Abstract 037: Role of Pro-opiomelanocortin (POMC) Specific PTP1B in Differential Regulation of Blood Pressure, Liver Lipid Accumulation and Glucose Tolerance in Response to a High Fat Diet

Abstract

Obese subjects are often resistant to leptin’s metabolic effects although blood pressure (BP) and sympathetic nervous system responses appear to be preserved. Protein tyrosine phosphatase 1B (PTP1B), a negative regulator of leptin signaling, may play a role in promoting this selective leptin resistance and causing metabolic dysfunction in obesity. Our previous studies suggest that the chronic BP responses to leptin are mediated via activation of pro-opiomelanocortin (POMC) neurons. The goal of this study was to determine if PTP1B in POMC neurons differentially controls metabolic functions and BP in mice fed a high fat diet (HFD). Male mice with POMC specific PTP1B deletion (POMC/PTP1B -/- ) and littermate controls (PTP1B flox/flox ) were fed a HFD from 6 to 22 wks of age. Baseline BP after 16 weeks of a HFD (95±2 vs. 95±3 mmHg) and BP responses to acute stress (Δ32±0 vs. Δ32±6 mmHg), measured by telemetry, were not different in POMC/PTP1B -/- compared to control mice, respectively. Heart rate (HR) was not different in POMC/PTP1B -/- and control mice during acute stress (699±4 vs. 697±15 bpm, respectively). Total body weight (TBW) and fat mass were reduced at 20 weeks of age in POMC/PTP1B -/- compared to controls (36.7±0.1 vs. 42.0±1 g TBW and 12.7±0.4 vs. 16.1±1.0 g fat mass, respectively). Liver weight of POMC/PTP1B -/- mice was less than in controls, and this was evident even when liver weight was normalized as % of TBW (4.5±0.2 vs. 5.0±0.2 %). POMC/PTP1B -/- males had reduced liver lipid accumulation compared to controls as measured by EchoMRI (0.08±0.03 vs. 0.15±0.03 g/g liver weight). Glucose tolerance was also improved by 46% in POMC/PTP1B -/- compared to controls as measured by AUC, 25856±1683 vs. 47267±5616 mg/dLx120min, respectively. These findings indicate that PTP1B signaling in POMC neurons plays a crucial role in regulating liver lipid accumulation and glucose tolerance but does not appear to mediate changes in BP or BP responses to acute stress in mice fed a high HFD (supported by NHLBI-PO1HL51971 and NIGMS P20GM104357)