Alterations in Hepatic Mitochondrial Compartment in a Model of Obesity and Insulin Resistance

Abstract

The objective of this paper is to evaluate adaptations in hepatic mitochondrial protein mass, function and efficiency in a rat model of high-fat diet-induced obesity and insulin resistance that displays several correlates to human obesity. Adult male rats were fed a high-fat diet for 7 weeks. Mitochondrial state 3 and state 4 respiratory capacities were measured in liver homogenate and isolated mitochondria by using nicotinamide adenine dinucleotide, flavin adenine dinucleotide and lipid substrates. Mitochondrial efficiency was evaluated by measuring proton leak kinetics. Mitochondrial mass was assessed by ultrastructural observations and citrate synthase (CS) activity measurements. Mitochondrial oxidative damage and antioxidant defence were also considered by measuring lipid peroxidation, aconitase and superoxide dismutase (SOD) specific activity. Whole body metabolic characteristics were obtained by measuring 24-h oxygen consumption (VO 2 ), carbon dioxide production (VCO 2 ), respiratory quotient (RQ) and nonprotein respiratory quotient (NPRQ), using indirect calorimetry with urinary nitrogen analysis. Whole body glucose homeostasis was assessed by measuring plasma insulin and glucose levels after a glucose load. Adult rats fed a high-fat diet for 7 weeks, exhibit not only obesity, insulin resistance and hepatic steatosis, but also reduced respiratory capacity and increased oxidative stress in liver mitochondria. Our present results indicate that alterations in the mitochondrial compartment induced by a high-fat diet are associated with the development of insulin resistance and ectopic fat storage in the liver. Our results thus fit in with the emerging idea that mitochondrial dysfunction can led to the development of metabolic diseases, such as obesity, type 2 diabetes mellitus and nonalcoholic steatohepatitis.

Gestational Protein Restriction in Mice Has Pronounced Effects on Gene Expression in Newborn Offspring's Liver and Skeletal Muscle; Protective Effect of Taurine

“…Despite the fact that the NP and LP diets are isocaloric, genes involved in energy metabolism, oxidative phosphorylation, and other mitochondrial genes were the ones most over represented on the list of changed gene sets (Tables 3 and 4). However, as CS activity can be considered a measure of mitochondrial mass (22), the results suggests a dysregulation of gene expression related to mitochondrial function rather than a change in mitochondrial mass. This may be in contrast to studies by Park et al (26), who found a significant decrease in mtDNA:gDNA ratio in both liver and skeletal muscle in 5-wk-old offspring of maternal LP rats.…”

“…As a measure of the mitochondrial fraction of tissue mass, citrate synthase (CS) specific enzyme activity and mRNA level (22) was determined in liver and skeletal muscle of the newborn pups. There was no difference between diet groups in either CS mRNA levels (Table S1, http://links.lww.com/PDR/A56) or CS enzyme specific activities (Table 1).…”

Quantitative Proteomic and Functional Analysis of Liver Mitochondria from High Fat Diet (HFD) Diabetic Mice

“…Several studies have reported increased respiration in the liver mitochondria of obesity models (17,54), and other models of obesity have exhibited decreased respiration in liver (55). Therefore, we carried out oxygen consumption experiment in purified mitochondria from our HFD model.…”

Proteome, Phosphoproteome, and Hydroxyproteome of Liver Mitochondria in Diabetic Rats at Early Pathogenic Stages

“…Numerous studies have revealed that various mitochondrial factors are of paramount importance in the pathogenesis of diabetes. For example, high fat diet-induced alterations in the mitochondrial compartment are associated with the development of insulin resistance and ectopic fat storage in liver (5). The dysfunction of mitochondria damages the pancreatic ␤-cells and contributes to the development of a hyperglycemic status (6).…”