RESUMO
The hypothalamic neurocircuitry that regulates energy homeostasis in adult rats is not fully developed until the third postnatal week. In particular, fibers from the hypothalamic arcuate nucleus, including both neuropeptide Y (NPY) and alpha-MSH fibers, do not begin to innervate downstream hypothalamic targets until the second postnatal week. However, alpha-MSH fibers from the brainstem and melanocortin receptors are present in the hypothalamus at birth. The present study investigated the melanocortin system in the early postnatal period by examining effects of the melanocortin receptor agonist melanotan II (MTII) on body weight, energy expenditure, and hypothalamic NPY expression. Rat pups were injected ip with MTII (3 mg/kg body weight) or saline on postnatal day (P) 5 to P6, P10-P11, or P15-P16 at 1700 and 0900 h and then killed at 1300 h. Stomach weight and brown adipose tissue uncoupling protein 1 mRNA were determined. In addition, we assessed central c-Fos activation 90 min after MTII administration and hypothalamic NPY mRNA after twice daily MTII administration from P5-P10 or P10-P15. MTII induced hypothalamic c-Fos activation as well as attenuating body weight gain in rat pups. Stomach weight was significantly decreased and uncoupling protein 1 mRNA was increased at all ages, indicating decreased food intake and increased energy expenditure, respectively. However, MTII had no effect on NPY mRNA levels in any hypothalamic region. These findings demonstrate that MTII can inhibit food intake and stimulate energy expenditure before the full development of hypothalamic feeding neurocircuitry. These effects do not appear to be mediated by changes in NPY expression.
Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Canais Iônicos/genética , Proteínas Mitocondriais/genética , Peptídeos Cíclicos/farmacologia , Receptores da Corticotropina/metabolismo , alfa-MSH/análogos & derivados , Animais , Animais Lactentes , Relação Dose-Resposta a Droga , Feminino , Mucosa Gástrica/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/crescimento & desenvolvimento , Hipotálamo/metabolismo , Imuno-Histoquímica , Hibridização In Situ , Masculino , Neuropeptídeo Y/genética , Tamanho do Órgão/efeitos dos fármacos , Peptídeos Cíclicos/administração & dosagem , Proteínas Proto-Oncogênicas c-fos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptores da Corticotropina/agonistas , Estômago/efeitos dos fármacos , Estômago/crescimento & desenvolvimento , Proteína Desacopladora 1 , alfa-MSH/administração & dosagem , alfa-MSH/farmacologiaRESUMO
In adult mammals, the adipocyte-derived hormone leptin acts on the brain to reduce food intake by regulating the activity of neurons in the arcuate nucleus of the hypothalamus (ARH). Here, we report that neural projection pathways from the ARH are permanently disrupted in leptin-deficient (Lepob/Lepob) mice and leptin treatment in adulthood does not reverse these neuroanatomical defects. However, treatment of Lepob/Lepob neonates with exogenous leptin rescues the development of ARH projections, and leptin promotes neurite outgrowth from ARH neurons in vitro. These results suggest that leptin plays a neurotrophic role during the development of the hypothalamus and that this activity is restricted to a neonatal critical period that precedes leptin's acute regulation of food intake in adults.
Assuntos
Núcleo Arqueado do Hipotálamo/fisiologia , Axônios/fisiologia , Comportamento Alimentar , Hipotálamo/crescimento & desenvolvimento , Leptina/fisiologia , Neurônios/fisiologia , Proteína Relacionada com Agouti , Animais , Animais Recém-Nascidos , Núcleo Arqueado do Hipotálamo/citologia , Núcleo Arqueado do Hipotálamo/crescimento & desenvolvimento , Carbocianinas , Técnicas de Cultura , Núcleo Hipotalâmico Dorsomedial/citologia , Núcleo Hipotalâmico Dorsomedial/crescimento & desenvolvimento , Núcleo Hipotalâmico Dorsomedial/fisiologia , Ingestão de Alimentos , Região Hipotalâmica Lateral/citologia , Região Hipotalâmica Lateral/crescimento & desenvolvimento , Região Hipotalâmica Lateral/fisiologia , Hipotálamo/citologia , Hipotálamo/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular , Leptina/deficiência , Leptina/genética , Leptina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Fibras Nervosas/fisiologia , Neuritos/fisiologia , Núcleo Hipotalâmico Paraventricular/citologia , Núcleo Hipotalâmico Paraventricular/crescimento & desenvolvimento , Núcleo Hipotalâmico Paraventricular/fisiologia , Proteínas/análise , Proteínas Recombinantes/farmacologia , Transdução de Sinais , alfa-MSH/análiseRESUMO
The arcuate nucleus of the hypothalamus (ARH) is a critical component of forebrain pathways that regulate a variety of neuroendocrine functions, including an important role in relaying leptin signals to other parts of the hypothalamus. However, neonatal rodents do not lose weight in response to leptin treatment in the same way as do adults, suggesting that certain aspects of leptin signaling pathways in the hypothalamus may not be mature. We tested this possibility by using DiI axonal labeling to examine the development of projections from the ARH to other parts of the hypothalamus in neonatal mice, paying particular attention to the innervation of the paraventricular nucleus (PVH), the dorsomedial nucleus (DMH), and the lateral hypothalamic area (LHA), each of which have been implicated in the regulation of feeding. The results indicate that ARH projections are quite immature at birth and appear to innervate the DMH, PVH, and LHA in succession, within distinct temporal domains. The projections from the ARH to the DMH develop rapidly and are established by the sixth postnatal day (P6), whereas those to the PVH develop significantly later, with the mature pattern of innervation first apparent between postnatal day 8 (P8)-P10. Furthermore, the ability of leptin to activate Fos in the PVH, DMH, and LHA appears to be age-dependent and correlates with the arrival of ARH projections to each nucleus. Taken together, these findings provide new insight into development of hypothalamic circuits and suggest an anatomical basis for the delayed postnatal regulation of food intake and body weight by leptin.