RESUMO
Changes to neonatal nutrition result in long-lasting impairments in energy balance, which may be described as metabolic programing. Astrocytes, which are interconnected by gap junctions, have emerged as important players in the hypothalamic control of food intake. In order to study the effects of nutritional programming on glial morphology and protein expression, cross-fostered male Wistar rats at postnatal day 3 were assigned to three groups based on litter size: small litter (3 pups per dam, SL), normal litter (10 pups per dam, NL), and large litter (16 pups per dam, LL). Rats from the SL group exhibited higher body weight throughout the study and hyperphagia after weaning. LL animals exhibited hyperphagia, high energy efficiency and catch-up of body weight after weaning. Both the SL and LL groups at postnatal day 60 (PN60) exhibited increased levels of plasma leptin, the Lee index (as an index of obesity), adiposity content, immunoreactivity toward T-cell protein tyrosine phosphatase (TCPTP), and glial fibrillary acidic protein (GFAP) in the arcuate nucleus (ARC) of the hypothalamus. Astrocyte morphology was altered in the ARC of SL and LL animals, and this effect occurred in parallel with a reduction in immunoreactivity toward connexin 30 (CX30). The data obtained demonstrate that both neonatal over- and underfeeding promote not only alterations in the metabolic status but also morphological changes in glial cells in parallel with increasing TCPTP and changes in connexin expression.
Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Conexinas/genética , Gliose/etiologia , Proteína Tirosina Fosfatase não Receptora Tipo 2/genética , Adiposidade/fisiologia , Animais , Animais Recém-Nascidos , Conexinas/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Gliose/genética , Gliose/metabolismo , Hiperfagia/complicações , Hiperfagia/genética , Hiperfagia/metabolismo , Hiperfagia/patologia , Hipotálamo/metabolismo , Tamanho da Ninhada de Vivíparos/fisiologia , Masculino , Obesidade/complicações , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Gravidez , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Ratos , Ratos Wistar , Fatores Sexuais , Fatores de TempoRESUMO
Neonatal nutritional changes induce long-lasting effects on energy homeostasis. Adiponectin influences food intake and body weight. The aim of this study was to investigate the effects of neonatal nutritional programming on the central stimulation of adiponectin. Male Wistar rats were divided on postnatal (PN) day 3 in litters of 3 (small litter, SL), 10 (normal litter, NL), or 16 pups/dam (large litter, LL). We assessed body weight gain for 60 days, adiponectin concentration, and white adipose tissue weight. We examined the response of SL, NL, and LL rats on body weight gain, food intake, oxygen consumption (VÌo2), respiratory exchange ratio (RER), calorimetry, locomotor activity, phosphorylated-AMP-activated protein kinase (AMPK) expression in the hypothalamus, and uncoupling protein (UCP)-1 in the brown adipose tissue after central stimulus with adiponectin. After weaning, SL rats maintained higher body weight gain despite similar food intake compared with NL rats. LL rats showed lower body weight at weaning, with a catch up afterward and higher food intake. Both LL and SL groups had decreased plasma concentrations of adiponectin at PN60. SL rats had increased white adipose tissue. Central injection of adiponectin decreased body weight and food intake and increased VÌo2, RER, calorimetry, p-AMPK and UCP- 1 expression in NL rats, but it had no effect on SL and LL rats, compared with the respective vehicle groups. In conclusion, neonatal under- and overfeeding induced an increase in body weight gain in juvenile and early adult life. Unresponsiveness to central effects of adiponectin contributes to the imbalance of the energy homeostasis in adult life induced by neonatal nutritional programming.
