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|Title:||Activation of GPR40 induces hypothalamic neurogenesis through p38- and BDNF-dependent mechanisms|
|Author:||Engel, Daiane F.|
Bobbo, Vanessa C. D.
Solon, Carina S.
Nogueira, Guilherme A.
Mendes, Natalia F.
Zanesco, Ariane M.
Velloso, Licio A.
|Abstract:||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|
|Citation:||Daiane F. Engel received financial support from the São Paulo Research Foundation (FAPESP #2018/01360-4 and #2019/10961-4). The authors thank Erika Roman, Joseane Morari, Marcio Cruz and Gerson Ferraz for laboratory management. The study was supported by Grants from the São Paulo Research Foundation (2013/07607-8), Conselho Nacional de Pesquisa e Desenvolvimento Cientifico, and the Innovation Fund Denmark (ANFA, 5133-00007B). We thank the access to equipment and assistance provided by the National Institute of Science and Technology on Photonics Applied to Cell Biology (INFABIC) at the State University of Campinas; INFABIC is co-funded by São Paulo Research Foundation (FAPESP) (2014/50938-8) and Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq) (465699/2014-6)|
|Appears in Collections:||FCM - Artigos e Outros Documentos|
FCA - Artigos e Outros Documentos
FENF - Artigos e Outros Documentos
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