Cardiovascular and metabolic regulation in mice with Shp2 deletion in forebrain neurons

Abstract

Previous studies showed that deletion of Src homology‐2 tyrosine phosphatase (Shp2) in forebrain neurons causes early‐onset obesity. In this study we determined whether Shp2 deletion in forebrain neurons alters energy balance and if the obesity in these mice is accompanied by elevations in blood pressure (BP) and heart rate (HR). Forebrain Shp2‐/‐ mice were generated by breeding Shp2flox mice with CamKIIα‐Cre mice. BP and HR were recorded by telemetry, and motor activity, oxygen consumption (VO2), and respiratory quotient (RQ) were monitored by indirect calorimetry for 4 days in 22‐week‐old Shp2‐/‐ (n=8) and control mice (WT, n=4). Compared to WT, Shp2‐/‐ mice were heavier (46±3 vs 32±1 g), hyperglycemic (182±18 vs 170±11 mg/dl), hyperleptinemic (15±2 vs 1.5±0.3 ng/ml), hyperinsulimenic (27.6±9.0 vs 17.2±5.3 μU/ml), and consumed the same amount of food (4.2±0.4 vs 4.5±0.2 g/day). Despite features of the metabolic syndrome, Shp2‐/‐ mice had similar BP and HR than WT (112±2 vs 113±1 mmHg and 640±14 and 650±40 bpm), and exhibited increased motility (668±285 vs 420±86 cm/hr), higher RQ (0.91±0.02 vs 0.86±0.06) and similar VO2 than WT (42.4±2.8 vs 40.3±1 ml/kg/min). These results suggest that forebrain deletion of Shp2 causes obesity associated with increased lipid storage as indicated by higher RQ values. Despite obesity and many metabolic abnormalities, 22‐week‐old Shp2 mice are not hypertensive. (PO1‐HL51971)