Abstract 21: Leptin-Induced Arterial Pressure Increase: Key Role of the PI3K Pathway
Leptin is an adipocyte-derived hormone that acts in the brain to decrease food intake and increases energy expenditure. Leptin also raises arterial pressure by increasing sympathetic nerve activity (SNA). We previously implicated PI3K as a downstream pathway in leptin receptor (ObRb) signaling that mediates the renal SNA effects of leptin. We used genetic approaches to test the hypothesis that bidirectional changes in PI3K activity (gain vs. loss of function) will be associated with contrasting changes in renal SNA and arterial pressure responses to leptin. PI3K signaling was enhanced in leptin-sensitive neurons in PtenΔObRb mice in which the lipid phosphatase Pten was ablated in cells that express ObRb, leading to accumulating PIP3 in these cells. For loss of function, we used p110αD933A/WT mice which carry a heterozygous mutation in the p110α subunit of PI3K specifically disrupting this pathway. Consistent with our previous findings, the increase in renal SNA caused by intracerebralventricular (ICV) injection of leptin (2 μg) was exaggerated and blunted in PtenΔObRb mice (286±41%) and p110αD933A/WT mice (-40±6%), respectively, relative to littermate controls (70±4%). These effects were specific to leptin, as the renal SNA response to ICV MTII (melanocortin receptors agonist) was comparable (P=0.3) between controls (196±36%), PtenΔObRb mice (159±98%) and p110αD933A/WT mice (194±36%). Interestingly, the PtenΔObRb mice had significantly (P<0.01) higher baseline radiotelemetric mean arterial pressure (MAP, 137±4 mmHg) as compared to littermate controls (107±2 mmHg). In contrast, despite being hyperleptinemic the p110αD933A/WT mice had normal (P=0.34) baseline MAP (112±1 mmHg) as compared to controls (113±2 mmHg). We further measured the arterial pressure response to leptin treatment. Intraperitoneal administration of leptin (60 μg) raised MAP in control mice by 13±5 mmHg and this response was significantly (P<0.05) enhanced in the PtenΔObRb mice (+35±14 mmHg). Conversely, the p110αD933A/WT mice had a significantly blunted (P<0.05) MAP response to leptin (-3±4 mmHg). Our data demonstrate the importance of PI3K signaling in leptin receptor-containing neurons for the regulation of arterial pressure and in mediating leptin effects.
- © 2012 by American Heart Association, Inc.