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SOCS3 Ablation in Leptin Receptor-Expressing Cells Causes Autonomic and Cardiac Dysfunctions in Middle-Aged Mice despite Improving Energy and Glucose Metabolism

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Autor(es):
Pedroso, Joao A. B. ; da Silva, Ivson B. ; Zampieri, Thais T. ; Totola, Leonardo T. ; Moreira, Thiago S. ; Taniguti, Ana P. T. ; Diniz, Gabriela P. ; Barreto-Chaves, Maria Luiza M. ; Donato, Jose, Jr.
Número total de Autores: 9
Tipo de documento: Artigo Científico
Fonte: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 23, n. 12, p. 19-pg., 2022-06-01.
Resumo

Leptin resistance is a hallmark of obesity. Treatments aiming to improve leptin sensitivity are considered a promising therapeutical approach against obesity. However, leptin receptor (LepR) signaling also modulates several neurovegetative aspects, such as the cardiovascular system and hepatic gluconeogenesis. Thus, we investigated the long-term consequences of increased leptin sensitivity, considering the potential beneficial and deleterious effects. To generate a mouse model with increased leptin sensitivity, the suppressor of cytokine signaling 3 (SOCS3) was ablated in LepR-expressing cells (LepR( increment SOCS3) mice). LepR( increment SOCS3) mice displayed reduced food intake, body adiposity and weight gain, as well as improved glucose tolerance and insulin sensitivity, and were protected against aging-induced leptin resistance. Surprisingly, a very high mortality rate was observed in aging LepR( increment SOCS3) mice. LepR( increment SOCS3) mice showed cardiomyocyte hypertrophy, increased myocardial fibrosis and reduced cardiovascular capacity. LepR( increment SOCS3) mice exhibited impaired post-ischemic cardiac functional recovery and middle-aged LepR( increment SOCS3) mice showed substantial arhythmic events during the post-ischemic reperfusion period. Finally, LepR( increment SOCS3) mice exhibited fasting-induced hypoglycemia and impaired counterregulatory response to glucopenia associated with reduced gluconeogenesis. In conclusion, although increased sensitivity to leptin improved the energy and glucose homeostasis of aging LepR( increment SOCS3) mice, major autonomic/neurovegetative dysfunctions compromised the health and longevity of these animals. Consequently, these potentially negative aspects need to be considered in the therapies that increase leptin sensitivity chronically. (AU)

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: 11/12893-4 - Papel do receptor de Angiotensina II do tipo 2 (AT2) no efeito cardioprotetor do Hormônio Tiroideano, em modelo de Isquemia/Reperfusão
Beneficiário:Ivson Bezerra da Silva
Modalidade de apoio: Bolsas no Brasil - Mestrado
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: 13/04703-6 - Sistema renina angiotensina subcelular como possível mediador do efeito cardioprotetor do hormônio tireoidiano no modelo de isquemia/reperfusão
Beneficiário:Ivson Bezerra da Silva
Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
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