RESUMO
We have previously shown that adult female rats exposed to intra-uterine malnutrition were normophagic, although obese and resistant to insulin-induced hypophagia. The present study aimed at examining aspects of another important catabolic component of energy homeostasis control, the hypothalamic serotonergic function, which inhibits feeding and stimulates energy expenditure. Pregnant dams were fed ad libitum or were restricted to 50 % of ad libitum intake during the first 2 weeks of pregnancy. Control and restricted 4-month-old progeny were studied. The restricted rats had increased body adiposity with normal daily food intake but failed to respond with hypophagia to an intracerebroventricular injection of serotonin (5-hydroxytryptamine; 5-HT). Stimulation, by food ingestion, of extracellular levels of serotonin in medial hypothalamus microdialysates was more pronounced and lasted longer in the restricted than in the control rats. In the restricted group, hypothalamic levels of 5-HT 2C receptor protein tended to be reduced (P = 0.07) while the levels of 5-HT1B receptor and serotonin transporter proteins were significantly elevated (36 and 79 %, respectively). In conclusion, female rats undernourished in utero had normophagic obesity as adults but had an absence of serotonin-induced hypophagia and low hypothalamic levels of the 5-HT 2C receptor. Compensatory adaptations for the functional serotonergic impairment were evidenced, such as an enhanced release of serotonin in response to a meal allied to up-regulated hypothalamic 5-HT1B and transporter expression. Whether these compensations will persist in later life warrants further investigation. Moreover, it cannot be ruled out that the serotonergic component of energy expenditure was already impaired, thus contributing to the observed body-fat phenotype.
Assuntos
Desnutrição/fisiopatologia , Obesidade/embriologia , Efeitos Tardios da Exposição Pré-Natal , Fenômenos Fisiológicos da Nutrição Pré-Natal/fisiologia , Serotonina/fisiologia , Animais , Peso Corporal/fisiologia , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Feminino , Doenças Fetais/fisiopatologia , Hipotálamo/metabolismo , Microdiálise/métodos , Obesidade/etiologia , Obesidade/fisiopatologia , Gravidez , Ratos , Ratos Wistar , Serotonina/farmacologiaRESUMO
Endogenous neuropeptide Y (NPY) levels increase during fasting and before dark onset in rats. The feeding that follows these states elicits the release of serotonin in the lateral hypothalamus (LH), as part of the physiological mechanisms controlling satiety. With the hypothesis that exogenous NPY-induced feeding should also stimulate serotonin, we measured its release in the LH of non-fasted rats, which received a single intracerebroventricular injection of either 1.0, 2.0, or 5.0 microg of NPY. After 1.0 microg, the cumulative 2-h intake was of 13 g and serotonin release significantly increased (54% peak). These feeding and serotonergic responses were highly similar to the ones we observed in a previous study, in which feeding followed an overnight fast. Thus, the 1.0 microg NPY dose stimulated intake while preserving the normal serotonergic activation. Contrarily, as the NPY dose was increased to either 2.0 or 5.0 microg, the cumulative 2-h intakes were of 18 g, but the serotonergic stimulation was absent. It is suggested that this dual NPY effect relies on a finely tuned control mechanism, reflecting the existence of a narrow range of NPY levels within which the serotonergic stimulation resembles those seen in physiological states.
Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Serotonina/metabolismo , Animais , Relação Dose-Resposta a Droga , Jejum , Masculino , Neuropeptídeo Y , RatosRESUMO
Insulin and angiotensin II (AngII) may act through overlapping intracellular pathways to promote cardiac myocyte growth. In this report insulin and AngII signaling, through the phosphatidylinositol 3-kinase (PI 3-kinase) and MAPK pathways, were compared in cardiac tissues of control and obese Zucker rats. AngII induced Janus kinase 2 tyrosine phosphorylation and coimmunoprecipitation with insulin receptor substrate 1 (IRS-1) and IRS-2 as well as an increase in tyrosine phosphorylation of IRS and its association with growth factor receptor-binding protein 2. Simultaneous treatment with both hormones led to marked increases in the associations of IRS-1 and -2 with growth factor receptor-binding protein 2 and in the dual phosphorylation of ERK1/2 compared with the administration of AngII or insulin alone. In contrast, an acute inhibition of both basal and insulin-stimulated PI 3-kinase activity was induced by both hormones. Insulin stimulated the phosphorylation of MAPK equally in lean and obese rats. Conversely, insulin-induced phosphorylation of Akt in heart was decreased in obese rats. Pretreatment with losartan did not change insulin-induced activation of ERK1/2 and attenuated the reduction of Akt phosphorylation in the heart of obese rats. Thus, the imbalance between PI 3-kinase-Akt and MAPK signaling pathways in the heart may play a role in the development of cardiovascular abnormalities observed in insulin-resistant states, such as in obese Zucker rats.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Angiotensina II/metabolismo , Hipoglicemiantes/metabolismo , Resistência à Insulina/fisiologia , Insulina/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Miocárdio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases , Vasoconstritores/metabolismo , Angiotensina II/farmacologia , Animais , Proteína Adaptadora GRB2 , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Janus Quinase 2 , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Obesidade/metabolismo , Fosforilação , Proteínas Tirosina Quinases/metabolismo , Proteínas/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Ratos , Ratos Wistar , Ratos Zucker , Receptor Cross-Talk/fisiologia , Vasoconstritores/farmacologiaRESUMO
Corticosteroids influence energy homeostasis through centrally-mediated stimulation of energy intake and inhibition of expenditure, while central serotonin (5-HT) has opposite effects. Both serotonergic dysfunction and high glucocorticoid levels may be relevant in obesity. The neurotoxin monosodium glutamate (MSG) induces a non-hyperphagic and hypometabolic obesity with hypercorticosteronemia. We investigated the influence of corticosterone levels on the serotonergic system of MSG-obese and control rats. Applying microdialysis, we found a similar feeding-induced stimulation of serotonin release in the lateral hypothalamus (LH) in sham-adrenalectomized control and MSG rats. The concomitant serum corticosterone variations were markedly distinct between them, in that an increase occurred in the control group, while the initially high levels of the MSG rats decreased with feeding. It is suggested that this lowering of corticosterone prevented a higher serotonergic activation, which would lead to a higher meal-induced thermogenesis and a better adequation of the caloric intake to a low metabolism. Adrenalectomy completely abolished the feeding-evoked serotonergic stimulation in both groups. This observation demonstrates that glucocorticoids are necessary for food intake to acutely stimulate 5-HT release and indicates that serotonergic activity in the LH is not likely to participate in the adrenalectomy-induced attenuation of the MSG-obesity.