Deletion of protein tyrosine phosphatase 1b improves peripheral insulin resistance and vascular function in obese, leptin-resistant mice via reduced oxidant tone

M. Irfan Ali, Pimonrat Ketsawatsomkron, Eric Jacques Belin de Chantemele, James D. Mintz, Kenjiro Muta, Christina Salet, Stephen Matthew Black, Michel L. Tremblay, David J Fulton, Mario B Marrero, David W Stepp

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Rationale: Obesity is a risk factor for cardiovascular dysfunction, yet the underlying factors driving this impaired function remain poorly understood. Insulin resistance is a common pathology in obese patients and has been shown to impair vascular function. Whether insulin resistance or obesity, itself, is causal remains unclear. Objective: The present study tested the hypothesis that insulin resistance is the underlying mediator for impaired NO-mediated dilation in obesity by genetic deletion of the insulin-desensitizing enzyme protein tyrosine phosphatase (PTP)1B in db/db mice. Methods and Results: The db/db mouse is morbidly obese, insulin-resistant, and has tissue-specific elevation in PTP1B expression compared to lean controls. In db/db mice, PTP1B deletion improved glucose clearance, dyslipidemia, and insulin receptor signaling in muscle and fat. Hepatic insulin signaling in db/db mice was not improved by deletion of PTP1B, indicating specific amelioration of peripheral insulin resistance. Additionally, obese mice demonstrate an impaired endothelium dependent and independent vasodilation to acetylcholine and sodium nitroprusside, respectively. This impairment, which correlated with increased superoxide in the db/db mice, was corrected by superoxide scavenging. Increased superoxide production was associated with increased expression of NAD(P)H oxidase 1 and its molecular regulators, Noxo1 and Noxa1. Conclusions: Deletion of PTP1B improved both endothelium dependent and independent NO-mediated dilation and reduced superoxide generation in db/db mice. PTP1B deletion did not affect any vascular function in lean mice. Taken together, these data reveal a role for peripheral insulin resistance as the mediator of vascular dysfunction in obesity.

Original languageEnglish (US)
Pages (from-to)1013-1022
Number of pages10
JournalCirculation research
Volume105
Issue number10
DOIs
StatePublished - Nov 1 2009

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Non-Receptor Type 1 Protein Tyrosine Phosphatase
Leptin
Oxidants
Vascular Resistance
Blood Vessels
Insulin Resistance
Superoxides
Obesity
Insulin
Endothelium
Dilatation
Obese Mice
NADPH Oxidase
Insulin Receptor
Nitroprusside
Dyslipidemias
Vasodilation
Acetylcholine
Fats
Pathology

Keywords

  • Leptin resistance
  • Obesity
  • PTP1B

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Deletion of protein tyrosine phosphatase 1b improves peripheral insulin resistance and vascular function in obese, leptin-resistant mice via reduced oxidant tone. / Ali, M. Irfan; Ketsawatsomkron, Pimonrat; Belin de Chantemele, Eric Jacques; Mintz, James D.; Muta, Kenjiro; Salet, Christina; Black, Stephen Matthew; Tremblay, Michel L.; Fulton, David J; Marrero, Mario B; Stepp, David W.

In: Circulation research, Vol. 105, No. 10, 01.11.2009, p. 1013-1022.

Research output: Contribution to journalArticle

Ali, M. Irfan ; Ketsawatsomkron, Pimonrat ; Belin de Chantemele, Eric Jacques ; Mintz, James D. ; Muta, Kenjiro ; Salet, Christina ; Black, Stephen Matthew ; Tremblay, Michel L. ; Fulton, David J ; Marrero, Mario B ; Stepp, David W. / Deletion of protein tyrosine phosphatase 1b improves peripheral insulin resistance and vascular function in obese, leptin-resistant mice via reduced oxidant tone. In: Circulation research. 2009 ; Vol. 105, No. 10. pp. 1013-1022.
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T1 - Deletion of protein tyrosine phosphatase 1b improves peripheral insulin resistance and vascular function in obese, leptin-resistant mice via reduced oxidant tone

AU - Ali, M. Irfan

AU - Ketsawatsomkron, Pimonrat

AU - Belin de Chantemele, Eric Jacques

AU - Mintz, James D.

