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 comorbidities 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.

Elevated TCA cycle function in the pathology of diet-induced hepatic insulin resistance and fatty liver

“…2G ). These data are consistent with recent fi ndings of upregulated hepatic mitochondrial respiration in HFD mice ( 24,25 ) and humans with diabetes ( 27 ). Despite …”

“…Downregulated fat oxidation during severe insulin resistance has been linked to impaired and increased in vitro respiration but that mitochondrial O 2 consumption and ATP synthesis are ineffi ciently coupled. These results are consistent with recent studies ( 18,24,25,27 ) and suggest that elevated in vivo hepatic TCA cycle fl ux during insulin resistance may be required to compensate for reduced mitochondrial coupling effi ciency.…”

“…Loss of insulin action is reported to degrade respiratory complexes 1 and 3 via downstream targets of Foxo1 ( 22 ), which might account for impaired mitochondrial function during a HFD. The alterations in isolated mitochondrial function observed here are generally consistent with previous reports of increased expression of respiratory proteins, oxidative capacity, uncoupled respiration, and impaired membrane potential in similar mouse models of insulin resistance ( 18,24,25 ), and with impaired hepatic ATP synthesis ( 3,20 ) in humans with insulin resistance. Mitochondrial dysfunction is somewhat paradoxical in the setting of increased gluconeogenesis, as this pathway traverses the mitochondria and requires mitochondrial-derived NADH and ATP for a number of its steps.…”

“…However, elevated TCA cycle fl ux partially resolves the paradox by supplying increased NADH/FADH 2 as compensation for dysfunctional respiration and by providing increased cataplerotic substrates to support overactive synthetic pathways. Although we found elevated TCA cycle function (16 weeks) to predate respiratory dysfunction in isolated mitochondria (32 weeks), it is possible that the latter was present even earlier, as reported in other studies ( 18,24,25 ) but not detected in our particular experimental protocol (i.e., fasting state, mitochondrial isolation procedure, etc. ).…”

“…Impaired insulin action predicts elevated oxidative metabolism (via PGC-1 ␣ , for example) ( 21 ), and uncoupled respiration should theoretically increase oxidative metabolism. Several ex vivo studies of mitochondria from HFD mice confi rm elevated respiration (24)(25)(26)(27), which may increase oxygen consumption and predispose liver to hypoxia ( 18 ). However, other studies implicate respiratory dysfunction in the deactivation of surtuins and PGC-1 ␣ , which in turn suppress hepatic fat oxidation and cause hepatic steatosis ( 22,23,28,29 ).…”