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


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.
Ali
M Irfan
MI
Vascular Biology Center, Medical College of Georgia, 1459 Laney Walker Blvd, Augusta, GA 30912, USA.
Ketsawatsomkron
Pimonrat
P
Belin de Chantemele
Eric J
EJ
Mintz
James D
JD
Muta
Kenjiro
K
Salet
Christina
C
Black
Stephen M
SM
Tremblay
Michel L
ML
Fulton
David J
DJ
Marrero
Mario B
MB
Stepp
David W
DW
D000109:Acetylcholine / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing; D000273:Adipose Tissue / Q000201:enzymology; D000818:Animals; D050171:Dyslipidemias / Q000201:enzymology / Q000235:genetics; D004730:Endothelium, Vascular / Q000201:enzymology*; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008820:Mice, Obese; D009132:Muscles / Q000201:enzymology; D009247:NADH, NADPH Oxidoreductases / Q000096:biosynthesis / Q000235:genetics; D000074624:NADPH Oxidase 1; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D009765:Obesity / Q000201:enzymology* / Q000235:genetics; D010084:Oxidation-Reduction / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics; D014665:Vasodilator Agents / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D020738:Leptin; C472286:Noxa1 protein, mouse; C472287:Noxo1 protein, mouse; D011506:Proteins; D014665:Vasodilator Agents; D013481:Superoxides; D009599:Nitroprusside; D009569:Nitric Oxide; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516609:Ptpn1 protein, mouse; D005947:Glucose; D000109:Acetylcholine