title: Protein tyrosine phosphatase 1B, a major regulator of leptin-mediated control of cardiovascular function.
abstract: BACKGROUND
  Obesity causes hypertension and sympathoactivation, a process proposed to be mediated by leptin. Protein tyrosine phosphatase 1B (PTP1B), a major new pharmaceutical target in the treatment of obesity and type II diabetes mellitus, constrains the metabolic actions of leptin, but the extent to which PTP1B regulates its cardiovascular effects is unclear. This study examined the hypothesis that PTP1B is a negative regulator of the cardiovascular effects of leptin.
  
  
  RESULTS
  PTP1B knockout mice had lower body fat but higher mean arterial pressure (116+/-5 versus 105+/-5 mm Hg, P<0.05) than controls. Leptin infusion produced a greater anorexic effect in PTP1B knockout mice and a marked increase in mean arterial pressure (135+/-5 mm Hg) in PTP1B knockout mice only. The decrease in mean arterial pressure in response to ganglionic blockade was higher in PTP1B knockout mice (-38+/-3% versus -29+/-3%, P<0.05), which suggests increased sympathetic tone. PTP1B deletion blunted mean arterial pressure responses to phenylephrine injection (55+/-10% versus 93+/-7%, P<0.05). Phenylephrine-induced aortic contraction was reduced in PTP1B knockout mice (57.7+/-9% versus 96.3+/-12% of KCl, P<0.05), consistent with desensitization to chronically elevated sympathetic tone. Furthermore, PTP1B deletion significantly reduced gene expression of 3 alpha(1)-adrenergic receptor subtypes, consistent with blunted constriction to phenylephrine.
  
  
  CONCLUSIONS
  These data indicate that PTP1B is a key regulator of the cardiovascular effects of leptin and that reduced vascular adrenergic reactivity provides a compensatory limit to the effects of leptin on mean arterial pressure.
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Belin de Chantemèle
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Muta
authors.forename: James
authors.initials: J
authors.lastname: Mintz
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.forename: Mario B
authors.initials: MB
authors.lastname: Marrero
authors.forename: David J
authors.initials: DJ
authors.lastname: Fulton
authors.forename: David W
authors.initials: DW
authors.lastname: Stepp
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D010641:Phenotype; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics* / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics; D013312:Stress, Physiological / Q000502:physiology; D013564:Sympathetic Nervous System / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D000317:Adrenergic alpha-Antagonists; D020738:Leptin; D018340:Receptors, Adrenergic, alpha-1; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D011224:Prazosin
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