RESUMEN
The effect of fish oil (FO) treatment on high-fat (HF) diet-induced obesity and metabolic syndrome was addressed by analyzing dysfunctions in cells of different adipose depots. For this purpose, mice were initially induced to obesity for 8 weeks following a treatment with FO containing high concentration of EPA compared to DHA (5:1), for additional 8 weeks (by gavage, 3 times per week). Despite the higher fat intake, the HF group showed lower food intake but higher body weight, glucose intolerance and insulin resistance, significant dyslipidemia and increased liver, subcutaneous (inguinal-ING) and visceral (retroperitoneal-RP) adipose depots mass, accompanied by adipocyte hypertrophy and decreased cellularity in both adipose tissue depots. FO treatment reversed all these effects, as well as it improved the metabolic activities of isolated adipocytes, such as glucose uptake and lipolysis in both depots, and de novo synthesis of fatty acids in ING adipocytes. HF diet also significantly increased both the pro and anti-inflammatory cytokines expression by adipocytes, while HF + FO did not differ from control group. Collectively, these data show that the concomitant administration of FO with the HF diet is able to revert metabolic changes triggered by the diet-induced obesity, as well as to promote beneficial alterations in adipose cell activities. The main mechanism underlying all systemic effects involves direct and differential effects on ING and RP adipocytes.
Asunto(s)
Adipocitos/metabolismo , Aceites de Pescado/uso terapéutico , Síndrome Metabólico/tratamiento farmacológico , Obesidad/etiología , Adipocitos/efectos de los fármacos , Adipoquinas/sangre , Adipoquinas/metabolismo , Animales , Células Cultivadas , Dieta Alta en Grasa/efectos adversos , Aceites de Pescado/administración & dosificación , Aceites de Pescado/farmacología , Glucosa/metabolismo , Lipólisis , Masculino , Síndrome Metabólico/etiología , Ratones , Ratones Endogámicos C57BL , Obesidad/complicacionesRESUMEN
IL-1ß-induced anorexia may depend on interactions of the cytokine with neuropeptides and neurotransmitters of the central nervous system control of energy balance and serotonin is likely to be one catabolic mediator targeted by IL-1ß. In the complex interplay involved in feeding modulation, nitric oxide has been ascribed a stimulatory action, which could be of significance in counteracting IL-1ß effects.The present study aims to explore the participation of the nitric oxide and the serotonin systems on the central mechanisms induced by IL-1ß and the relevance of their putative interactions to IL-1ß hypophagia in normal rats.Serotonin levels were determined in microdialysates of the ventromedial hypothalamus after a single intracerebroventricular injection of 10 ng of IL-1ß , with or without the pre-injection of 20 µg of the nitric oxide precursor L-arginine. IL-1ß significantly stimulated hypothalamic serotonin extracellular levels, with a peak variation of 130 ± 37% above baseline. IL- 1ß also reduced the 4-h and the 24-h food intakes (by 23% and 58%, respectively). The IL-1ß-induced serotonergic activation was abolished by the pre-injection of L-arginine while the hypophagic effect was unaffected.The data showed that one central effect of IL-1ß is serotonergic stimulation in the ventromedial hypothalamus, an action inhibited by nitric oxide activity. It is suggested that, although serotonin participates in IL-1ß anorexia, other mechanisms recruited by IL-1ß in normal rats are able to override the absence of the serotonergic hypophagic influence.
