Activation of GPR40 induces hypothalamic neurogenesis through p38-and BDNF-dependent mechanisms

Autor(es)

Engel, Daiane F. ^{[1, 2]} ; Bobbo, Vanessa C. D. ^{[1, 2]} ; Solon, Carina S. ^{[1, 2]} ; Nogueira, Guilherme A. ^{[1, 2]} ; Moura-Assis, Alexandre ^{[1, 2]} ; Mendes, Natalia F. ^{[1, 2]} ; Zanesco, Ariane M. ^{[1, 2]} ; Papangelis, Athanasios ^[3] ; Ulven, Trond ^[3] ; Velloso, Licio A. ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Lab Cell Signaling, BR-13084970 Campinas, SP - Brazil

^[2] Univ Estadual Campinas, Obes & Comorbid Res Ctr, BR-13084970 Campinas, SP - Brazil

^[3] Univ Copenhagen, Dept Drug Design & Pharmacol, DK-2100 Copenhagen - Denmark

• Tipo de documento: Artigo Científico
• Fonte: SCIENTIFIC REPORTS; v. 10, n. 1 JUL 6 2020.
• Citações Web of Science: 0

Resumo

Hypothalamic adult neurogenesis provides the basis for renewal of neurons involved in the regulation of whole-body energy status. In addition to hormones, cytokines and growth factors, components of the diet, particularly fatty acids, have been shown to stimulate hypothalamic neurogenesis; however, the mechanisms behind this action are unknown. Here, we hypothesized that GPR40 (FFAR1), the receptor for medium and long chain unsaturated fatty acids, could mediate at least part of the neurogenic activity in the hypothalamus. We show that a GPR40 ligand increased hypothalamic cell proliferation and survival in adult mice. In postnatal generated neurospheres, acting in synergy with brain-derived neurotrophic factor (BDNF) and interleukin 6, GPR40 activation increased the expression of doublecortin during the early differentiation phase and of the mature neuronal marker, microtubule-associated protein 2 (MAP2), during the late differentiation phase. In Neuro-2a proliferative cell-line GPR40 activation increased BDNF expression and p38 activation. The chemical inhibition of p38 abolished GPR40 effect in inducing neurogenesis markers in neurospheres, whereas BDNF immunoneutralization inhibited GPR40-induced cell proliferation in the hypothalamus of adult mice. Thus, GPR40 acts through p38 and BDNF to induce hypothalamic neurogenesis. This study provides mechanistic advance in the understating of how a fatty acid receptor regulates adult hypothalamic neurogenesis. (AU)

• Processo FAPESP: 13/07607-8 - CMPO - Centro Multidisciplinar de Pesquisa em Obesidade e Doenças Associadas
• Beneficiário: Licio Augusto Velloso
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 14/50938-8 - INCT 2014: em Fotônica Aplicada à Biologia Celular INFABiC
• Beneficiário: Hernandes Faustino de Carvalho
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 18/01360-4 - Caracterização do papel do receptor GPR40 na modulação de precursores de neurônios POMC no hipotálamo adulto e sua influência no controle da homeostase energética
• Beneficiário: Daiane Fátima Engel
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 19/10961-4 - Estudo dos mecanismos envolvidos na modulac'ao da neuroplasticidade hipotalamica pelo receptor GPR40: potencial papel na neurogenese adulta
• Beneficiário: Daiane Fátima Engel
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado