Abstract 27: Leptin Reduces Food Intake but Fails to Raise Blood Pressure In Mice With Deficiency of Insulin Receptor Substrate (IRS2) In the Entire Brain or Specifically in Pomc Neurons

Abstract

Insulin receptor substrate (IRS2) is one of three major leptin receptor signaling pathways. However, its role in mediating the chronic effects of leptin on appetite, blood pressure and glucose regulation is unclear. In the present study we tested whether deletion of IRS2 in the whole brain or specifically in proopiomelanocortin (Pomc) neurons attenuates the chronic cardiovascular and metabolic responses to leptin. Mice with IRS2 deletion in the entire brain (IRS2 flox/flox /Nestin-Cre, n=7), specifically in Pomc neurons (IRS2 flox/flox /Pomc-Cre, n=7) and control IRS2 flox/flox mice (n=9) were instrumented with telemetry probes for measurement of 24-hr mean arterial pressure (MAP) and heart rate (HR) and venous catheters for saline or leptin infusions. After a 5-day control period, mice received leptin infusion (2 μg/kg/min, iv) for 7 days. Compared to IRS2 flox/flox , IRS2 flox/flox /Pomc-Cre mice had similar body weight and food intake (33±1 vs 35±1g and 3.6±0.5 vs 3.8±0.2 g/day) and higher MAP and HR (110±2 vs 102±2 mmHg and 641±9 vs 616±5 bpm). IRS2 flox/flox /Nestin-Cre mice were heavier (38±1.5 g), had increased food intake (4.5±1.0 g/day), and higher MAP and HR (108±1.5 mmHg and 659±9.0 bpm) compared to control mice. Leptin infusion for 7 days in control IRS2 flox/flox mice gradually increased MAP by 5 mmHg despite decreasing food intake by 31%. In contrast, leptin infusion did not change MAP in IRS2 flox/flox /Nestin-Cre and IRS2 flox/flox /Pomc-Cre mice. The anorexic effect of leptin, however, was not attenuated in IRS2 flox/flox /Pomc-Cre or IRS2 flox/flox /Nestin-Cre mice (-35% and -34%, respectively). In addition, deletion of IRS2 in the whole brain or Pomc neurons did not impair the ability of leptin to reduce plasma glucose levels (IRS2 flox/flox : 170±15 to 130±12; IRS2 flox/flox /Pomc-Cre: 180±20 to 150±15; IRS2 flox/flox /Nestin-Cre: 160±10 to 131±20 mg/dL) These results indicate that activation of IRS2 signaling in the CNS, and particularly in Pomc neurons, is essential for the long-term actions of leptin to raise MAP and HR but not for its anorexic or antidiabetic effects. (NHLBI-PO1HL51971/ AHA SDG5680016)