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

Jaume Padilla,Ryan D Sheldon,Nathan T Jenkins,David S Bayless,M Harold Laughlin,R Scott Rector,Nicholas J Fleming,Pamela K Thorne,Kasey A Lansford

doi:10.1002/phy2.225

Jaume Padilla, Ryan D Sheldon + Show 7 more

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https://doi.org/10.1002/phy2.225

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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.

Highlights

Characterized as a mediator of vascular smooth muscle relaxation (Ignarro et al 1987; Palmer et al 1987), nitric oxide (NO) has since been implicated in a wide range of physiological processes in different tissues including adipose tissue (AT)
As expected (McAllister et al 2008), treatment of L-NAME resulted in a decrease in serum NOx levels in both groups of rats (Fig. 1)
L-NAME treatment produced a small but statistically significant decrease in percent body fat in Otsuka Long Evans Tokushima Fatty (OLETF), but not LETO, rats. This effect of L-NAME on the body composition of OLETF rats may be related to decreased food intake induced by L-NAME (Fig. 2)

Summary

Introduction

Characterized as a mediator of vascular smooth muscle relaxation (Ignarro et al 1987; Palmer et al 1987), nitric oxide (NO) has since been implicated in a wide range of physiological processes in different tissues including adipose tissue (AT). While the anti-inflammatory effects of NO on the vasculature are established (Rudic et al 1998; Laroux et al 2001; Kuhlencordt et al 2009; Gomez-Guzman et al 2011; Hossain et al 2012), recent evidence indicates that NO exerts an anti-inflammatory effect in AT. In this regard, eNOS knockout mice exhibit increased inflammation in epidydimal AT, compared to wild-type counterparts, indicating that NO derived from eNOS is crucial for maintenance of a low-inflammatory state within the visceral AT (Handa et al 2011). Whether the anti-inflammatory influence of NO signaling is present in other AT depots beyond the viscera including perivascular and brown AT is uncertain

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