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

• Published in: Scientific reports Vol. 10; no. 1; p. 11047
• Main Authors: Engel, Daiane F., Bobbo, Vanessa C. D., Solon, Carina S., Nogueira, Guilherme A., Moura-Assis, Alexandre, Mendes, Natalia F., Zanesco, Ariane M., Papangelis, Athanasios, Ulven, Trond, Velloso, Licio A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.07.2020; Nature Publishing Group
• Subjects: 631/378/368/2431; 631/45/882; Animals; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - physiology; Cell activation; Cell differentiation; Cell growth; Cell Line; Cell proliferation; Cell Proliferation - drug effects; Cell Proliferation - physiology; Cell survival; Cell Survival - drug effects; Cell Survival - physiology; Doublecortin protein; Energy balance; Fatty acids; Growth factors; Humanities and Social Sciences; Hypothalamus; Hypothalamus - cytology; Hypothalamus - drug effects; Hypothalamus - physiology; Imidazoles - pharmacology; Interleukin 6; Interleukin-6 - physiology; Ligands; Male; Methylamines - pharmacology; Mice; Mice, Inbred C57BL; Microtubule-associated protein 2; Models, Neurological; multidisciplinary; Neurogenesis; Neurogenesis - physiology; Neurons - drug effects; Neurons - physiology; Neurospheres; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - physiology; Propionates - pharmacology; Protein Kinase Inhibitors - pharmacology; Pyridines - pharmacology; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - physiology; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-68110-2

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.