leptin and Mitochondrial-Diseases

Acquired disturbances of several aspects of cellular metabolism appear pathologically important in sporadic Alzheimer's disease (SAD). Among these, brain glucose utilization is reduced in the early stages of the disease. Hyperinsulinemia, which is a characteristic finding of insulin resistance, results in a central insulin deficit. Insufficient insulin signaling impairs the intricate balance of nitric oxide regulation of the central nervous system. Reduction in central insulin decreases neuronal nitric oxide synthase and increases inducible synthase activity. This, in turn, decreases astrocytic energy substrates and antioxidant supply of neurons. In addition, an increase in peroxynitrite formation impairs redox balance. Hyperleptinemia and glucose excess, which are the other parameters of insulin resistance, may worsen the reduced astrocytic energy supply and the ongoing inflammation via the inhibition of AMP-activated protein kinase (AMPK). Consequently, energy deficit and inflammation in neuronal tissue may cause neurodegeneration of SAD.

Topics: Alzheimer Disease; AMP-Activated Protein Kinases; Antioxidants; Astrocytes; Blood-Brain Barrier; Brain; Cerebral Amyloid Angiopathy; Diabetes Mellitus; Glucose; Humans; Inflammation; Insulin Resistance; Ketones; Leptin; Liver; Mitochondrial Diseases; Multienzyme Complexes; Nerve Degeneration; Oxidation-Reduction; Peroxynitrous Acid; Protein Serine-Threonine Kinases

It has been recognized that there is a relationship between prenatal growth restriction and the development of metabolic-related diseases in later life, a process involved in mitochondrial dysfunction. In addition, intrauterine growth retardation (IUGR) increases the susceptibility of offspring to high-fat (HF) diet-induced metabolic syndrome. Recent findings suggested that HF feeding decreased mitochondrial oxidative capacity and impaired mitochondrial function in skeletal muscle. Therefore, we hypothesized that the long-term consequences of IUGR on mitochondrial biogenesis and function make the offspring more susceptible to HF diet-induced mitochondrial dysfunction. Normal birth weight (NBW), and IUGR pigs were allotted to control or HF diet in a completely randomized design, individually. After 4 weeks of feeding, growth performance and molecular pathways related to mitochondrial function were determined. The results showed that IUGR decreased growth performance and plasma insulin concentrations. In offspring fed a HF diet, IUGR was associated with enhanced plasma leptin levels, increased concentrations of triglyceride and malondialdehyde (MDA), and reduced glycogen and ATP contents in skeletal muscle. High fat diet-fed IUGR offspring exhibited decreased activities of lactate dehydrogenase (LDH) and glucose-6-phosphate dehydrogenase (G6PD). These alterations in metabolic traits of IUGR pigs were accompanied by impaired mitochondrial respiration function, reduced mitochondrial DNA (mtDNA) contents, and down-regulated mRNA expression levels of genes responsible for mitochondrial biogenesis and function. In conclusion, our results suggest that IUGR make the offspring more susceptible to HF diet-induced mitochondrial dysfunction.

Topics: Animals; Blood Glucose; Diet, High-Fat; DNA, Mitochondrial; Eating; Female; Fetal Growth Retardation; Glucosephosphate Dehydrogenase; Glycogen; Insulin; Lactic Acid; Leptin; Male; Membrane Potentials; Metabolic Syndrome; Mitochondria; Mitochondrial Diseases; Muscle, Skeletal; Pregnancy; Proton-Translocating ATPases; RNA, Messenger; Swine; Triglycerides