Introduction: The liver is particularly susceptible to the detrimental effects of a high fat diet (HFD), and rapidly develops insulin resistance. While the underlying mechanisms associated with hepatic insulin resistance are not fully understood, mitochondria play a crucial role in regulating lipid metabolism and redox balance. Recently, dietary nitrate was shown to attenuate HFD-induced glucose intolerance, however the mechanism(s) remains unknown. Therefore, in the present study we examined the possibility that dietary nitrate increased mitochondrial lipid-supported respiration and/or attenuated reactive oxygen species (ROS) emission.
Methods: Male C57Bl/6J mice (n = 22) were randomly assigned to consume a control diet (10% fat), HFD (60% fat), or HFD with 4mM sodium nitrate in drinking water for 8 weeks. Whole body glucose tolerance and energy expenditure (indirect calorimetry) were determined, and mitochondrial respiration and reactive oxygen species (ROS) emission were assessed in liver samples.
Results: Compared to control animals, the consumption of HFD increased whole body fat oxidation and body mass, and induced glucose intolerance. The consumption of dietary nitrate did not affect HFD-mediated changes in energy expenditure, rates of fat oxidation or body mass, but nevertheless attenuated the induction of glucose intolerance. Within the liver, HFD-feeding in the presence or absence of dietary nitrate, did not alter pyruvate or lipid (palmitoyl-CoA) supported respiration, or the sensitivity to malonyl-CoA-mediated inhibition of lipid-supported respiration. In contrast, while HFD increased the endogenous ROS production, nitrate prevented this response.
Conclusion: These data demonstrate that nitrate supplementation attenuated the HFD-mediated induction of whole-body glucose intolerance in association with a reduction in ROS emission within the liver. Future research needs to determine causality between these observations.
G. DesOrmeaux: None. H.L. Petrick: None. H. Brunetta: None. G. Holloway: None.
Natural Sciences and Engineering Research Council of Canada (400362)