title: Protein tyrosine phosphatase-1B contributes to LPS-induced leptin resistance in male rats.
abstract: Leptin resistance is induced by the feedback inhibitors tyrosine phosphatase-1B (PTP1B) and decreased Src homology 2 domain-containing tyrosine phosphatase-2 (SHP-2) signaling. To investigate the participation of PTP1B and SHP-2 in LPS-induced leptin resistance, we injected repeated (6-LPS) intraperitoneal LPS doses (100 μg/kg ip) for comparison with a single (1-LPS) treatment and evaluated the expression of SHP-2, PTP1B, p-ERK1/2, and p-STAT3 in the hypothalamus of male Wistar rats. The single LPS treatment increased the expression of p-STAT3 and PTP1B but not SHP-2. The repeated LPS treatment reduced SHP-2, increased PTP1B, and did not change p-STAT3. We observed that the PTP1B expression induced by the endotoxin was highly colocalized with leptin receptor cells in the hypothalamus of LepRb-IRES-Cre-tdTomato reporter mice. The single, but not the repeated, LPS treatment decreased the food intake and body weight. Leptin had no stimulatory effect on the hypophagia, body weight loss, or pSTAT3 expression in 6-LPS rats, indicating leptin unresponsiveness. Notably, the PTP1B inhibitor (3.0 nmol/rat in 5 μl icv) restored the LPS-induced hypophagia in 6-LPS rats and restored the ability of leptin to reduce food intake and body weight as well as to phosphorylate STAT3 in the arcuate, paraventricular, and ventromedial nuclei of the hypothalamus. The present data suggest that an increased PTP1B expression in the hypothalamus underlies the development of leptin resistance during repeated exposure to LPS. Our findings contribute to understanding the mechanisms involved in leptin resistance during low-grade inflammation as seen in obesity.
authors.affiliation: Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil; and.
authors.forename: Beatriz de Carvalho
authors.initials: Bde C
authors.lastname: Borges
authors.affiliation: Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil; and.
authors.forename: Rodrigo C
authors.initials: RC
authors.lastname: Rorato
authors.affiliation: Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil; and.
authors.forename: Ernane Torres
authors.initials: ET
authors.lastname: Uchoa
authors.affiliation: Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil; and.
authors.forename: Paula B
authors.initials: PB
authors.lastname: Marangon
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Carol F
authors.initials: CF
authors.lastname: Elias
authors.affiliation: Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil; and.
authors.forename: Jose
authors.initials: J
authors.lastname: Antunes-Rodrigues
authors.affiliation: Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Brazil; and llelias@fmrp.usp.br.
authors.forename: Lucila L K
authors.identifier: http://orcid.org/0000-0002-6271-758X
authors.initials: LL
authors.lastname: Elias
mesh_terms: D000818:Animals; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism*; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism
chemical_list: D020738:Leptin; D008070:Lipopolysaccharides; D054411:Receptors, Leptin; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; C516610:Ptpn1 protein, rat
keywords: Src homology 2 domain-containing tyrosine phosphatase-2; endotoxemia; extracellular signal-regulated kinases; leptin resistance; protein tyrosine phosphatase-1B