Increased mitochondrial oxidative phosphorylation in the liver is associated with obesity and insulin resistance

Abstract

Obesity is the result of excess energy intake relative to expenditure, however little is known about why some individuals are more prone to weight gain than others. Inbred strains of mice also vary in their susceptibility to obesity and therefore represent a valuable model to study the genetics and physiology of weight gain and its co-morbidities such as type 2 diabetes. C57BL/6J mice are susceptible to obesity and insulin resistance when fed an obesogenic diet, whereas A/J mice are resistant despite increased caloric intake. Analysis of B6- and A/J-derived chromosome substitution strains and congenic strains revealed a complex genetic and physiological basis for this phenotype. To improve our understanding of the molecular mechanisms underlying susceptibility to metabolic disease we analyzed global gene expression patterns in 6C1 and 6C2 congenic strains. 6C1 is susceptible whereas 6C2 is resistant to diet-induced obesity. In addition, we demonstrate that 6C1 is glucose intolerant and insulin resistant relative to 6C2. Pathway analysis of global gene expression patterns in muscle, adipose, and liver identified expression level differences between 6C1 and 6C2 in pathways related to basal transcription factors, endocytosis, and mitochondrial oxidative phosphorylation (OxPhos). The OxPhos expression differences were subtle but evident in each complex of the electron transport chain and were associated with a marked increase in mitochondrial oxidative capacity in the livers of the obese strain 6C1 relative to the obesity-resistant strain 6C2. These data suggests the importance of hepatic mitochondrial function in the development of obesity and insulin resistance.

Figure 1. Map of chromosome 6 congenic strains

Analysis of strains 6C1 and 6C2 define Obrq2, a 30.3 Mb diet-induced obesity-resistance QTL. IR, Insulin resistant. IS, Insulin sensitive.

Figure 2. Elevated glucose and insulin levels in strain 6C1 relative to strain 6C2

(A) Strain 6C1 had increased fasting glucose levels as well as higher glucose levels during a GTT relative to strain 6C2. (B) Insulin levels are increased in strain 6C1 relative to 6C2 following the injection of equivalent glucose loads during the GTT. (C) Compared to 6C2, 6C1 has a decreased ability to clear glucose from the blood stream in response to a bolus intraperitoneal injection of insulin at a rate of 0.75U/kg of body weight. * p<0.05, **p<0.01, ***p<0.0001

Figure 3. Genes in the oxidative phosphorylation pathway are upregulated in 6C1 relative to 6C2

Each column represents one sample (chip) and each row represents one gene. The range of colors corresponds to the range of expression values (red = high, blue = low). Genes contributing to the core enrichment are shown in red.

Figure 4. Gene expression is upregulated in the liver of strain 6C1 relative to 6C2 following 100 days on the HFSC diet in each electron transport chain complex

Genes were classified according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) (18).