findings from this study suggest that mitochondrial dysfunction is not a cause, but the consequence of hepatic insulin resistance. The data further indicate that only selected mitochondrial pathways are impaired during severe insulin resistance, while others are induced and that interventions that target mitochondrial metabolism may not completely normalize hepatic metabolism if they indiscriminately induce all mitochondrial pathways.

Mitochondria are organelles in each cell outside the nucleus and are the energy source of all cells. As such, they are crucial to the healthy functioning of cells. Recent research has shown that mitochondrial dysfunction underlies a broad spectrum of disease, from maternally inherited genetic disorders to metabolism defects, aging, stroke, and neurodegenerative diseases such as Parkinson's, Alzheimer's, and Lou Gehrig's disease. This book brings together top researchers whose work in examining the pathophysiologic processes will lead to new strategies for prevention and treatment.

Due to the resultant health consequences and considerable increase in prevalence, obesity has become a major worldwide health problem. “Obesity and Lipotoxicity” is a comprehensive review of the recent researches to provide a better understanding of the lipotoxicity-related mechanisms of obesity and the potential for the development of new treatment strategies. This book overviews the biochemical pathways leading to obesity-related metabolic disorders that occur subsequent to lipotoxicity. Chapters examine the deleterious effects of nutrient excess at molecular level including the cellular and molecular aspects of breast cancer, resistance to leptin, insulin, adiponectin, and interconnection between the circadian clock and metabolic pathways during high-fat feeding. “Lipotoxicity and Obesity” will be a useful resource for clinicians and basic science researchers, such as biochemists, toxicologists, immunologists, nutritionists, adult and pediatric endocrinologists, cardiologists, as well as students who are thought in this field.