Padilla Jaume, Jenkins Nathan T, Thorne Pamela K, Lansford Kasey A, Fleming Nicholas J, Bayless David S, Sheldon Ryan D, Rector R Scott, Laughlin M Harold
Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri ; Child Health, University of Missouri, Columbia, Missouri ; Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri.
Kinesiology, University of Georgia, Athens, Georgia.
Physiol Rep. 2014 Feb 7;2(2):e00225. doi: 10.1002/phy2.225. eCollection 2014 Feb 1.
We tested the hypothesis that a decrease in bioavailability of nitric oxide (NO) would result in increased adipose tissue (AT) inflammation. In particular, we utilized the obese Otsuka Long Evans Tokushima Fatty rat model (n = 20) and lean Long Evans Tokushima Otsuka counterparts (n = 20) to determine the extent to which chronic inhibition of NO synthase (NOS) with N (ω) -nitro-l-arginine methyl ester (L-NAME) treatment (for 4 weeks) upregulates expression of inflammatory genes and markers of immune cell infiltration in retroperitoneal white AT, subscapular brown AT, periaortic AT as well as in its contiguous aorta free of perivascular AT. As expected, relative to lean rats (% body fat = 13.5 ± 0.7), obese rats (% body fat = 27.2 ± 0.8) were hyperlipidemic (total cholesterol 77.0 ± 2.1 vs. 101.0 ± 3.3 mg/dL), hyperleptinemic (5.3 ± 0.9 vs. 191.9 ± 59.9 pg/mL), and insulin-resistant (higher HOMA IR index [3.9 ± 0.8 vs. 25.2 ± 4.1]). Obese rats also exhibited increased expression of proinflammatory genes in perivascular, visceral, and brown ATs. L-NAME treatment produced a small but statistically significant decrease in percent body fat (24.6 ± 0.9 vs. 27.2 ± 0.8%) and HOMA IR index (16.9 ± 2.3 vs. 25.2 ± 4.1) in obese rats. Further, contrary to our hypothesis, we found that expression of inflammatory genes in all AT depots examined were generally unaltered with L-NAME treatment in both lean and obese rats. This was in contrast with the observation that L-NAME produced a significant upregulation of inflammatory and proatherogenic genes in the aorta. Collectively, these findings suggest that chronic NOS inhibition alters transcriptional regulation of proinflammatory genes to a greater extent in the aortic wall compared to its adjacent perivascular AT, or visceral white and subscapular brown AT depots.
我们检验了一氧化氮（NO）生物利用度降低会导致脂肪组织（AT）炎症增加这一假设。具体而言，我们利用肥胖的大冢长-埃文斯-德岛脂肪大鼠模型（n = 20）和瘦的大冢长-埃文斯-德岛对照大鼠（n = 20），来确定用N（ω）-硝基-L-精氨酸甲酯（L-NAME）处理（持续4周）慢性抑制一氧化氮合酶（NOS）在多大程度上上调了腹膜后白色AT、肩胛下棕色AT、主动脉周围AT及其相邻的无血管周围AT的主动脉中炎症基因的表达和免疫细胞浸润标志物。正如预期的那样，相对于瘦大鼠（体脂百分比=13.5±0.7），肥胖大鼠（体脂百分比=27.2±0.8）患有高脂血症（总胆固醇77.0±2.1对101.0±3.3mg/dL）、高瘦素血症（5.3±0.9对191.9±59.9pg/mL）和胰岛素抵抗（更高的HOMA-IR指数[3.9±0.8对25.2±4.1]）。肥胖大鼠在血管周围、内脏和棕色AT中也表现出促炎基因表达增加。L-NAME处理使肥胖大鼠的体脂百分比（24.6±0.9对27.2±0.8%）和HOMA-IR指数（16.9±2.3对25.2±4.1）出现了轻微但具有统计学意义的下降。此外，与我们的假设相反，我们发现在瘦大鼠和肥胖大鼠中，L-NAME处理后所有检测的AT库中的炎症基因表达总体上未发生改变。这与L-NAME在主动脉中显著上调炎症和促动脉粥样硬化基因的观察结果形成了对比。总的来说，这些发现表明，与相邻的血管周围AT、内脏白色和肩胛下棕色AT库相比，慢性NOS抑制在主动脉壁中对促炎基因转录调控的改变程度更大。
