Abstract P179: Time Restricted Feeding Improves Blood Pressure and Heart Rate Rhythms as Well as Activation of NOS3 and AMP Kinase in Mice on a Chronic High Fat Diet

Abstract

Irregular timing of food intake increases cardiometabolic disease and hypertension risk. A chronic high fat diet (HFD) leads to loss of endothelial function and reduced activation of endothelial NO synthase (NOS3). We hypothesized that restricting food availability to the active period in mice on HFD will restore the blood pressure rhythm and NOS3 activation. Mice (male 8-week old, C57BL/6J) were given normal diet (ND; 10% fat) or HFD (45% fat) for 20 weeks ad lib. During the final 2 weeks, food availability was limited to the active phase (restricted feed, RF) in half the HFD mice. Mean arterial pressure (MAP), heart rate (HR), and locomotor activity were measured by telemetry. At the end of the study, 24 hr MAP, HR, and locomotor activity were similar in all groups. However, RF significantly increased the difference in MAP and HR between active and inactive periods in mice on HFD (MAP: ND: 16±0.7 mmHg, HFD: 15±0.8 mmHg, HFD+RF: 18±0.9 mmHg, n=6-8, p=0.01; HR: ND: 68±5.1 bpm, HFD: 69±6.5 bpm, HFD+RF: 113±7.9 bpm, n=6-8, p<0.01). The active-inactive difference in activity was similar in ND, HFD, and HFD+RF (p>0.05). At the end of the study, aorta (Ao) and renal vessels (RV) were isolated in the middle of the active period (ZT17). Western blotting revealed that diet or RF did not affect total NOS3, total Akt kinase (Akt), pAkt(S473), or total AMPK abundance in either vascular bed. pNOS3(S1177) abundance in Ao was improved by RF in HFD mice (ND: 8.5±4.7 rdu, HFD: 0.5±0.2 rdu, HFD+RF: 2.1±0.6 rdu, n=4, p=0.06). RF in HFD mice increased aortic pAMPK(T172) activation at ZT17 but not in renal vessels (Ao: ND: 0.2±0.1 rdu, HFD: 0.2±0.1 rdu, HFD+RF: 0.7±0.2 rdu, n=4-5, p=0.01; RV: ND: 0.8±0.2 rdu, HFD: 0.5±0.1 rdu, HFD+RF: 0.7±0.2 rdu, n=5-6, p=0.30). Plasma nitrite was significantly decreased in HFD and HFD+RF mice at ZT17 compared to ND mice (HFD: 0.6±0.04 μM; HFD+RF: 0.7±0.03 μM; ND: 1.4±0.3 μM; n=6, p=0.03). Our findings indicate that RF increases the differences in diurnal MAP and HR as well as increased activation of NOS3 and AMP kinase in mice on a chronic high fat diet. In conclusion, these results suggest that timing of food intake on a HFD improves MAP and HR rhythms possibly via increased activation of NOS3 and AMPK.