Abstract 061: Prevention Of Oxidative Stress In The Paraventricular Nucleus (PVN) Does Not Attenuate Hypertension During High Fat Diet (HFD), Despite Blunting Weight Gain.

Abstract

We recently reported that PVN-specific deletion of the NADPH oxidase subunit p22 phox attenuates oxidative stress in this brain region and prevents diet-induced obesity (DIO) in mice. In addition to its importance in the regulation of energy homeostasis, the PVN is a well-described cardiovascular regulatory center. Since increased oxidative stress in the central nervous system is causally linked to both hypertension and obesity, we hypothesized that attenuating oxidative stress in the PVN would reduce sympathetic nerve activity (SNA) and improve hypertension during HFD. In mice harboring loxP-sites flanking the p22 phox gene (p22 phox/flox ), we tested if p22 phox deletion in the PVN reduces arterial pressure (AP) and heart rate (HR) during HFD. For these experiments, p22 phox/flox mice underwent bilateral PVN-targeted injection of adenoviral vectors encoding Cre recombinase (AdCre) or control LacZ (AdLacZ). Following 1-week recovery, mice were started on a 42% HFD or normal chow (NC). After 7 weeks of HFD, radiotelemeters were implanted and 3 weeks later (after 10 weeks HFD) we recorded AP and HR. HFD caused a significant elevation in AP (AdLacZ NC: 104 ± 2.8 mmHg vs. AdLacZ HFD 113 ± 0.6 mmHg n = 3-5, P < 0.05) and HR (AdLacZ NC: 487 ± 7 bpm vs. AdLacZ HFD 537 ± 12 bpm; n = 3-5, P < 0.05). Importantly, despite a significant reduction in body weight after deletion of p22 phox in the PVN (AdLacZ HFD: 32 ± 1.2 g, vs. AdCre HFD 27 ± 0.6 g, P < 0.05), removal of oxidative stress in the PVN did not blunt AP (AdLacZ HFD 113 ± 0.6 mmHg vs. AdCre HFD: 112 ± 2.0 mmHg, n = 5, P > 0.05) or HR (AdLacZ HFD 537 ± 12.3 bpm vs. AdCre HFD: 540 ± 6.3 bpm, n = 5, P > 0.05). We utilized power spectral analysis of AP variability to assess SNA in mice during NC and HFD. We found that HFD elevated SNA similarly in AdLacZ and AdCre mice (1.7-fold and 1.5-fold, respectively vs. NC mice, P > 0.05). Thus, while our data demonstrate that oxidative stress in the PVN is a major player in the regulation of metabolism and adiposity, these results suggest that PVN oxidative stress does not contribute to increased SNA, AP or HR during HFD. While the underlying mechanism(s) of this divergence is currently being investigated, these data emphasize that there is differential central neural regulation of cardiovascular and metabolic responses to HFD.