Asunto(s)
Regulación del Apetito/fisiología , Arginina/administración & dosificación , Hipotálamo/metabolismo , Interleucina-1beta/administración & dosificación , Serotonina/metabolismo , Animales , Anorexia/inducido químicamente , Anorexia/metabolismo , Cromatografía Líquida de Alta Presión , Ingestión de Alimentos/fisiología , Hipotálamo/efectos de los fármacos , Inyecciones Intraventriculares , Masculino , Microdiálisis , Óxido Nítrico/metabolismo , Ratas , Ratas ZuckerRESUMEN
Hypothalamic serotonin inhibits food intake and stimulates energy expenditure. High-fat feeding is obesogenic, but the role of polyunsaturated fats is not well understood. This study examined the influence of different high-PUFA diets on serotonin-induced hypophagia, hypothalamic serotonin turnover, and hypothalamic protein levels of serotonin transporter (ST), and SR-1B and SR-2C receptors. Male Wistar rats received for 9 weeks from weaning a diet high in either soy oil or fish oil or low fat (control diet). Throughout 9 weeks, daily intake of fat diets decreased such that energy intake was similar to that of the control diet. However, the fish group developed heavier retroperitoneal and epididymal fat depots. After 12 h of either 200 or 300 µg intracerebroventricular serotonin, food intake was significantly inhibited in control group (21-25%) and soy group (37-39%) but not in the fish group. Serotonin turnover was significantly lower in the fish group than in both the control group (-13%) and the soy group (-18%). SR-2C levels of fish group were lower than those of control group (50%, P = 0.02) and soy group (37%, P = 0.09). ST levels tended to decrease in the fish group in comparison to the control group (16%, P = 0.339) and the soy group (21%, P = 0.161). Thus, unlike the soy-oil diet, the fish-oil diet decreased hypothalamic serotonin turnover and SR-2C levels and abolished serotonin-induced hypophagia. Fish-diet rats were potentially hypophagic, suggesting that, at least up to this point in its course, the serotonergic impairment was either compensated by other factors or not of a sufficient extent to affect feeding. That fat pad weight increased in the absence of hyperphagia indicates that energy expenditure was affected by the serotonergic hypofunction.
Asunto(s)
Grasas Insaturadas en la Dieta/farmacología , Ingestión de Alimentos/efectos de los fármacos , Aceites de Pescado/farmacología , Serotonina/metabolismo , Tejido Adiposo/anatomía & histología , Animales , Dieta , Aceites de Pescado/administración & dosificación , Humanos , Ácido Hidroxiindolacético/química , Ácido Hidroxiindolacético/metabolismo , Hipotálamo/química , Hipotálamo/metabolismo , Infusiones Intraventriculares , Masculino , Tamaño de los Órganos , Distribución Aleatoria , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT1B/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Serotonina/administración & dosificación , Serotonina/química , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Aceite de Soja/administración & dosificación , Aceite de Soja/farmacologíaRESUMEN
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.
Asunto(s)
Desnutrición/fisiopatología , Obesidad/embriología , Efectos Tardíos de la Exposición Prenatal , Fenómenos Fisiologicos de la Nutrición Prenatal/fisiología , Serotonina/fisiología , Animales , Peso Corporal/fisiología , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Femenino , Enfermedades Fetales/fisiopatología , Hipotálamo/metabolismo , Microdiálisis/métodos , Obesidad/etiología , Obesidad/fisiopatología , Embarazo , Ratas , Ratas Wistar , Serotonina/farmacologíaRESUMEN
OBJECTIVE: We evaluated whether insulin hypophagia and hypothalamic signaling are affected in adult rats exposed to intrauterine undernutrition. METHODS: Pregnant rats ate ad libitum throughout pregnancy and lactation (control, C) or 50% of control intake in the first 2 wk of pregnancy (restricted, R). Four-month-old C and R progeny received insulin or vehicle intracerebroventricular injections for evaluation of 24-h food intake, hypothalamic insulin receptor (IR), and IR substrate-1 (IRS-1) protein content and tyrosine phosphorylation, pp185 phosphorylation, and IRS-1 association with phosphatidylinositol 3-kinase (PI3-K). RESULTS: With respect to males, R males had normal body composition and insulin-induced hypophagia. IR protein levels were lower but IR phosphorylation was higher in R than in C males. IRS-1 levels and phosphorylation were similar between C and R males, insulin stimulated an IRS-1/PI3-K association in C but not in R males, and pp185 phosphorylation was higher in R than in C males. For females, body fat and serum leptin were elevated in R females. Insulin inhibited food intake in C but not in R females. Insulin-induced IR phosphorylation and protein levels of IR and IRS-1 were higher in R than in C females. However, IRS-1 and pp185 phosphorylation and IRS-1/PI3-K association were significantly stimulated by insulin in C but not in R females. CONCLUSIONS: Female adult rats exposed to intrauterine undernutrition had increased adiposity, marked impairment of hypothalamic insulin signaling, and loss of insulin-induced hypophagia. These disturbances were less severe or even absent in male progeny. The findings show that female progeny are more susceptible than their male siblings to the effects of maternal malnutrition.
