ABSTRACT
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.
Subject(s)
Eating/physiology , Inflammation/physiopathology , Leptin/physiology , Animals , Arachidonic Acids/physiology , Body Weight/drug effects , Body Weight/physiology , Cyclic AMP-Dependent Protein Kinases/physiology , Diet , Dietary Fats/pharmacology , Eating/drug effects , Endocannabinoids , Endotoxins/pharmacology , Gas Chromatography-Mass Spectrometry , Glycerides/physiology , Immunohistochemistry , Inflammation/chemically induced , Interleukin-10/biosynthesis , Interleukin-10/genetics , Leptin/blood , Lipopolysaccharides/pharmacology , Male , Phosphorylation , Rats , Rats, Wistar , Receptor, Melanocortin, Type 4/biosynthesis , Receptor, Melanocortin, Type 4/genetics , Receptor, Melanocortin, Type 4/physiology , Receptors, Interleukin-10/biosynthesis , Receptors, Interleukin-10/genetics , Receptors, Leptin/biosynthesis , Receptors, Leptin/genetics , Reverse Transcriptase Polymerase Chain Reaction , STAT3 Transcription Factor/biosynthesis , STAT3 Transcription Factor/genetics , Signal Transduction/physiology , Suppressor of Cytokine Signaling 3 Protein , Suppressor of Cytokine Signaling Proteins/biosynthesis , Suppressor of Cytokine Signaling Proteins/geneticsABSTRACT
A melatonina, (MLT) um hormônio produzido pela pineal, em sua síntese obedecida por ritmo circadiano que é coordenado pelo sistema retino-hipotálamo-pineal, sendo ativado pela escuridäo. Estudos recentes relacionam a pinealectomia cirúrgica à induçäo de estado pré-diabético e simulaçäo de síndrome dos ovários policísticos. Aferir alteraçöes no perfil bioquímico do colesterol, triglicérides, glicose e progesterona em ratas expostas à luz contínua (LC). Foram utilizadas 42 ratas mantidas em gaiolas individuais e divididas em 3 grupos. Grupo de Estudo - GE (n=22) animais expostos a LC por 8 meses. No 4§ mês realizou-se Ooforectomia à direita e iniciou-se a administraçäo de MLT (200 mg IM) diariamente por 4 meses. Grupo controle I - (GCI) (n=10) animais expostos à LC por 8 meses. Grupo Controle II - GCII (n=10) animais expostos a LC por 8 meses, no 4§ mês realizou-se Ooforectomia à direita e administrou-se etanol por 4 meses. Ao final do experimento foi realizada Ooforectomia à esquerda nos 3 grupos. Coletou-se 1 ml de sangue no início, no 4§ e 8§ mês de experimento para dosagem bioquímica. A análise estatística foi realizada segundo a análise de variância por postos de Friedmann e teste de Mann Whitney. Näo observou-se relaçäo ou variaçäo entre os valores bioquímicos estudados. Os valores de progesterona sugeriram a presença de estado anovulatório crônico nos animais estudados. Em ratas, os níveis de glicemia, colesterol e triglicérides näo se alteraram frente à pinealectomia física. Estes resultados podem ter sofrido forte influência pelo estresse induzido pela luz. Outros estudos precisam confirmar a associaçäo de melatonina, diabete mellitus e síndrome dos ovários policísticos