Changes in Leptin Signaling by SOCS3 Modulate Fasting-Induced Hyperphagia and Weight Regain in Mice

Autor(es)

Pedroso, Joao A. B. ; Silveira, Marina A. ; Lima, Leandro B. ; Furigo, Isadora C. ; Zampieri, Thais T. ; Ramos-Lobo, Angela M. ; Buonfiglio, Daniella C. ; Teixeira, Pryscila D. S. ; Frazao, Renata ; Donato, Jr., Jose

• Tipo de documento: Artigo Científico
• Fonte: Endocrinology; v. 157, n. 10, p. 3901-3914, OCT 2016.
• Citações Web of Science: 9

Resumo

Weight regain frequently follows interventions that reduce body weight, leading to a failure in long-term obesity treatment. Inhibitory proteins of the leptin signaling pathway, such as the suppressor of cytokine signaling 3 (SOCS3), have been studied in conditions that predispose animals to obesity. However, whether SOCS3 modulates postrestriction hyperphagia and weight regain remains unknown. Mice lacking SOCS3 protein specifically in leptin receptor (LepR)-expressing cells (LepR SOCS3 knockout {[}KO]) were generated and studied in fasting and refeeding conditions. LepR SOCS3 KO mice exhibited increased leptin sensitivity in the hypothalamus. Notably, LepR SOCS3 KO males and females showed attenuated food intake and weight regain after 48 hours of fasting. Postrestriction hyperleptinemia was also prevented in LepR SOCS3 KO mice. Next, we studied possible mechanisms and neural circuits involved in the SOCS3 effects. SOCS3 deletion did not prevent fasting-or refeeding-induced c-Fos expression in the arcuate nucleus of the hypothalamus (ARH) nor fasting-induced increased excitability of ARH LepR-expressing cells. On the other hand, SOCS3 ablation reduced the mRNA levels of hypothalamic orexigenic neuropeptides during fasting (neuropeptide Y, agouti-related protein, orexin, and melanin-concentrating hormone). In summary, our findings suggest that increased leptin sensitivity contributes to the maintenance of a reduced body weight after food deprivation. In addition, the attenuated postrestriction food intake observed in mutant mice was not explained by fasting-induced changes in the activity of ARH neurons but exclusively by a lower transcription of orexigenic neuropeptides during fasting. These results indicate a partial dissociation between the regulation of neuronal activity and gene expression in ARH LepR-expressing cells. (AU)

• Processo FAPESP: 13/25032-2 - O papel do SOCS3 no controle da hiperfagia, reganho de peso corporal e gliconeogênese após um período de restrição alimentar
• Beneficiário: João Alfredo Bolivar Pedroso
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 10/18086-0 - Bases moleculares da resistência à leptina
• Beneficiário: Jose Donato Junior
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 14/11752-6 - Estudo das funções da leptina durante o período intrauterino e infância no camundongo
• Beneficiário: Angela Maria Ramos Lobo
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 12/12202-4 - Modulação das propriedades biofísicas de neurônios Kiss1 por fatores circadianos
• Beneficiário: Renata Frazão
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 15/10992-6 - Estudo da programação metabólica por meio de diferentes abordagens
• Beneficiário: Jose Donato Junior
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/07908-8 - Puberdade precoce na obesidade infantil: possíveis mecanismos e influência da leptina
• Beneficiário: Renata Frazão
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 12/15517-6 - Fatores moleculares envolvidos nas alterações metabólicas durante a gestação: papel do SOCS3
• Beneficiário: Thais Tessari Zampieri
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 13/21722-4 - Estudo do mecanismo de ação da Bromocriptina e de antagonistas de prolactina no tratamento do Diabetes Mellitus tipo 2 e da Obesidade.
• Beneficiário: Isadora Clivatti Furigo
• Modalidade de apoio: Bolsas no Brasil - Doutorado