Perspectives of “PUFA-GPR40 Signaling” Crucial for Adult Hippocampal Neurogenesis

Abstract

Both cognitive functions and mental health are known to be influenced by diet, although the underlying mechanisms are not well understood. However, there is a consensus that the brain responds to changes in the fatty acid composition of diet, and that simultaneous changes in neural membrane components occur to affect membrane fluidity, gene expression and neuronal functions. For polyunsaturated fatty acids (PUFA), various functions in the neurons have been proposed such as lipid storage, membrane synthesis, b-oxidation, enzyme activity and transcription programs. PUFA have recently emerged as a new class of modulator for the synaptic transmission and plasticity in the brain. As chaperones, fatty acid binding proteins (FABP) facilitate the transport of PUFA to specific compartments in the neurons. Both PUFA and FABP are nowadays known to be major regulators of adult neurogenesis, and circumstantial evidence implicates adult hippocampal neurogenesis in learning, memory and emotions. The survival of newborn neurons is increased by enriched environment and hippocampus-dependent stimuli. The key molecule that can explain synergistic effects of PUFA and stimuli should be brainderived neurotrophic factor (BDNF), because this molecule is synthesized predominantly in hippocampal neurons for the structural remodeling and synaptic plasticity. In response to exercise, dietary energy restriction, or cognitive stimulation, levels of BDNF are increased in the hippocampus to promote adult neurogenesis. The recent discovery that newborn neurons and glia in the primate hippocampus express the free fatty acid-receptor, G protein-coupled receptor 40 (GPR40), was a minor breakthrough in the research on adult neurogenesis, because PUFA-GPR40 binding can lead to BDNF production via activations of cAMP-response element binding protein (CREB). CREB-dependent gene expression is crucial for a variety of neuronal functions such as learning, memory and emotions through BDNF synthesis. GPR40 may be one of the candidates explaining the effects of PUFA upon neuronal