Protein tyrosine phosphatase 1B (PTP1B): a major regulator of leptin‐mediated control of cardiovascular function

Abstract

Obesity causes hypertension and sympathoactivation. Leptin, constrained by PTP1B, may link obesity to sympathoactivation but molecular mechanisms are unclear. Cardiovascular effects of PTP1B deletion are unknown. This study determined blood pressure (BP) regulation and vascular function in PTP1B KO mice compared to control (Balb/c). PTP1B KO mice had lower body fat but higher BP (116±5 vs. 105±5 mmHg, p<0.01) than controls. Leptin infusion produced a greater anorexic effect in PTP1B KO mice and a marked increase in BP (135±5 mmHg) in PTP1B KO mice only. Drops in BP to ganglionic blockade were higher in PTP1B KO mice (‐38±3% vs. ‐29±3%, p<0.05) suggesting increased sympathetic tone. PTP1B deletion blunted BP rise to Phenylephrine (PE) injection (55±10% vs. 93±7%, p<0.01). In aorta, PE‐induced contraction was reduced in PTP1B KO mice (57.7±9% vs. 96.3±12 of KCl, p<0.05) with no effect on serotonin‐mediated contraction. PTP1B deletion did not alter endothelial dilation and L‐NAME treatment did not restore PE‐mediated constriction. PTP1B deletion significantly reduced gene expression of three alpha‐1 adrenergic receptor sub‐types, consistent with reduced adrenergic tone. Leptin infusion further reduced adrenergic reactivity. These data indicate that PTP1B is a key determinant of the cardiovascular effects of leptin and that reduced adrenergic tone provides a compensatory limit to leptin's effects on BP.