Shp2 signaling in POMC neurons is important for leptin’s actions on blood pressure, Energy balance, And glucose regulation

Previous studies showed that Src homology-2 tyrosine phosphatase (Shp2) is an important regulator of body weight. In this study, we examined the impact of Shp2 defi- ciency specifically in proopiomelanocortin (POMC) neurons on met- abolic and cardiovascular function and on chronic blood pressure (BP) and metabolic responses to leptin. Mice with Shp2 deleted in POMC neurons (Shp2/Pomc-cre) and control mice (Shp2^flox/flox) were im- planted with telemetry probes and venous catheters for measurement of mean arterial pressure (MAP) and leptin infusion. After at least 5 days of stable control measurements, mice received leptin infusion (2µg·kg-¹·day-¹ iv) for 7 days. Compared with Shp2^flox/flox controls, Shp2/Pomc-cre mice at 22 wk of age were slightly heavier (34±1 vs. 31±1 g) but consumed a similar amount of food (3.9±0.3 vs. 3.8±0.2 g/day). Leptin infusion reduced food intake in Shp2^flox/flox mice (2.6±0.5 g) and Shp2/Pomc-cre mice (3.2±0.3 g). Despite decreasing food intake, leptin infusion increased MAP in control mice, whereas no significant change in MAP was observed in Shp2/Pomc-cre mice. Leptin infusion also decreased plasma glucose and insulin levels in controls (12±1to6±1µU/ml and 142±12 to 81±8 mg/100 ml) but not in Shp2/Pomc-cre mice. Leptin increased VO₂ by 16 2% in controls and 7±1% in Shp2/Pomc-cre mice. These results indicate that Shp2 signaling in POMC neurons contributes to the long-term BP and antidiabetic actions of leptin and may play a modest role in normal regulation of body weight.