Protein tyrosine phosphatase 1B, a major regulator of leptin-mediated control of cardiovascular function

Eric Jacques Belin de Chantemele, Kenjiro Muta, James Mintz, Michel L. Tremblay, Mario B Marrero, David J Fulton, David W Stepp

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

Background - Obesity causes hypertension and sympathoactivation, a process proposed to be mediated by leptin. Protein tyrosine phosphatase IB (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. Methods and 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 α 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.

Original languageEnglish (US)
Pages (from-to)753-763
Number of pages11
JournalCirculation
Volume120
Issue number9
DOIs
StatePublished - Nov 12 2009

Fingerprint

Non-Receptor Type 1 Protein Tyrosine Phosphatase
Leptin
Knockout Mice
Arterial Pressure
Phenylephrine
Obesity
Protein Tyrosine Phosphatases
Constriction
Adrenergic Agents
Adrenergic Receptors
Type 2 Diabetes Mellitus
Blood Vessels
Adipose Tissue
Hypertension
Gene Expression
Injections
Pharmaceutical Preparations

Keywords

  • Adrenergic
  • Alpha
  • Arteries
  • Blood
  • Hypertension
  • Nervous system
  • Obesity
  • Pressure
  • Receptors
  • Sympathetic
  • Vasoconstriction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Protein tyrosine phosphatase 1B, a major regulator of leptin-mediated control of cardiovascular function. / Belin de Chantemele, Eric Jacques; Muta, Kenjiro; Mintz, James; Tremblay, Michel L.; Marrero, Mario B; Fulton, David J; Stepp, David W.

In: Circulation, Vol. 120, No. 9, 12.11.2009, p. 753-763.

Research output: Contribution to journalArticle

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abstract = "Background - Obesity causes hypertension and sympathoactivation, a process proposed to be mediated by leptin. Protein tyrosine phosphatase IB (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. Methods and 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 α 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.",
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T1 - Protein tyrosine phosphatase 1B, a major regulator of leptin-mediated control of cardiovascular function

AU - Belin de Chantemele, Eric Jacques

AU - Muta, Kenjiro

AU - Mintz, James

AU - Tremblay, Michel L.

AU - Marrero, Mario B

AU - Fulton, David J

AU - Stepp, David W

PY - 2009/11/12

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N2 - Background - Obesity causes hypertension and sympathoactivation, a process proposed to be mediated by leptin. Protein tyrosine phosphatase IB (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. Methods and 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 α 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.

AB - Background - Obesity causes hypertension and sympathoactivation, a process proposed to be mediated by leptin. Protein tyrosine phosphatase IB (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. Methods and 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 α 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.

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KW - Arteries

KW - Blood

KW - Hypertension

KW - Nervous system

KW - Obesity

KW - Pressure

KW - Receptors

KW - Sympathetic

KW - Vasoconstriction

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