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

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.

• 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