d-arg-dmt-lys-phe-nh2 and Obesity

High dietary fat intake leads to insulin resistance in skeletal muscle, and this represents a major risk factor for type 2 diabetes and cardiovascular disease. Mitochondrial dysfunction and oxidative stress have been implicated in the disease process, but the underlying mechanisms are still unknown. Here we show that in skeletal muscle of both rodents and humans, a diet high in fat increases the H(2)O(2)-emitting potential of mitochondria, shifts the cellular redox environment to a more oxidized state, and decreases the redox-buffering capacity in the absence of any change in mitochondrial respiratory function. Furthermore, we show that attenuating mitochondrial H(2)O(2) emission, either by treating rats with a mitochondrial-targeted antioxidant or by genetically engineering the overexpression of catalase in mitochondria of muscle in mice, completely preserves insulin sensitivity despite a high-fat diet. These findings place the etiology of insulin resistance in the context of mitochondrial bioenergetics by demonstrating that mitochondrial H(2)O(2) emission serves as both a gauge of energy balance and a regulator of cellular redox environment, linking intracellular metabolic balance to the control of insulin sensitivity.

Topics: Adenosine Diphosphate; Adolescent; Adult; Animals; Antioxidants; Blood Glucose; Body Mass Index; Catalase; Dietary Fats; Electron Transport; Glucose Clamp Technique; Glucose Tolerance Test; Glutathione; Glutathione Disulfide; Humans; Hydrogen Peroxide; Insulin; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Muscle Fibers, Skeletal; Obesity; Oligopeptides; Oxidation-Reduction; Oxidative Stress; Oxygen Consumption; Rats; Rats, Sprague-Dawley; Rodentia; Young Adult

Topics: Animals; Diet; Diet, High-Fat; Extracellular Vesicles; Female; Fructose; Glomerular Filtration Rate; Humans; Kidney; Kidney Glomerulus; Metabolic Syndrome; Mitochondria; Obesity; Oligopeptides; Podocytes; Renal Circulation; Sus scrofa; Urine

Obesity is a major risk factor for the development of chronic kidney disease, even independent of its association with hypertension, diabetes, and dyslipidemia. The primary pathologic finding of obesity-related kidney disease is glomerulopathy, with glomerular hypertrophy, mesangial matrix expansion, and focal segmental glomerulosclerosis. Proposed mechanisms leading to renal pathology include abnormal lipid metabolism, lipotoxicity, inhibition of AMP kinase, and endoplasmic reticulum stress. Here we report dramatic changes in mitochondrial structure in glomerular endothelial cells, podocytes, and proximal tubular epithelial cells after 28 weeks of a high-fat diet in C57BL/6 mice. Treatment with SS-31, a tetrapeptide that targets cardiolipin and protects mitochondrial cristae structure, during high-fat diet preserved normal mitochondrial structure in all kidney cells, restored renal AMP kinase activity, and prevented intracellular lipid accumulation, endoplasmic reticulum stress, and apoptosis. SS-31 had no effect on weight gain, insulin resistance or hyperglycemia. However, SS-31 prevented loss of glomerular endothelial cells and podocytes, mesangial expansion, glomerulosclerosis, macrophage infiltration, and upregulation of proinflammatory (TNF-α, MCP-1, NF-κB) and profibrotic (TGF-β) cytokines. Thus, mitochondria protection can overcome lipotoxicity in the kidney and represent a novel upstream target for therapeutic development.

Topics: AMP-Activated Protein Kinases; Animals; Apoptosis; Blood Glucose; Body Weight; Capillaries; Diet, High-Fat; Drug Evaluation, Preclinical; Endoplasmic Reticulum Stress; Endothelium, Vascular; Glomerulonephritis; Kidney Tubules, Proximal; Lipid Metabolism; Mice, Inbred C57BL; Microscopy, Electron, Transmission; Mitochondria; Obesity; Oligopeptides; Podocytes