AU - Muta, Kenjiro

AU - Salet, Christina

AU - Black, Stephen Matthew

AU - Tremblay, Michel L.

AU - Fulton, David J

AU - Marrero, Mario B

AU - Stepp, David W

PY - 2009/11/1

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N2 - Rationale: Obesity is a risk factor for cardiovascular dysfunction, yet the underlying factors driving this impaired function remain poorly understood. Insulin resistance is a common pathology in obese patients and has been shown to impair vascular function. Whether insulin resistance or obesity, itself, is causal remains unclear. Objective: The present study tested the hypothesis that insulin resistance is the underlying mediator for impaired NO-mediated dilation in obesity by genetic deletion of the insulin-desensitizing enzyme protein tyrosine phosphatase (PTP)1B in db/db mice. Methods and Results: The db/db mouse is morbidly obese, insulin-resistant, and has tissue-specific elevation in PTP1B expression compared to lean controls. In db/db mice, PTP1B deletion improved glucose clearance, dyslipidemia, and insulin receptor signaling in muscle and fat. Hepatic insulin signaling in db/db mice was not improved by deletion of PTP1B, indicating specific amelioration of peripheral insulin resistance. Additionally, obese mice demonstrate an impaired endothelium dependent and independent vasodilation to acetylcholine and sodium nitroprusside, respectively. This impairment, which correlated with increased superoxide in the db/db mice, was corrected by superoxide scavenging. Increased superoxide production was associated with increased expression of NAD(P)H oxidase 1 and its molecular regulators, Noxo1 and Noxa1. Conclusions: Deletion of PTP1B improved both endothelium dependent and independent NO-mediated dilation and reduced superoxide generation in db/db mice. PTP1B deletion did not affect any vascular function in lean mice. Taken together, these data reveal a role for peripheral insulin resistance as the mediator of vascular dysfunction in obesity.

AB - Rationale: Obesity is a risk factor for cardiovascular dysfunction, yet the underlying factors driving this impaired function remain poorly understood. Insulin resistance is a common pathology in obese patients and has been shown to impair vascular function. Whether insulin resistance or obesity, itself, is causal remains unclear. Objective: The present study tested the hypothesis that insulin resistance is the underlying mediator for impaired NO-mediated dilation in obesity by genetic deletion of the insulin-desensitizing enzyme protein tyrosine phosphatase (PTP)1B in db/db mice. Methods and Results: The db/db mouse is morbidly obese, insulin-resistant, and has tissue-specific elevation in PTP1B expression compared to lean controls. In db/db mice, PTP1B deletion improved glucose clearance, dyslipidemia, and insulin receptor signaling in muscle and fat. Hepatic insulin signaling in db/db mice was not improved by deletion of PTP1B, indicating specific amelioration of peripheral insulin resistance. Additionally, obese mice demonstrate an impaired endothelium dependent and independent vasodilation to acetylcholine and sodium nitroprusside, respectively. This impairment, which correlated with increased superoxide in the db/db mice, was corrected by superoxide scavenging. Increased superoxide production was associated with increased expression of NAD(P)H oxidase 1 and its molecular regulators, Noxo1 and Noxa1. Conclusions: Deletion of PTP1B improved both endothelium dependent and independent NO-mediated dilation and reduced superoxide generation in db/db mice. PTP1B deletion did not affect any vascular function in lean mice. Taken together, these data reveal a role for peripheral insulin resistance as the mediator of vascular dysfunction in obesity.

KW - Leptin resistance

KW - Obesity

KW - PTP1B

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