Papel do receptor adrenérgico β3 na obesidade induzida pela dieta
Data
2013-10-30
Autores
Preite, Nailliw Zanini 
Orientadores
Ribeiro, Miriam Oliveira
Tipo
Dissertação de mestrado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
A obesidade é um distúrbio caracterizado pelo acúmulo excessivo de gordura corporal, podendo ser consequência de um aumento na ingestão calórica ou de defeitos no gasto energético, e está diretamente relacionada ao desenvolvimento da síndrome metabólica. O principal sítio de termogênese facultativa, mecanismo envolvido no aumento do gasto energético durante exposição ao frio ou a uma maior ingestão calórica, é o tecido adiposo marrom (BAT). O BAT é ativado pelo sistema nervoso simpático através da liberação de noradrenalina (NA), que se liga aos receptores adrenérgicos β1, β2 e β3, expressos neste tecido. A importância dos receptores β na termogênese do BAT fica clara quando estudamos animais com nocaute para suas três isoformas: são obesos e sensíveis ao frio. Dessa forma, a compreensão dos mecanismos envolvidos na termogênese facultativa constitui uma esperança no tratamento da obesidade. Entretanto, a função isolada da isoforma β3 nesse processo ainda não é clara e, portanto, o objetivo deste trabalho foi avaliar o papel do receptor β3 na obesidade induzida pela dieta. Para tanto, camundongos selvagens FVB e camundongos com nocaute para o receptor adrenérgico β3 (KOβ3) foram tratados com dieta rica em gordura (40%) por 8 semanas, e tiveram seu consumo alimentar e peso corporal medidos diariamente. Ao final do protocolo, foram determinados os níveis séricos de glicose, colesterol e triglicérides destes animais. Foi medida a expressão da UCP1 no BAT por western blot e a expressão gênica de enzimas relacionados ao metabolismo lipídico através de PCR em tempo real. Também foi realizada avaliação histológica do tecido adiposo branco (WAT) e do fígado dos animais. Outro grupo de camundongos teve sua sensibilidade ao frio e a resposta termogênica do BAT mediante infusão aguda de NA, avaliadas. Os resultados obtidos mostraram que o receptor adrenérgico β3 apresenta papel fundamental na regulação do peso corporal, uma vez que animais KOβ3 alimentados com dieta rica em gordura apresentaram obesidade significativamente mais severa do que animais controle, dislipidemia e hipertrofia dos adipócitos brancos com infiltração de leucócitos. No entanto, surpreendentemente, esses animais não apresentaram sensibilidade ao frio e seu BAT estava termogenicamente ativo, sugerindo que a termogênese facultativa estava intacta e que a obesidade observada nesses animais não foi resultado de defeitos no gasto energético. Por isso, foi investigado o processo de lipólise no WAT dos animais FVB e KOβ3, estimulando adipócitos isolados com isoproterenol, e foi possível observar que a lipólise estava sensivelmente reduzida nos animais KOβ3. Em conclusão, este estudo mostrou que o receptor adrenérgico β3 não é fundamental para a termogênese facultativa, mas é chave para o processo de lipólise no WAT.
