Protein tyrosine phosphatase 1B, a major regulator of leptin-mediated control of cardiovascular function.
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.
Belin de Chantemèle
Eric J
EJ
Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912, USA.
Muta
Kenjiro
K
Mintz
James
J
Tremblay
Michel L
ML
Marrero
Mario B
MB
Fulton
David J
DJ
Stepp
David W
DW
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
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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