Abstract
Obesity-derived inflammation and metabolic dysfunction has been related to the activity of the inducible nitric oxide synthase (iNOS). To understand the interrelation between metabolism, obesity and NO., we evaluated the effects of obesity-induced NO. signaling on liver mitochondrial function. We used mouse strains containing mitochondrial nicotinamide transhydrogenase activity, while prior studies involved a spontaneous mutant of this enzyme, and are, therefore, more prone to oxidative imbalance. Wild-type and iNOS knockout mice were fed a high fat diet for 2, 4 or 8 weeks. iNOS knockout did not protect against diet-induced metabolic changes. However, the diet decreased fatty-acid oxidation capacity in liver mitochondria at 4 weeks in both wild-type and knockout groups; this was recovered at 8 weeks. Interestingly, other mitochondrial functional parameters were unchanged, despite significant modifications in insulin resistance in wild type and iNOS knockout animals. Overall, we found two surprising features of obesity-induced metabolic dysfunction: (i) iNOS does not have an essential role in obesity-induced insulin resistance under all experimental conditions and (ii) liver mitochondria are resilient to functional changes in obesity-induced metabolic dysfunction.
Highlights
Nitric oxide (NO.) is a gaseous membrane-permeable free radical that acts as a cellular signaling molecule through many mechanisms including activating soluble guanylyl cyclases, covalent modification of amino acids residues and lipids, scavenging of superoxide, and competing with molecular oxygen within mitochondrial Complex IV [1,2]
We identified that after 1.5 weeks on a high fat diets (HFD), mice already exhibited increased body mass and adiposity. inducible nitric oxide synthase (iNOS) KO mice were more susceptible to body mass gain and had an increased content of fat mass even on the Low Fat Diet (LFD) (Fig 1)
INOS KO animals were found to be spontaneously hypercholesterolemic [28], a finding that we observed at 4 weeks in both LFD and HFD groups (S1 Table)
Summary
Nitric oxide (NO.) is a gaseous membrane-permeable free radical that acts as a cellular signaling molecule through many mechanisms including activating soluble guanylyl cyclases, covalent modification of amino acids residues and lipids, scavenging of superoxide (forming peroxynitrite), and competing with molecular oxygen within mitochondrial Complex IV [1,2]. It is important to note that most studies in mice were conducted using the C57BL/6J mouse from Jackson Laboratories, a strain with a spontaneous mutation in the mitochondrial nicotinamide nucleotide transferase (NNT), which hampers the production of mitochondrial NADPH and impacts significantly on mitochondrial redox state [18] This strain has been shown to be prone to the development of metabolic diseases [18,19,20,21]. After 2, 4 and 8 weeks of high fat feeding to induce obesity, we did not observe any protection against loss of insulin sensitivity by iNOS absence, nor did we observe an overt, sustained, decline in liver mitochondrial function We believe these findings, while negative and unexpected, are important to re-evaluate the suggested protagonist role of liver mitochondrial dysfunction and inflammatory NO. While negative and unexpected, are important to re-evaluate the suggested protagonist role of liver mitochondrial dysfunction and inflammatory NO. signaling in the development of diet-induced insulin resistance
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