Assuntos
Adiponectina/metabolismo , Animais Recém-Nascidos/fisiologia , Metabolismo Energético/fisiologia , Homeostase/fisiologia , Fenômenos Fisiológicos da Nutrição/fisiologia , Adiponectina/genética , Tecido Adiposo/crescimento & desenvolvimento , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/fisiologia , Animais , Ingestão de Alimentos/fisiologia , Metabolismo Energético/genética , Feminino , Homeostase/genética , Masculino , Desnutrição/fisiopatologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Atividade Motora , Hipernutrição/fisiopatologia , Consumo de Oxigênio/fisiologia , Gravidez , Ratos , Ratos Wistar , Aumento de PesoRESUMO
Leptin resistance is induced by the feedback inhibitors tyrosine phosphatase-1B (PTP1B) and decreased Src homology 2 domain-containing tyrosine phosphatase-2 (SHP-2) signaling. To investigate the participation of PTP1B and SHP-2 in LPS-induced leptin resistance, we injected repeated (6-LPS) intraperitoneal LPS doses (100 µg/kg ip) for comparison with a single (1-LPS) treatment and evaluated the expression of SHP-2, PTP1B, p-ERK1/2, and p-STAT3 in the hypothalamus of male Wistar rats. The single LPS treatment increased the expression of p-STAT3 and PTP1B but not SHP-2. The repeated LPS treatment reduced SHP-2, increased PTP1B, and did not change p-STAT3. We observed that the PTP1B expression induced by the endotoxin was highly colocalized with leptin receptor cells in the hypothalamus of LepRb-IRES-Cre-tdTomato reporter mice. The single, but not the repeated, LPS treatment decreased the food intake and body weight. Leptin had no stimulatory effect on the hypophagia, body weight loss, or pSTAT3 expression in 6-LPS rats, indicating leptin unresponsiveness. Notably, the PTP1B inhibitor (3.0 nmol/rat in 5 µl icv) restored the LPS-induced hypophagia in 6-LPS rats and restored the ability of leptin to reduce food intake and body weight as well as to phosphorylate STAT3 in the arcuate, paraventricular, and ventromedial nuclei of the hypothalamus. The present data suggest that an increased PTP1B expression in the hypothalamus underlies the development of leptin resistance during repeated exposure to LPS. Our findings contribute to understanding the mechanisms involved in leptin resistance during low-grade inflammation as seen in obesity.
Assuntos
Resistência a Medicamentos , Inflamação/metabolismo , Leptina/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 1/fisiologia , Animais , Resistência a Medicamentos/efeitos dos fármacos , Resistência a Medicamentos/genética , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/genética , Obesidade/metabolismo , Ratos , Ratos Wistar , Receptores para Leptina/genética , Receptores para Leptina/metabolismoRESUMO
Hypophagia induced by inflammation is associated with Janus kinase (JAK)-2/signal transducer and activator of transcription (STAT) 3 signaling pathway, and leptin-mediated hypophagia is also mediated by JAK2-STAT3 pathway. We have previously reported that lipopolysaccharide (LPS) did not reduce food intake in leptin-resistant high-fat diet (HFD) rats but maintained body weight loss. We investigated whether changes in p-STAT3 expression in the hypothalamus and brain stem could account for the desensitization of hypophagia in HFD animals after a low LPS dose (100 µg/kg). Wistar rats fed standard diet (3.95 kcal/g) or HFD (6.3 kcal/g) for 8 wk were assigned into control diet-saline, control diet-LPS, HFD-saline, and HFD-LPS groups. LPS reduced feeding in the control diet but not HFD. This group showed no p-STAT3 expression in the paraventricular nucleus (PVN) and ventromedial hypothalamic nucleus (VMH), but sustained, though lower than control, p-STAT3 in the nucleus of the solitary tract (NTS) and raphe pallidus (RPa). LPS decreased body weight in HFD rats and increased Fos expression in the NTS. LPS increased body temperature, oxygen consumption, and energy expenditure in both control diet and HFD rats, and this response was more pronounced in HFD-LPS group. Brown adipose tissue (BAT) thermogenesis and increased energy expenditure seem to contribute to body weight loss in HFD-LPS. This response might be related with increased brain stem activation. In conclusion, LPS activates STAT3-mediated pathway in the hypothalamus and brain stem, leading to hypophagia, however, LPS effects on food intake, but not body weight loss, are abolished by leptin resistance induced by HFD. The preserved STAT3 phosphorylation in the brain stem suggests that unresponsiveness to LPS on STAT3 activation under HFD might be selective to the hypothalamus.