Asunto(s)
Animales Recién Nacidos/metabolismo , Hipotálamo/fisiopatología , Insulina/metabolismo , Desnutrición/fisiopatología , Fenómenos Fisiologicos Nutricionales Maternos/fisiología , Receptor de Insulina/metabolismo , Animales , Composición Corporal/fisiología , Dieta Reductora , Ingestión de Alimentos/fisiología , Femenino , Hipotálamo/metabolismo , Inyecciones Intraventriculares , Proteínas Sustrato del Receptor de Insulina , Péptidos y Proteínas de Señalización Intracelular , Lactancia/fisiología , Masculino , Desnutrición/sangre , Desnutrición/metabolismo , Fosfoproteínas/metabolismo , Fosforilación , Embarazo , Preñez/metabolismo , Preñez/fisiología , Efectos Tardíos de la Exposición Prenatal , Ratas , Ratas Wistar , Factores Sexuales , Transducción de Señal/fisiologíaRESUMEN
OBJECTIVE: Using rats we examined whether maternal intake of hydrogenated fat rich in trans fatty acids affects brain fatty acid profile, hypothalamic content of insulin receptor and insulin receptor substrate-1 proteins, and the hypophagic effect of centrally administered insulin in 3-mo-old male progeny. METHODS: Throughout pregnancy and lactation, Wistar rats ate isocaloric/normolipidic diets with soybean oil (control) or soybean oil-derived hydrogenated fat (trans diet) as a fat source. Upon weaning, the trans offspring continued on the trans diet (trans group) or were switched to a control diet (trans-control group). RESULTS: Compared with control rats, trans rats had lower brain levels of eicosapentaenoic acid. Compared with trans rats, trans-control rats had increased levels of total polyunsaturated fatty acids and arachidonic acid and decreased levels of trans fatty acids, saturated fatty acids, and monounsaturated fatty acids. Insulin receptor and insulin receptor substrate-1 levels were significantly lower (44% and 38%, respectively) in trans than in control rats. In trans-control rats, insulin receptor was 26% lower (P < 0.05), whereas insulin receptor substrate-1 was 50% lower, than in control rats. Insulin decreased 24-h feeding in control (27%) and trans (38%) rats but failed to do so in trans-control rats. The latter group had increased serum glucose levels. CONCLUSIONS: The data suggest that the early (intrauterine/perinatal) exposure to hydrogenated fat rich in trans fatty acids programmed the hypothalamic feeding control mechanisms. As young adults, only trans-control animals showed loss of insulin-induced hypophagia, indicating that the mismatch between early and later nutritional environments was relevant. However, the trans group also showed signs of altered appetite signaling mechanisms, suggesting that the early adaptations may have deleterious consequences later in life.
Asunto(s)
Grasas de la Dieta/administración & dosificación , Ingestión de Alimentos/efectos de los fármacos , Insulina/farmacología , Lactancia , Efectos Tardíos de la Exposición Prenatal , Ácidos Grasos trans/administración & dosificación , Animales , Regulación del Apetito/efectos de los fármacos , Glucemia/análisis , Química Encefálica , Grasas de la Dieta/análisis , Ácido Eicosapentaenoico/análisis , Ácidos Grasos/análisis , Femenino , Hidrogenación , Hipotálamo/química , Hipotálamo/efectos de los fármacos , Hipotálamo/fisiología , Insulina/administración & dosificación , Insulina/sangre , Proteínas Sustrato del Receptor de Insulina , Fosfoproteínas/análisis , Embarazo , Ratas , Ratas Wistar , Receptor de Insulina/análisis , Aceite de Soja/administración & dosificación , Aceite de Soja/químicaRESUMEN
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.
Asunto(s)
Ingestión de Alimentos/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Serotonina/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Ayuno , Masculino , Neuropéptido Y , RatasRESUMEN
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.