Obesity is a disorder characterized by excessive accumulation of body fat, which may be result of an increase in caloric intake or of defects in energy expenditure and is directly related to the development of metabolic syndrome. The main site of facultative thermogenesis, mechanism involved in increased of energy expenditure during cold exposure or during a higher caloric intake is the brown adipose tissue (BAT). BAT is activated by the sympathetic nervous system through the release of norepinephrine (NE), which binds to adrenergic receptors β1, β2 e β3, expressed in this tissue. The importance of β receptors in BAT's thermogenesis becomes clear when we study animals with knockout to its three isoforms: They are obese and coldsensitive. In this way, understanding the mechanisms involved in facultative thermogenesis represents a hope in the treatment of obesity. However, the isolated function of β3 isoform in this process is still unclear and, therefore, the purpose of this study was to evaluate the role of receptor β3 in diet-induced obesity. For that, wildtype FVB mice and knockout for β3 adrenergic receptor mice (KOβ3) were treated with high fat diet (40%) for 8 weeks, and had their food intake and body weight measured daily. At the end of the protocol, the serum levels of glucose, cholesterol and triglycerides of these animals were determined. After that, were measured the expression of UCP1 in BAT by western blot, and gene expression of enzymes related to lipid metabolism through real time PCR. The histological evaluation of white adipose tissue (WAT) and liver was also performed. Another group of mice had its sensitivity to cold and thermogenic response of BAT by acute infusion of NE evaluated. The results showed the β3 adrenergic receptor plays a fundamental role in the regulation of body weight, once KOβ3 animals fed with high-fat diet presented obesity significantly more severe than control animals, dyslipidemia and hypertrophy of white adipocytes with infiltration of leukocytes. However, surprisingly, these animals did not exhibit sensitivity to cold and their BAT was thermogenically active, suggesting that facultative thermogenesis was intact and the obesity observed in these animals was not due of defects in energy expenditure. For this reason, lipolysis in WAT of FVB and KOβ3 animals was investigated stimulating isolated adipocytes with isoproterenol, and was possible to observe that lipolysis was significantly reduced in KOβ3 animals. In conclusion, this study showed that β3 adrenergic receptor is not essential for the facultative thermogenesis, but is the key for the lipolysis in WAT.
Obesity is a disorder characterized by excessive accumulation of body fat, which may be result of an increase in caloric intake or of defects in energy expenditure and is directly related to the development of metabolic syndrome. The main site of facultative thermogenesis, mechanism involved in increased of energy expenditure during cold exposure or during a higher caloric intake is the brown adipose tissue (BAT). BAT is activated by the sympathetic nervous system through the release of norepinephrine (NE), which binds to adrenergic receptors β1, β2 e β3, expressed in this tissue. The importance of β receptors in BAT's thermogenesis becomes clear when we study animals with knockout to its three isoforms: They are obese and coldsensitive. In this way, understanding the mechanisms involved in facultative thermogenesis represents a hope in the treatment of obesity. However, the isolated function of β3 isoform in this process is still unclear and, therefore, the purpose of this study was to evaluate the role of receptor β3 in diet-induced obesity. For that, wildtype FVB mice and knockout for β3 adrenergic receptor mice (KOβ3) were treated with high fat diet (40%) for 8 weeks, and had their food intake and body weight measured daily. At the end of the protocol, the serum levels of glucose, cholesterol and triglycerides of these animals were determined. After that, were measured the expression of UCP1 in BAT by western blot, and gene expression of enzymes related to lipid metabolism through real time PCR. The histological evaluation of white adipose tissue (WAT) and liver was also performed. Another group of mice had its sensitivity to cold and thermogenic response of BAT by acute infusion of NE evaluated. The results showed the β3 adrenergic receptor plays a fundamental role in the regulation of body weight, once KOβ3 animals fed with high-fat diet presented obesity significantly more severe than control animals, dyslipidemia and hypertrophy of white adipocytes with infiltration of leukocytes. However, surprisingly, these animals did not exhibit sensitivity to cold and their BAT was thermogenically active, suggesting that facultative thermogenesis was intact and the obesity observed in these animals was not due of defects in energy expenditure. For this reason, lipolysis in WAT of FVB and KOβ3 animals was investigated stimulating isolated adipocytes with isoproterenol, and was possible to observe that lipolysis was significantly reduced in KOβ3 animals. In conclusion, this study showed that β3 adrenergic receptor is not essential for the facultative thermogenesis, but is the key for the lipolysis in WAT.
Descrição
Citação
PREITE, Nailliw Zanini. Papel do receptor adrenérgico β3 na obesidade induzida pela dieta. São Paulo, 2013. 82 f. Dissertação (Mestrado em Medicina Translacional) – Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, 2013.