High Fat Diet and Deficient Antioxidant Status as Contributing Factors to Mitocho

高脂肪饮食和缺乏抗氧化状态是三户町的影响因素

• 批准号: 8270031
• 负责人: Lucinda Carnell
• 金额: $ 7.76万
• 依托单位: CENTRAL WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2014-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8270031
• 关键词: Address; Adverse effects; Animal Feed; Animal Model; Animals; Antioxidants; Binding; Caenorhabditis elegans; Calcium; Cells; Consumption; Data; Defect; Development; Diet; Dietary Fats; Disease; Environmental Risk Factor; Epidemic; Exposure to; Fatty acid glycerol esters; Feeding behaviors; Functional disorder; Generations; Genetic; Glucose Intolerance; Glutathione; Health; Hydrogen Peroxide; Insulin; Intracellular Accumulation of Lipids; Lead; Link; Lipid Peroxidation; Lipids; Longevity; Maps; Measures; Membrane; Membrane Potentials; Metabolic Diseases; Metabolism; Mitochondria; Mitochondrial Membrane Protein; Mitochondrial Proteins; Modeling; Movement; Mus; Muscle function; Mutation; NAD(P)+ transhydrogenase; NADP; Nematoda; Neurophysiology - biologic function; Non-Insulin-Dependent Diabetes Mellitus; Onset of illness; Organism; Oxidative Stress; Pancreas; Pathway interactions; Patients; Physiological; Physiological Processes; Play; Potassium Channel; Process; Production; Proteins; Quantitative Trait Loci; Reactive Oxygen Species; Risk Factors; Role; Sensory; Stearic Acids; Superoxides; System; Testing; Tissues; Unsaturated Fats; Work; age related; egg; gene function; insulin secretion; mitochondrial dysfunction; mitochondrial membrane; model development; mutant; neuromuscular function; prevent; public health relevance; respiratory; response; saturated fat; therapeutic target

DESCRIPTION (provided by applicant): Type 2 diabetes is a serious metabolic disorder that has reached epidemic proportions worldwide. Decreased insulin secretion associated with the pancreatic 2 cells is a risk factor for the development of the disease. One model for the development of this risk factor is increased mitochondrial dysfunction and reactive oxygen species (ROS) generation. Support of this model comes from identification of a genetic link between defective nicotinamide nucleotide transhydrogenase (NNT) gene function and decreased insulin secretion (Freeman 2006b). NNT is a mitochondrial membrane protein that generates NADPH, which is required for the reduction of glutathione, an important antioxidant in ROS scavenger pathways. Another factor linking type 2 diabetes to mitochondrial dysfunction is intracellular lipid accumulation. Consumption of high- fat diets is an environmental factor that is associated with disease onset and with mitochondrial damage through the generation of ROS. Exactly how high-fat diets or intracellular lipid accumulation lead to mitochondrial dysfunction or how mitochondrial proteins contribute to this process is unclear. Thus, the effects of saturated and unsaturated fat diets and the role of the mitochondrial protein, NNT, on mitochondrial function will be investigated using the nematode, C. elegans. C. elegans is an established model for examining mitochondrial function and its physiological consequences. Previous studies have demonstrated that nnt-1 mutants have increased sensitivity to oxidative stress and recent preliminary data suggests that animals fed a high saturated fat diet have increased ROS production and movement deficits. Whole animal studies measuring mitochondrial function can be performed in conjunction with physiological function over the life span of the animal thus allowing a direct comparison between mitochondrial function and overall health of the organism. The hypothesis that NNT mutations and high-fat diet in combination will exacerbate mitochondrial and physiological dysfunction via increased ROS production and lipid peroxidation will be tested. The prediction that treating animals with mitochondrial-targeted antioxidants will diminish adverse effects will also be tested. These studies will clarify the origin of ROS and indicate whether or not further studies on mitochondrial-targeted therapeutic treatments of patients with type 2 diabetes are warranted. PUBLIC HEALTH RELEVANCE: Type 2 diabetes is a serious disease that has reached epidemic proportions worldwide. Recent evidence suggests that mitochondria may play a critical role in the development of the disease, however, mitochondrial dysfunction has not been clearly linked to physiological consequences. The proposed work will address the potential effects of dietary fat and genetic pre-disposition on mitochondrial and physiological dysfunction. Results will clarify the role of mitochondria and indicate whether or not further studies on mitochondrial-targeted therapeutic treatments of patients with type 2 diabetes are warranted.

DESCRIPTION (provided by applicant): Type 2 diabetes is a serious metabolic disorder that has reached epidemic proportions worldwide. Decreased insulin secretion associated with the pancreatic 2 cells is a risk factor for the development of the disease. One model for the development of this risk factor is increased mitochondrial dysfunction and reactive oxygen species (ROS) generation. Support of this model comes from identification of a genetic link between defective nicotinamide nucleotide transhydrogenase (NNT) gene function and decreased insulin secretion (Freeman 2006b). NNT is a mitochondrial membrane protein that generates NADPH, which is required for the reduction of glutathione, an important antioxidant in ROS scavenger pathways. Another factor linking type 2 diabetes to mitochondrial dysfunction is intracellular lipid accumulation. Consumption of high- fat diets is an environmental factor that is associated with disease onset and with mitochondrial damage through the generation of ROS. Exactly how high-fat diets or intracellular lipid accumulation lead to mitochondrial dysfunction or how mitochondrial proteins contribute to this process is unclear. Thus, the effects of saturated and unsaturated fat diets and the role of the mitochondrial protein, NNT, on mitochondrial function will be investigated using the nematode, C. elegans. C. elegans is an established model for examining mitochondrial function and its physiological consequences. Previous studies have demonstrated that nnt-1 mutants have increased sensitivity to oxidative stress and recent preliminary data suggests that animals fed a high saturated fat diet have increased ROS production and movement deficits. Whole animal studies measuring mitochondrial function can be performed in conjunction with physiological function over the life span of the animal thus allowing a direct comparison between mitochondrial function and overall health of the organism. The hypothesis that NNT mutations and high-fat diet in combination will exacerbate mitochondrial and physiological dysfunction via increased ROS production and lipid peroxidation will be tested. The prediction that treating animals with mitochondrial-targeted antioxidants will diminish adverse effects will also be tested. These studies will clarify the origin of ROS and indicate whether or not further studies on mitochondrial-targeted therapeutic treatments of patients with type 2 diabetes are warranted. PUBLIC HEALTH RELEVANCE: Type 2 diabetes is a serious disease that has reached epidemic proportions worldwide. Recent evidence suggests that mitochondria may play a critical role in the development of the disease, however, mitochondrial dysfunction has not been clearly linked to physiological consequences. The proposed work will address the potential effects of dietary fat and genetic pre-disposition on mitochondrial and physiological dysfunction. Results will clarify the role of mitochondria and indicate whether or not further studies on mitochondrial-targeted therapeutic treatments of patients with type 2 diabetes are warranted.