Differential regulation of adipose tissue and vascular inflammatory gene expression by chronic systemic inhibition of NOS in lean and obese rats

Abstract

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 Nω‐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.

Role of habitual physical activity in modulating vascular actions of insulin

“…The link between NO and ET-1 (Alonso & Radomski, 2003) is also supported by recent data from our group demonstrating that chronic systemic NOS inhibition in rats increases expression of ET-1 in the aorta (Fig. 5; Padilla et al 2014). Furthermore, we found in rats that cessation of wheel running for 7 days, and thus removal of the vascular shear stimulus, increases expression of ET-1 in arteries that perfuse the hindlimbs (e.g.…”

“…5; Padilla et al 2014). Furthermore, we found in rats that cessation of wheel running for 7 days, and thus removal of the vascular shear stimulus, increases expression of ET-1 in arteries that perfuse the hindlimbs (e.g.…”

“…We found that soleus muscle feed arteries, known to be chronically exposed to high levels of blood flow and thus shear stress, displayed greater insulin-stimulated dilatation than gastrocnemius Figure 5. Endothelin-1 (ET-1) mRNA is upregulated in the aorta of rats chronically treated with L-NAME (in drinking water) for 4 weeks (n = 10 per group) L-NAME, NG-nitro-L-arginine methyl ester From Padilla et al (2014) with permission. # denotes significant difference between groups of rats.…”

Dietary olive oil induces cannabinoid CB2 receptor expression in adipose tissue of ApcMin/+ transgenic mice

“…Over-expression of constitutive forms of NOS in adipose tissue has been demonstrated to prevent diet-induced obesity, whereas an increase of the inducible NOS seems to enhance both adipocyte size and inflammation [23]. Recent studies have demonstrated that NOS seems to regulate inflammatory genes expression in adipose tissue [24, 25] and the inhibition of its activity has been demonstrated to promote adipose tissue inflammation[26, 27]. …”

Ultraviolet radiation, vitamin D and the development of obesity, metabolic syndrome and type-2 diabetes

“…44 NOS inhibitors such as L-NAME (N ω nitro-L-arginine methyl ester), lowered endogenous nitric oxide production and reduced circulating levels of nitric oxide metabolites, 47,48 but had inconsistent effects on the development of obesity and metabolic dysfunction. [47][48][49][50][51] eNOS -/-mice lack endothelial nitric oxide synthase (eNOS) activity, and have an impaired capacity to produce nitric oxide and its metabolites in the cardiovascular system. 52 Besides being hypertensive, these mice have defective energy expenditure, increased white fat accumulation, exhibit insulin resistance and increased hepatic triglyceride levels.…”