RESUMO
Acute exposure to bacterial lipopolysaccharide (LPS) is a potent inducer of immune response as well as hypophagia. Nevertheless, desensitization of responses to LPS occurs during long-term exposure to endotoxin. We induced endotoxin tolerance, injecting repeated (6LPS) LPS doses compared with single (1LPS) treatment. 1LPS, but not 6LPS group, showed decreased food intake and body weight, which was associated with an increased plasma leptin and higher mRNA expression of OB-Rb, MC4R, and SOCS3 in the hypothalamus. Hypophagia induced by 1LPS was associated with lower levels of 2-arachidonoylglycerol (2-AG), increased number of p-STAT3 neurons, and decreased AMP-activated protein kinase (AMPK) activity. Desensitization of hypophagia in the 6LPS group was related to high 2-AG, with no changes in p-STAT3 or increased p-AMPK. Leptin decreased food intake, body weight, 2-AG levels, and AMPK activity and enhanced p-STAT3 in control rats. However, leptin had no effects on 2-AG, p-STAT3, or p-AMPK in the 1LPS and 6LPS groups. Rats treated with HFD to induce leptin resistance showed neither hypophagia nor changes in p-STAT3 after 1LPS, suggesting that leptin and LPS recruit a common signaling pathway in the hypothalamus to modulate food intake reduction. Desensitization of hypophagia in response to repeated exposure to endotoxin is related to an inability of leptin to inhibit AMPK phosphorylation and 2-AG production and activate STAT3. SOCS3 is unlikely to underlie this resistance to leptin signaling in the endotoxin tolerance. The present model of prolonged inflammatory challenge may contribute to further investigations on mechanisms of leptin resistance.
Assuntos
Ingestão de Alimentos/fisiologia , Inflamação/fisiopatologia , Leptina/fisiologia , Animais , Ácidos Araquidônicos/fisiologia , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Dieta , Gorduras na Dieta/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Endocanabinoides , Endotoxinas/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Glicerídeos/fisiologia , Imuno-Histoquímica , Inflamação/induzido quimicamente , Interleucina-10/biossíntese , Interleucina-10/genética , Leptina/sangue , Lipopolissacarídeos/farmacologia , Masculino , Fosforilação , Ratos , Ratos Wistar , Receptor Tipo 4 de Melanocortina/biossíntese , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/fisiologia , Receptores de Interleucina-10/biossíntese , Receptores de Interleucina-10/genética , Receptores para Leptina/biossíntese , Receptores para Leptina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/biossíntese , Fator de Transcrição STAT3/genética , Transdução de Sinais/fisiologia , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/biossíntese , Proteínas Supressoras da Sinalização de Citocina/genéticaRESUMO
BACKGROUND/AIM: Changes in tissue levels of 2-arachidonoylglycerol (2-AG), an endocannabinoid, during the evolution of bile duct ligation (BDL) may indicate that endocannabinoids have a role in the hemodynamic changes that occur in this condition. METHODS: 2-AG levels, in various organs and vascular beds of BDL rats, 2 and 4 weeks post surgery, were determined. Untouched and sham-operated (SO) rats were used as controls. RESULTS: 2-AG content of a specific organ was not a static finding and depended on the rat's age, the time from the surgical procedure and the type of procedure. The most pronounced changes were observed in BDL rats 4 weeks post surgery. In these rats, hepatic, pulmonary, cardiac and renal medullary and papillary 2-AG levels were highest observed. No changes in splenic, aortic and renal cortical 2-AG levels were observed. In addition a stepwise increase in 2-AG levels from the cortex to the papilla was detected and was followed by a decrease in creatinine clearance. CONCLUSIONS: 2-AG probably has a role in the pathophysiologic changes in the liver, heart, lung and kidney that follows BDL.