scholarly journals Increased Hypothalamic Protein Tyrosine Phosphatase 1B Contributes to Leptin Resistance with Age

Endocrinology ◽  
2007 ◽  
Vol 148 (1) ◽  
pp. 433-440 ◽  
Author(s):  
Christopher D. Morrison ◽  
Christy L. White ◽  
Zhong Wang ◽  
Seung-Yub Lee ◽  
David S. Lawrence ◽  
...  
Keyword(s):  
Food Intake ◽  
Protein Tyrosine Phosphatase ◽  
Middle Age ◽  
Tyrosine Phosphatase ◽  
Leptin Resistance ◽  
Protein Tyrosine Phosphatase 1B ◽  
Sprague Dawley ◽  
Protein Tyrosine ◽  
Leptin Sensitivity ◽  
Old Rats

Animals at advanced ages exhibit a reduction in central leptin sensitivity. However, changes in growth, metabolism, and obesity risk occur much earlier in life, particularly during the transition from youth to middle age. To determine when initial decreases in central leptin sensitivity occur, leptin-dependent suppression of food intake was tested in 8-, 12-, and 20-wk-old male, chow-fed Sprague Dawley rats. Intracerebroventricular leptin injection (3 μg) suppressed 24-h food intake in 8- and 12-wk-old rats (P < 0.05) but not 20-wk-old rats. To identify potential cellular mediators of this resistance, we focused on protein tyrosine phosphatase 1B (PTP1B), a recently described inhibitor of leptin signaling. PTP1B protein levels, as determined by Western blot, were significantly higher in mediobasal hypothalamic punches collected from 20-wk-old rats, compared with 8-wk-old rats (P < 0.05). When 20-wk-old rats were fasted for 24 h, levels of hypothalamic PTP1B decreased (P < 0.05), coincident with a restoration of leptin sensitivity. To directly test whether inhibition of PTP1B restores leptin sensitivity, 20-wk-old chow-fed rats were pretreated with a pharmacological PTP1B inhibitor 1 h before leptin, and 24-h food intake was recorded. As expected, leptin alone produced a small but nonsignificant reduction in food intake. However, pretreatment with the PTP1B inhibitor resulted in a marked improvement in leptin-dependent suppression of food intake (P < 0.05). These data are consistent with the hypothesis that increases in PTP1B contribute to hypothalamic leptin resistance as rats transition into middle age.

scholarly journals Leptin resistance following over-expression of protein tyrosine phosphatase 1B in liver

2006 ◽  
Vol 36 (1) ◽  
pp. 163-174 ◽  
Author(s):  
N T Lam ◽  
S D Covey ◽  
J T Lewis ◽  
S Oosman ◽  
T Webber ◽  
...  
Keyword(s):  
Food Intake ◽  
Plasma Glucose ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Leptin Resistance ◽  
Protein Tyrosine Phosphatase 1B ◽  
High Fat ◽  
Peripheral Tissues ◽  
Protein Tyrosine ◽  
Over Expression

Obesity is typically associated with resistance to leptin, yet the mechanism by which leptin signaling becomes impaired is poorly understood. Here we sought to determine if the development of obesity and leptin resistance correlates with increased expression of protein tyrosine phosphatase 1B (PTP1B) in peripheral tissues and whether over-expression of this phosphatase, specifically in liver, could alter the leptin-mediated effects on feeding and glucose metabolism. Obesity was induced in mice through a high-fat diet that resulted in hyperglycemia, hyperinsulinemia and hyperleptinemia. Resistance to leptin was confirmed as exogenous leptin administration reduced food intake in animals on low-fat, but not high-fat diets. Diet-induced resistance to leptin and insulin was associated with increased hepatic levels of PTP1B. Intriguingly, hepatic adenoviral over-expression of PTP1B in ob/ob mice attenuated the ability of exogenous leptin to reduce both plasma glucose levels and food intake. These findings suggest that leptin reduces both plasma glucose and food intake in part through actions on the liver, and hepatic leptin resistance resulting from over-expression of PTP1B may contribute to the development of both diabetes and obesity.

scholarly journals Reduction of Hypothalamic Protein Tyrosine Phosphatase Improves Insulin and Leptin Resistance in Diet-Induced Obese Rats

Endocrinology ◽  
2008 ◽  
Vol 149 (8) ◽  
pp. 3870-3880 ◽  
Author(s):  
Paty Karoll Picardi ◽  
Vivian Cristine Calegari ◽  
Patrícia de Oliveira Prada ◽  
Juliana Contin Moraes ◽  
Eliana Araújo ◽  
...  
Keyword(s):  
Food Intake ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Third Ventricle ◽  
Leptin Resistance ◽  
High Fat ◽  
Protein Tyrosine ◽  
Reduced Body ◽  
Hypothalamic Nuclei ◽  
Obese Rats

Protein tyrosine phosphatase (PTP1B) has been implicated in the negative regulation of insulin and leptin signaling. PTP1B knockout mice are hypersensitive to insulin and leptin and resistant to obesity when fed a high-fat diet. We investigated the role of hypothalamic PTP1B in the regulation of food intake, insulin and leptin actions and signaling in rats through selective decreases in PTP1B expression in discrete hypothalamic nuclei. We generated a selective, transient reduction in PTP1B by infusion of an antisense oligonucleotide designed to blunt the expression of PTP1B in rat hypothalamic areas surrounding the third ventricle in control and obese rats. The selective decrease in hypothalamic PTP1B resulted in decreased food intake, reduced body weight, reduced adiposity after high-fat feeding, improved leptin and insulin action and signaling in hypothalamus, and may also have a role in the improvement in glucose metabolism in diabetes-induced obese rats.

Inhibition of Protein Tyrosine Phosphatase 1B by Lutein Derivatives isolated from Mexican Oregano (Lippia graveolens)

2018 ◽  
Vol 17 (3) ◽  
pp. 134-139
Author(s):  
R.M. Perez-Gutierrez
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Inhibitory Activity ◽  
Spectroscopic Data ◽  
Methanol Extract ◽  
Tyrosine Phosphatase ◽  
Positive Control ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Ic50 Value ◽  
Ic50 Values

Methanol extract from Lippia graveolens (Mexican oregano) was studied in order to identify inhibitory bioactives for protein tyrosine phosphatase 1B (PTP1B). Known flavone as lutein (1), and another flavone glycoside such as lutein-7-o-glucoside (2), 6-hydroxy-lutein-7-ohexoside (3) and lutein-7-o-ramnoide (4) were isolated from methanol extract of aerial parts of the Lippia graveolens. All isolates were identified based on extensive spectroscopic data analysis, including UV, IR, NMR, MS and compared with spectroscopic data previously reported. These flavones were evaluated for PTP1B inhibitory activity. Among them, compounds 1 and 3 displayed potential inhibitory activity against PTP1B with IC50 values of 7.01 ± 1.25 μg/ml and 18.4 μg/ml, respectively. In addition, compound 2 and 4 showed moderate inhibitory activity with an IC50 value of 23.8 ± 6.21 and 67.8 ± 5.80 μg/ml respectively. Among the four compounds, luteolin was found to be the most potent PTP1B inhibitor compared to the positive control ursolic acid, with an IC50 value of 8.12 ± 1.06 μg/ml. These results indicate that flavonoids constituents contained in Lippia graveolens can be considered as a natural source for the treatment of type 2 diabetes.

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