Assuntos
Dieta Hiperlipídica , Hipotálamo/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Peso Corporal/fisiologia , Gorduras na Dieta/metabolismo , Ingestão de Alimentos/fisiologia , Hipotálamo/metabolismo , Leptina/metabolismo , Masculino , Ratos , Ratos Wistar , Transdução de Sinais/fisiologiaRESUMO
BACKGROUND: Changes in the nutritional supply during the perinatal period can lead to metabolic disturbances and obesity in adulthood. OBJECTIVE: The divergent litter size model was used to investigate the hypothalamic sensitivity to leptin and ghrelin as well as the mechanisms involved in the disruption of food intake and energy expenditure. METHODS: On postnatal day 3 (P3), male Wistar rats were divided into 3 groups: small litter (SL - 3 pups), normal litter (NL - 10 pups), and large litter (LL - 16 pups). Animals at P60 were intraperitoneally treated with leptin (500 µg/Kg), ghrelin (40 µg/Kg), or vehicle (0.9% NaCl) at 5 pm and the following parameters were assessed: food intake and body weight; immunostaining of p-STAT-3 in the hypothalamus; Western Blotting analysis of p-AMPKα and UCP2 in the mediobasal hypothalamus (MBH), and UCP1 in the interscapular brown adipose tissue (BAT); or heat production, VO2, VCO2, and locomotor activity. RESULTS: SL rats had earlier leptin and ghrelin surges, while LL rats had no variations. At P60, after leptin treatment, LL rats showed hypophagia and increased p-STAT-3 expression in the arcuate nucleus, but SL rats had no response. After ghrelin treatment, LL rats did not have the orexigenic response or AMPKα phosphorylation in the MBH, while SL animals, unexpectedly, decreased body weight gain, without changes in food intake, and increased metabolic parameters and UCP1 expression in the BAT. CONCLUSIONS: Changes in the nutritional supply at early stages of life modify leptin and ghrelin responsiveness in adulthood, programming metabolic and central mechanisms, which contribute to overweight and obesity in adulthood.
Assuntos
Grelina/metabolismo , Hiperfagia/metabolismo , Hipotálamo/metabolismo , Leptina/metabolismo , Desnutrição/metabolismo , Envelhecimento , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Peso Corporal , Ingestão de Alimentos , Metabolismo Energético/fisiologia , Feminino , Tamanho da Ninhada de Vivíparos , Masculino , Obesidade/etiologia , Gravidez , Ratos , Ratos Wistar , Fator de Transcrição STAT3/metabolismoRESUMO
Adrenalectomy (ADX) induces hypophagia and glucocorticoids counter-regulate the peripheral metabolic effects of insulin. This study evaluated the effects of ADX on ICV (lateral ventricle) injection of insulin-induced changes on food intake, mRNA expression of hypothalamic neuropeptides (insulin receptor (InsR), proopiomelanocortin, cocaine and amphetamine-regulated transcript (Cart), agouti-related protein, neuropeptide Y (Npy) in the arcuate nucleus of the hypothalamus (ARC), corticotrophin-releasing factor in the paraventricular nucleus of the hypothalamus) and hypothalamic protein content of insulin signaling-related molecules (insulin receptor substrate (IRS) 1, protein kinase B (AKT), extracellular-signal-regulated kinase (ERK1/2), c-Jun N-terminal kinase (JNK), protein tyrosine phosphatase-1B (PTP1B) and T cell protein tyrosine phosphatase (TCPTP)) Compared with sham animals, ADX increased the hypothalamic content of pJNK/JNK, PTP1B and TCPTP, as well as decreased mRNA expression of InsR, and corticosterone (B) treatment reversed these effects. Insulin central injection enhanced hypothalamic content of pAKT/AKT and Cart mRNA expression, decreased Npy mRNA expression and food intake only in sham rats, without effects in ADX and ADX + B rats. Insulin did not alter the hypothalamic phosphorylation of IRS1 and ERK1/2 in the three experimental groups. These data demonstrate that ADX reduces the expression of InsR and increases insulin counter-regulators in the hypothalamus, as well as ADX abolishes hypophagia, activation of hypothalamic AKT pathway and changes in Cart and Npy mRNA expression in the ARC induced by insulin. Thus, the higher levels of insulin counter-regulatory proteins and lower expression of InsR in the hypothalamus are likely to underlie impaired insulin-induced hypophagia and responses in the hypothalamus after ADX.
Assuntos
Adrenalectomia/métodos , Ingestão de Alimentos/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Insulina/farmacologia , Animais , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Corticosterona/farmacologia , Expressão Gênica/efeitos dos fármacos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Hipotálamo/metabolismo , Injeções Intraventriculares , Insulina/administração & dosagem , Masculino , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Ratos Wistar , Receptor de Insulina/genética , Receptor de Insulina/metabolismoRESUMO
The involvement of sympathoadrenal axis activity in obesity onset was investigated using the experimental model of treating neonatal rats with monosodium L-glutamate. To access general sympathetic nervous system activity, we recorded the firing rates of sympathetic superior cervical ganglion nerves in animals. Catecholamine content and secretion from isolated adrenal medulla were measured. Intravenous glucose tolerance test was performed, and isolated pancreatic islets were stimulated with glucose and adrenergic agonists. The nerve firing rate of obese rats was decreased compared to the rate for lean rats. Basal catecholamine secretion decreased whereas catecholamine secretion induced by carbachol, elevated extracellular potassium, and caffeine in the isolated adrenal medulla were all increased in obese rats compared to control. Both glucose intolerance and hyperinsulinaemia were observed in obese rats. Adrenaline strongly inhibited glucose-induced insulin secretion in obese animals. These findings suggest that low sympathoadrenal activity contributes to impaired glycaemic control in prediabetic obese rats.
