Dallaire Patrice, Bellmann Kerstin, Laplante Mathieu, Gélinas Stéphanie, Centeno-Baez Carolina, Penfornis Patrice, Peyot Marie-Line, Latour Martin G, Lamontagne Julien, Trujillo Maria E, Scherer Philipp E, Prentki Marc, Deshaies Yves, Marette André
Department of Anatomy and Physiology, Laval University, Québec, Québec, Canada.
Diabetes. 2008 Aug;57(8):1999-2011. doi: 10.2337/db08-0540. Epub 2008 May 5.
Synthetic ligands for peroxisome proliferator-activated receptor-gamma (PPAR-gamma) improve insulin sensitivity in obesity, but it is still unclear whether inflammatory signals modulate their metabolic actions. In this study, we tested whether targeted disruption of inducible nitric oxide (NO) synthase (iNOS), a key inflammatory mediator in obesity, modulates the metabolic effects of rosiglitazone in obese mice.
iNOS(-/-) and iNOS(+/+) were subjected to a high-fat diet or standard diet for 18 weeks and were then treated with rosiglitazone for 2 weeks. Whole-body insulin sensitivity and glucose tolerance were determined and metabolic tissues harvested to assess activation of insulin and AMP-activated protein kinase (AMPK) signaling pathways and the levels of inflammatory mediators.
Rosiglitazone was found to similarly improve whole-body insulin sensitivity and insulin signaling to Akt/PKB in skeletal muscle of obese iNOS(-/-) and obese iNOS(+/+) mice. However, rosiglitazone further improved glucose tolerance and liver insulin signaling only in obese mice lacking iNOS. This genotype-specific effect of rosiglitazone on glucose tolerance was linked to a markedly increased ability of the drug to raise plasma adiponectin levels. Accordingly, rosiglitazone increased AMPK activation in muscle and liver only in obese iNOS(-/-) mice. PPAR-gamma transcriptional activity was increased in adipose tissue of iNOS(-/-) mice. Conversely, treatment of 3T3-L1 adipocytes with a NO donor blunted PPAR-gamma activity.
Our results identify the iNOS/NO pathway as a critical modulator of PPAR-gamma activation and circulating adiponectin levels and show that invalidation of this key inflammatory mediator improves the efficacy of PPAR-gamma agonism in an animal model of obesity and insulin resistance.
过氧化物酶体增殖物激活受体γ（PPAR-γ）的合成配体可改善肥胖症中的胰岛素敏感性，但炎症信号是否调节其代谢作用仍不清楚。在本研究中，我们测试了肥胖症中的关键炎症介质诱导型一氧化氮（NO）合酶（iNOS）的靶向破坏是否调节罗格列酮对肥胖小鼠的代谢作用。
将iNOS（-/-）和iNOS（+/+）小鼠给予高脂饮食或标准饮食18周，然后用罗格列酮治疗2周。测定全身胰岛素敏感性和葡萄糖耐量，并采集代谢组织以评估胰岛素和AMP激活的蛋白激酶（AMPK）信号通路的激活以及炎症介质水平。
发现罗格列酮同样改善肥胖iNOS（-/-）和肥胖iNOS（+/+）小鼠骨骼肌中的全身胰岛素敏感性和胰岛素向Akt/PKB的信号传导。然而，罗格列酮仅在缺乏iNOS的肥胖小鼠中进一步改善了葡萄糖耐量和肝脏胰岛素信号传导。罗格列酮对葡萄糖耐量的这种基因型特异性作用与该药物显著提高血浆脂联素水平的能力有关。因此，罗格列酮仅在肥胖iNOS（-/-）小鼠的肌肉和肝脏中增加AMPK激活。iNOS（-/-）小鼠脂肪组织中的PPAR-γ转录活性增加。相反，用NO供体处理3T3-L1脂肪细胞会减弱PPAR-γ活性。
我们的结果确定iNOS/NO途径是PPAR-γ激活和循环脂联素水平的关键调节因子，并表明该关键炎症介质的失活可提高肥胖和胰岛素抵抗动物模型中PPAR-γ激动作用的疗效。
