Nevertheless, under certain types of stimuli, hypothalamic neurogenesis can increase substantially and impact whole body energy homeostasis 9, 12, 17. Physiological adult hypothalamic neurogenesis occurs at a much lower rate than neurogenesis in the subventricular and subgranular zones, the most important anatomical sources of newborn neurons in adulthood 18. However, upon long-lasting exposure to the damaging effects of obesity and aging, neuronal loss may be reverted only by the generation of new neurons 16, 17. If neuronal loss is prevented by modifications in the diet or inhibition of hypothalamic inflammation, whole body energy homeostasis is restored 8, 15. This phenomenon generates an imbalance in neuronal orexigenic and anorexigenic subpopulations and further contributes to the progression of increased adiposity and metabolic complications 10– 15. In aging and obesity, hypothalamic neurons are damaged by inflammation they undergo abnormal function and eventually apoptosis 10– 15. ![]() However, a number of environmental and genetic factors can affect the function and viability of hypothalamic neurons, changes that result in abnormal regulation of body mass 6– 9. They are responsive to hormones, neural signals, and nutrients that indicate the energy stores in the body as long as orexigenic and anorexigenic responses are preserved, body mass stability is sustained over time 3– 5. Neurons of the mediobasal hypothalamus play central roles in the homeostatic control of food intake and energy expenditure 1, 2. This study provides mechanistic advance in the understating of how a fatty acid receptor regulates adult hypothalamic neurogenesis. Thus, GPR40 acts through p38 and BDNF to induce hypothalamic neurogenesis. 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. In Neuro-2a proliferative cell-line GPR40 activation increased BDNF expression and p38 activation. 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. We show that a GPR40 ligand increased hypothalamic cell proliferation and survival in adult mice. 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. 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. Hypothalamic adult neurogenesis provides the basis for renewal of neurons involved in the regulation of whole-body energy status.
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