Abstract 012: Brain Endoplasmic Reticulum (ER) Stress Reduces Appetite and Increases Blood Pressure Independent of the Melanocortin-4 Receptor in Rats

Abstract

Although there is evidence that chronic endoplasmic reticulum (ER) stress affects hypothalamic pathways that regulate food intake, body weight and blood pressure (BP), the specific mechanisms are unclear. One key pathway for controlling energy balance and BP is the central nervous system (CNS) melanocortin system. However, the importance of this system in mediating the effects of ER stress on metabolic and cardiovascular function is unclear. In this study we examined the role of the melanocortin-4 receptor (MC4R) in controlling blood pressure (BP) and metabolic functions during chronic brain ER stress. MC4R knockout (MC4R -/- , n=5) and control wild-type Wistar Hannover rats (WT, n=5) were implanted with blood pressure (BP) telemetry transmitters and an intracerebroventricular (ICV) cannula was inserted into the third ventricle at 22 weeks of age. After 10 days of recovery, food intake, BP and HR were measured 24-hrs/day. After stable baseline measurements for 4 days, thapsigargin (TG, 5μg/5μl, ICV) was injected daily for 3 consecutive days to induce ER stress. At baseline, MC4R -/- rats ate 23% more food and were 41% heavier than WT rats. MAP was slightly higher (115±3 vs. 109±2 mmHg) and HR was lower (318±10 vs. 363±6 bpm) in MC4R-/- rats. Induction of brain ER stress decreased food intake (26%) while causing no changes in blood glucose levels (WT: 94±4 vs. 98±3 and MC4R-/-: 110±6 vs.116±4 mg/dl) or HR in both groups. Induction of brain ER stress also raised BP in both groups (7 and 5 mmHg, respectively for WT and MC4R -/- rats). These results suggest that chronic brain ER stress-induced reductions in appetite and increases in BP are independent of MC4R signaling. (NHLBI-PO1HL51971, NIGMS- P20GM104357 and AHA SDG5680016)