Abstract 23: Increasing Leptin Sensitivity in Proopiomelanocortin Neurons Does not Sensitize the Cardiovascular System to Leptin
Leptin-mediated control of metabolic function requires activation of the proopiomelanocortin (POMC) neurons in the hypothalamus. Whether POMC neurons also control the cardiovascular effects of leptin still remain to be determined. In order to test the hypothesis that POMC neurons regulate leptin-mediated cardiovascular control, protein tyrosine phosphatase 1B (PTP1B), the molecular restrain of the leptin signaling pathway was deleted in the whole animal (PTP1BKO/WT) or specifically in POMC neurons (PTP1BPOMC/flox) of mice on the C57Bl/6 background using the Cre-Lox technique. PTP1B deletion in POMC neurons recapitulates the protective effects of the total KO on the control of body weight and insulin sensitivity. Conscious blood pressure (BP) measurements (telemetry) revealed that neither baseline (PTP1BWT: 103±4 vs. PTP1BKO: 104±7, PTP1Bflox: 112±3 vs. PTP1BPOMC: 117±6 mmHg) nor BP response to chronic leptin infusion (PTP1BWT: 105±6 vs. PTP1BKO: 107±5, PTP1Bflox: 119±3 vs. PTP1BPOMC: 118±3 mmHg) or cage switch stress were affected by the deletion of PTP1B in PTP1BKO and PTP1BPOMC. Sympathetic tone, assessed by measuring the drop in BP in response to ganglionic blockade was increased in PTP1BKO but not in PTP1BPOMC. Vascular adrenergic tone, an index of chronic sympatho-activation inversely correlated to the level of sympathetic activity was measured in isolated aortic rings via wire myography. Aortic rings from PTP1BKO mice exhibited a reduced adrenergic tone (PTP1BWT: 95±7 vs. PTP1BKO: 46±6% of KCl, p<0.05), whereas PTP1BPOMC presented an increased vascular constriction (PTP1Bflox: 85±79 vs. PTP1BPOMC: 112±13% of KCl, p<0.05) non-specific to the adrenergic response. However, the reduction in vascular adrenergic tone induced by chronic leptin infusion was preserved in PTP1BPOMC mice. These data suggest that POMC neurons do not regulate basal sympathetic tone towards the vasculature. These data also highlight the key role of POMC neurons in the control of metabolic function but minimalize their role in the regulation of cardiovascular effects of leptin.
- © 2012 by American Heart Association, Inc.