Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil.
Departamento de Fisiologia e Biofísica, Instituto de Ciência Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
PLoS One. 2019 Feb 4;14(2):e0211733. doi: 10.1371/journal.pone.0211733. eCollection 2019.
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.
肥胖引起的炎症和代谢功能障碍与诱导型一氧化氮合酶（iNOS）的活性有关。为了了解代谢、肥胖和一氧化氮之间的相互关系，我们评估了肥胖诱导的一氧化氮信号对肝线粒体功能的影响。我们使用了含有线粒体烟酰胺转氢酶活性的小鼠品系，而之前的研究涉及到这种酶的自发突变体，因此更容易出现氧化失衡。野生型和 iNOS 基因敲除小鼠分别用高脂肪饮食喂养 2、4 或 8 周。iNOS 基因敲除不能预防饮食引起的代谢变化。然而，在 4 周时，饮食降低了野生型和基因敲除组肝线粒体中脂肪酸氧化能力；这种情况在 8 周时得到恢复。有趣的是，尽管野生型和 iNOS 基因敲除动物的胰岛素抵抗有显著改变，但其他线粒体功能参数没有变化。总的来说，我们发现肥胖引起的代谢功能障碍有两个令人惊讶的特征：（i）在所有实验条件下，iNOS 并不是肥胖引起的胰岛素抵抗所必需的；（ii）肝线粒体对肥胖引起的代谢功能障碍中的功能变化具有很强的适应能力。