Assuntos
Medula Suprarrenal/fisiopatologia , Insulina/metabolismo , Obesidade/fisiopatologia , Estado Pré-Diabético/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Medula Suprarrenal/química , Medula Suprarrenal/efeitos dos fármacos , Animais , Glicemia/análise , Cafeína/farmacologia , Carbacol/farmacologia , Catecolaminas/análise , Catecolaminas/metabolismo , Teste de Tolerância a Glucose , Insulina/sangue , Secreção de Insulina , Masculino , Obesidade/induzido quimicamente , Ratos , Ratos Wistar , Glutamato de SódioRESUMO
Poisonings may have their consequences minimized by the acquisition of knowledge concerning its etiologies, evolutions and means of prevention. In Brazil, the progressive increase of toxic emergencies justifies the acquisition and analysis of regional and decentralized data concerning toxic emergencies. The aim of this retrospective and descriptive study was to evaluate data on the toxicology occurrence registered at the University Hospital/UFJF from 2000 to 2004. Data were collected using a structured instrument which comprised: age range, gender, profession, average hospitalization time, etiology and possible reasons for the intoxication, drug categories, where the patients live and the most important exposure route to the poisonous agent. The possible relationship among the data was also examined. The profile found for poisoning in the 50 cases analyzed, was that accidents are more common from 0 to 5 years old (24%) and male gender (68%), the majority of the cases happened in the city of Juiz de Fora (78%) and oral exposure. The most important poisonous agents were found to be the psychotropics (60%). Definition of a profile helps promoting educative activities and expands poisoning prevention campaigns by public health agencies. Therefore, these facts strengthen the importance of an Information Service net to prevent and reduce intoxications and the irrational use of drugs.
Assuntos
Intoxicação/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Hospitais Universitários , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Intoxicação/etiologia , Estudos Retrospectivos , Fatores de Tempo , Adulto JovemRESUMO
Intoxicações podem ter suas consequências minimizadas através da ampliação do conhecimento sobre suas origens, evoluções e providências quanto a medidas preventivas. No Brasil, o aumento progressivo das emergências tóxicas justifica a sua análise, de forma descentralizada e regionalizada. Este trabalho objetivou caracterizar dados sobre a ocorrência de intoxicações admitidas no Hospital Universitário/UFJF, entre 2000 e 2004. A coleta foi realizada mediante pesquisa em prontuários cadastrados no banco de dados do referido hospital. Os dados foram analisados através de estatística descritiva, permitindo estabelecer o perfil do grupo quanto às variáveis idade, sexo, local de origem do paciente, profissão, período de hospitalização, etiologia, razão da intoxicação, classe terapêutica de fármacos envolvidos e via de exposição ao agente toxicante. Crianças de zero a cinco anos e indivíduos do sexo masculino foram os mais acometidos, representando 24 por cento e 68 por cento, respectivamente. A maioria dos casos ocorreu em Juiz de Fora (78 por cento) e a via oral foi a mais frequente. Os psicotrópicos foram os principais agentes toxicantes (60 por cento). Os resultados evidenciaram a importância de atividades educativas dirigidas às comunidades e a relevância dos serviços de informação para prevenir e reduzir as intoxicações e o uso irracional de fármacos.
Poisonings may have their consequences minimized by the acquisition of knowledge concerning its etiologies, evolutions and means of prevention. In Brazil, the progressive increase of toxic emergencies justifies the acquisition and analysis of regional and decentralized data concerning toxic emergencies. The aim of this retrospective and descriptive study was to evaluate data on the toxicology occurrence registered at the University Hospital/UFJF from 2000 to 2004. Data were collected using a structured instrument which comprised: age range, gender, profession, average hospitalization time, etiology and possible reasons for the intoxication, drug categories, where the patients live and the most important exposure route to the poisonous agent. The possible relationship among the data was also examined. The profile found for poisoning in the 50 cases analyzed, was that accidents are more common from 0 to 5 years old (24 percent) and male gender (68 percent), the majority of the cases happened in the city of Juiz de Fora (78 percent) and oral exposure. The most important poisonous agents were found to be the psychotropics (60 percent). Definition of a profile helps promoting educative activities and expands poisoning prevention campaigns by public health agencies. Therefore, these facts strengthen the importance of an Information Service net to prevent and reduce intoxications and the irrational use of drugs.