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Doctoral Thesis
DOI
10.11606/T.42.2017.tde-16052017-142324
Document
Author
Full name
João Alfredo Bolivar Pedroso
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2016
Supervisor
Committee
Donato Júnior, José (President)
Festuccia, William Tadeu Lara
Mori, Marcelo Alves da Silva
Ropelle, Eduardo Rochete
Silva, Francemilson Goulart da
Title in Portuguese
O efeito da deleção do SOCS3 em células responsivas à leptina em diferentes condições experimentais.
Keywords in Portuguese
Emagrecimento
Gliconeogênese
Leptina
Obesidade
Abstract in Portuguese
O Objetivo do presente trabalho foi investigar os efeitos do aumento da sensibilidade à leptina sobre a ingestão alimentar, o balanço energético e modulação da homeostase glicêmica. Para tanto, camundongos com deleção do gene SOCS3 em células que expressam o receptor de leptina (LepR SOCS3 KO) foram submetidos, iniciamente, à obesidade induzida pela dieta. Observamos que a deleção condicional do SOCS3 não foi capaz de prevenir o ganho de peso induzido pela dieta, mas aumentou a sensibilidade à ação da insulina. A seguir, acompanhamos outro grupo de animais a restrição alimentar e, na sequencia, a hiperfagia e peso corporal. Constatamos que a ausência do SOCS3 em células responsivas à leptina promoveu redução da hiperfagia alimentar e menor ganho de peso no período de realimentação; no entanto, foi observado comprometimento nos mecanismos de controle da glicemia durante o período de restrição alimentar, particularmente, através da modulação no sistema nervoso simpático. Nossos resultados ajudam os efeitos metabólicos da leptina em diferentes condições fisiológicas. Por fim, nossos dados apontam possíveis efeitos colaterais de futuras estratégias que visam aumentar a sensibilidade à leptina como alternativa para o tratamento da obesidade.
Title in English
The effect of SOCS3 deletion from leptin responsive cells in different experimental conditions.
Keywords in English
Gluconeogenesis
Leptin
Obesity
Abstract in English
The objective of this study was to investigate the effects of leptin sensitivity on food intake, energy balance and modulation of glycemic homeostasis. We produced mice lacking SOCS3 only in leptin receptor-expressing cells (LepR SOCS3 KO mice). Mice received high-fat diet to induce obesity. Inactivation of SOCS3 only in LepR-expressing cells protected against leptin resistance induced by diet-induced obesity (DIO), but did not prevent weight gain. However, LepR SOCS3 KO mice were protected from insulin resistance induced by DIO. Next, another group of animals were subjected to a 48 hours fasting, followed by refeeding. LepR SOCS3 KO mice showed attenuated food intake and weight regain after a 48 h fasting. Post-restriction hyperleptinemia was also prevented in LepR SOCS3 KO mice. Remarkably, LepR SOCS3 KO mice showed impaired glucose control during fasting, leading to hypoglycemia. To investigate the mechanisms of action, we showed that increased leptin sensibility modulates the sympathetic nervous system and can be harmful to glucose homeostasis during fasting. In conclusion, our results help to understand the effects of leptin to prevent obesity, but also highlight possible side effects from strategies that increase leptin sensitivity.
 
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Release Date
2019-05-16
Publishing Date
2017-05-16
 
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