Inhibition of hypothalamic Foxo 1 expression reduced food intake in diet-induced obesity rats J...
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Inhibition of hypothalamic Foxo 1 expression reduced food intake in diet-induced obesity rats
J Physiol 587.10 2341-2351, 2009
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Desequilíbrio entre ingestão alimentar e gasto energético
Obesidade
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Hipotálamo
Peptídios ingestão alimentar
Sinais neurais, metabólicos e humorais
Insulina e leptina inibem apetite
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Matsuzaki et al., 2003
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FOXO 1 hipotalâmica
importante regulador da ingestão alimentar e do balanço energético
transcrição de neuropeptídios orexigênicos: NPY e AgRP
Transcrição de POMC (anorexígeno)
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Objetivos
Verificar a contribuição da Foxo1 hipotalâmica na ingestão alimentar e no ganho de peso em ratos com obesidade induzida pela dieta (DIO)
Microinfusão icv de Foxo1-ASO no hipotálamo
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Métodos
Ratos Wistar machos de 4 semanas de idade
Controles: dieta padrãoDIO: dieta hiperlipídica por 8 semanas
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Parâmetros fisiológicos e metabólicos
TTI (1U/kg pc insulina) após 6 h de jejum Glicemia: 0, 4, 8, 12, 16 minvelocidade de desaparecimento da glicose plasmática
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Canulação intracerebroventricular Estereotaxia VL
Injeção de oligonucleotídios sense e antisense Foxo 1 (2x/dia) – 24, 48 e 72 h
Controle Sense Antisense (ASO)
Métodos
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Injeção icv salina ou insulina (10-6 M) após 6h de jejum
Ingestão alimentar
Métodos
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Métodos Análise de proteínas no hipotálamo por
WB
Extração nuclear para caracterizar a expressão e a localização subcelular de Foxo1 em hipotálamos de ratos tratados ou não com Foxo-ASO
WB com anti-CBP/p300 ou Foxo1
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A glicemia de jejum foi semelhante entre os grupos
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A insulina foi menos eficaz nos ratos DIO
31%
41%21%
14%
27%
63%
31%
41%
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50%85%
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Conclusão A microinfusão icv de insulina:
• reduziu a expressão de Foxo1 no hipotálamo de ratos controles, mas não em ratos DIO
• aumentou a fosforilação de Foxo 1 em extensão maior nos ratos controles que nos animais DIO
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Conclusão Os dados sugerem que a fosforilação e a degradação de
Foxo 1 hipotalâmica são requeridas para a indução de anorexia pela insulina
Três dias de tratamento com Foxo1-ASO reduziu a ingestão alimentar, o ganho de peso, a gordura epididimal e os níveis de insulina no jejum e aumentou a sensibilidade à insulina em animais DIO, mas não em controles
A resistência central à insulina diminuiu a fosforilação e a degradação da Foxo1 induzidas pela insulina
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Conclusão
Uma dieta hiperlipídica prejudicou a fosforilação hipotalâmica da Foxo1 e aumentou sua atividade nuclear, aumentando a resposta hiperfágica nos ratos
A manipulação farmacológica da Foxo1 poderia ser usada para prevenir ou tratar a obesidade