Leptin resistance and desensitization of hypophagia during prolonged inflammatory challenge are associated with high ptp1b expression in the hypothalamus
B. Borges, R. Rorato, P. Marangon, E. Uchoa, J. Antunes-Rodrigues & L. Elias
Repeated exposure to lipopolysaccharide (LPS) leads to endotoxin tolerance. Desensitization of hypophagia in response to repeated exposure to endotoxin is related to an inability of leptin to phosphorylate STAT-3 protein. Protein tyrosine phosphatase 1B (PTP1B) activity is known to contribute to leptin resistance by inhibiting leptin signaling. In this study, we induced endotoxin tolerance, injecting repeated LPS doses (6LPS) (100 μg/kg, i.p.) in comparison with single (1LPS) treatment and control group treated with saline. Food intake, body weight and plasma leptin levels were determined after lps or saline injection. Brain tissue was collected from another set of rats for determination of PTP1B expression in the mediobasal hypothalamus by western blotting. A third set of rats was pre-treated with PTP1B inhibitor (3 nM/rat in 5rl, i.c.v.v) for determination of food intake and body weight after LPS or saline injection. 1LPS group, but not 6LPS group, showed decreased food intake and body weight, associated with an increased plasma leptin concentration. 6LPS, but not single LPS rats, showed higher expression of PTP1B in the mediobasal hypothalamus. Hypophagia and body weight loss induced by 1LPS were potentiated by PTP1B inhibitor, when compared with vehicle treatment. Interestingly, pre-treatment with PTP1B inhibitor induced hypophagia in animals treated with 6LPS. The present data suggest that increased PTP1B activity contributes to the development of leptin resistance during tolerance to endotoxin. The present model of prolonged inflammatory challenge may contribute to further investigations on mechanisms of leptin resistance.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details unavailable.