Abstract 009: Vertical Sleeve Gastrectomy Reduces Mean Arterial Blood Pressure and Hypothalamic Endoplasmic Reticulum Stress Independent of Body Weight in Mice

Abstract

Bariatric surgery, such as vertical sleeve gastrectomy (VSG), results in remission of hypertension (HTN) and type 2 diabetes. The mechanism(s) by which this occurs remain elusive, but reduction in endoplasmic reticulum (ER) stress is a central concept. For example, VSG-induced reductions in ER stress in peripheral tissues contribute to improved insulin sensitivity. ER stress in the hypothalamus promotes development of HTN; however, brain ER stress has not been assessed in the context of bariatric surgery. Therefore, we hypothesized that VSG would ameliorate high fat diet (HFD)-induced HTN and this would be associated with reductions in hypothalamic ER stress. We have validated a mouse model of VSG that exhibits body weight-independent improvements in glucose homeostasis and peripheral ER stress. Here, male C57 mice (8 wks) were placed on a HFD (60%), which was maintained throughout the study. These mice underwent sham (n=4) or VSG (n=6) surgery and radiotelemeter implantation at 16 wks of age. Sham mice were food restricted to match their body weight to VSG mice (S-WM), to study the body weight-independent effects of VSG. At 2.5 months after surgery mice were fasted (6 hrs) and euthanized for tissue collection. Energy intake and body weight were reduced by ~25% after VSG compared with pre-operative values (39 ± 2 vs 30 ± 2g; P<0.01). Energy intake, body weight and adiposity did not differ between groups. Mean arterial pressure (MAP) was measured by telemetry at 2 and 6 wks after surgery. VSG mice exhibited lower MAP compared with S-WM (S-WM = 112.2 ± 1.4, VSG = 99.5 ± 2.3mmHg; P<0.01). Strikingly, the percent decrease in MAP from 2 to 6 wks after surgery was 4-fold greater in VSG compared with S-WM (%ΔMAP: S-WM = 9.3 ± 2.8, VSG = -5.2 ± 2.6; P<0.001). We assessed the PERK pathway of ER stress and inflammation in the hypothalamus by immunoblotting. Normalized PERKThr980 phosphorylation, downstream eIF2αSer51 phosphorylation and TNFα were reduced by 35%, 29% and 55% in VSG compared with S-WM, respectively (pPERK/PERK (AU): S-WM = 1.2 ± 0.2, VSG = 0.8 ± 0.1; peIF/eIF: S-WM = 1.2 ± 0.1, VSG = 0.8 ± 0.1; TNFα/tubulin: S-WM = 1.4 ± 0.3, VSG = 0.6 ± 0.1; P<0.05). Therefore, VSG produces body weight-independent reductions in MAP which may be due to VSG-induced reductions in hypothalamic ER stress.