RESUMO
Here, we investigated whether pharmacological PPARγ activation modulates key early events in brown adipose tissue (BAT) recruitment induced by acute cold exposure with the aim of unraveling the interrelationships between sympathetic and PPARγ signaling. Sprague-Dawley rats treated or not with the PPARγ ligand rosiglitazone (15 mg·kg(-1)·day(-1), 7 days) were kept at 23°C or exposed to cold (5°C) for 24 h and evaluated for BAT gene expression, sympathetic activity, thyroid status, and adrenergic signaling. Rosiglitazone did not affect the reduction in body weight gain and the increase in feed efficiency, Vo(2), and BAT sympathetic activity induced by 24-h cold exposure. Rosiglitazone strongly attenuated the increase in serum total and free T4 and T3 levels and BAT iodothyronine deiodinase type 2 (D2) and PGC-1α mRNA levels and potentiated the reduction in BAT thyroid hormone receptor (THR) ß mRNA levels induced by cold. Administration of T3 to rosiglitazone-treated rats exacerbated the cold-induced increase in energy expenditure but did not restore a proper activation of D2 and PGC-1α, nor further increased uncoupling protein 1 expression. Regarding adrenergic signaling, rosiglitazone did not affect the changes in BAT cAMP content and PKA activity induced by cold. Rosiglitazone alone or in combination with cold increased CREB binding to DNA, but it markedly reduced the expression of one of its major coactivators, CREB binding protein. In conclusion, pharmacological PPARγ activation impairs short-term cold elicitation of BAT adrenergic and thyroid signaling, which may result in abnormal tissue recruitment and thermogenic activity.
Assuntos
Tecido Adiposo Marrom/metabolismo , Temperatura Baixa , Iodeto Peroxidase/metabolismo , PPAR gama/metabolismo , Proteínas de Ligação a RNA/metabolismo , Glândula Tireoide/fisiologia , Fatores de Transcrição/metabolismo , Regulação para Cima/fisiologia , Animais , Masculino , Modelos Animais , PPAR gama/agonistas , PPAR gama/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Ratos , Ratos Sprague-Dawley , Rosiglitazona , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Tiazolidinedionas/farmacologia , Tiroxina/sangue , Fatores de Tempo , Tri-Iodotironina/sangue , Iodotironina Desiodinase Tipo IIRESUMO
Previous studies showed that the antipsychotic drugs (APDs) sulpiride (SUL) and risperidone (RIS) induced body weight gain (BWG), hyperphagia, and increased serum levels of leptin, prolactin and corticosterone in female rats. Neither SUL nor RIS increased BWG or food intake (FI) in male rats. To further develop the animal model of APD-induced obesity, SUL (20 mg/kg/sc), RIS (0.5 mg/kg/sc) or vehicle (1 cm(3)/kg/sc) were administered to female Wistar rats for 10 or 12 days. Body composition, fat tissue morphology, energy expenditure and food efficiency were assessed in animals fed a high-fat diet. In another experiment, macronutrient selection was evaluated in animals fed with pure diets. SUL and RIS significantly increased BWG and FI, with a stronger effect of SUL. Both drugs increased fat gain and food efficiency, and did not modify energy expenditure. Obesity was due to adipocyte hyperplasia. SUL-treated rats significantly decreased fat intake (p = 0.039), showed a tendency to increase protein intake and did not modify carbohydrate consumption. No differences were observed between the RIS and the vehicle group. The macronutrient selection pattern differs from that observed in obese people undergoing APD treatment and in most animal models of obesity. Those findings suggest that SUL administration does not properly model APD treatment in humans. Results on macronutient selection in RIS-treated rats must be considered as preliminary, since in this experiment the animals did not gain weight significantly. Other diet protocols and lower APD doses must be tested to further characterize the RIS model.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Antipsicóticos/farmacologia , Composição Corporal/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Risperidona/farmacologia , Sulpirida/farmacologia , Adipócitos/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Contagem de Células/métodos , Corticosterona/sangue , Gorduras na Dieta/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Leptina/sangue , Prolactina/sangue , Proteínas/metabolismo , Ratos , Ratos WistarRESUMO
Obesity and related metabolic disorders are important side effects of some antipsychotic drugs (APs). The currently available animal model of AP-induced bodyweight gain (BWG) in rats is based on administration of sulpiride (SUL). However, this model has important limitations. For example, SUL is a pure dopamine antagonist, whereas most APs in current clinical use interact with multiple neurotransmitter receptors involved in food intake (FI) and metabolism regulation. Therefore, we evaluated the effects of risperidone (RIS, 0.125, 0.25 or 0.5 mg/kg during 16 days) on BWG and FI in male and female rats. Comparison between RIS (0.5 mg/kg), SUL (20 mg/kg) and vehicle (VEH) during 12 days was also conducted in females. In male rats, RIS did not significantly affect BWG, FI, glucose tolerance or leptin levels, even though prolactin and corticosterone were significantly elevated. In females, both APs significantly increased BWG and FI, but the effect was stronger with SUL. The BWG was significantly associated with an increase in body fat. Serum leptin levels were increased only in SUL-treated rats. The area under the curve for glucose (AUGC) was significantly lower in the SUL group, but it was similar for insulin in all treatment groups. The area under the curve for insulin (AUIC) and BWG positively correlated only in the RIS group. Prolactin and corticosterone were significantly increased by both APs. Serum estradiol levels were significantly increased by RIS but not by SUL, but progesterone levels were similar in both groups. The observed positive correlation between BWG and the AUIC during RIS administration suggests that this agent may represent a better model of AP administration in humans. The animal model of RIS-induced obesity in rats might be improved by testing other doses, route of administration and type of diet.
Assuntos
Antipsicóticos/farmacologia , Glicemia/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Hormônios/sangue , Risperidona/farmacologia , Sulpirida/farmacologia , Animais , Corticosterona/sangue , Estradiol/sangue , Feminino , Teste de Tolerância a Glucose , Masculino , Progesterona/sangue , Prolactina/sangue , Radioimunoensaio , Ratos , Ratos Wistar , Caracteres Sexuais , Fatores de TempoRESUMO
La administración intraportal o intraperitoneal (IP) de adrenalina (A) produce hipofagia en la rata, mientras que la inyección intravenosa o intramuscular (IM) no lo hace. Se ha sugerido que la A actúa a nivel hepático para controlar la ingesta de alimento por medio de aferencias vagales hacia el cerebro. En el presente trabajo se utilizó la expresión del gene C-fos como índice de actividad neuronal y se compararon los efectos respectivos de la A IP e IM sobre la ingesta y la activación de áreas del cerebro que reciben información vagal aferente. Ratas Wistar machos fueron inyectadas con solución salina o A (100µg/Kg) por vía IP o IM. En un primer experimento, se determinó el consumo de alimento. En un segundo experimento, se analizó inmunohistoquímicamente la expresión de c-fos en diversas áreas del cerebro. La A IP redujo el consumo de alimento en un 75 por ciento (p<0.01) mientras que la A IM no tuvo efecto alguno. Los resultados de la expresión de c-fos indican que aquellas regiones del núcleo del tracto solitario/área postrema que reciben aferencias gastrointestinales y hepática son activadas de manera específica por la administración IP de A. Esto concuerda con la posibilidad de que su efecto hipofágico implique aferencias vagales, posiblemente de origen hepático. Sin embargo, algunos niveles superiores de integración, como los núcleos parabraquial y paraventricular no parecen estar involucrados, o lo están de manera inespecífica