Evaluation of Interleukin-6's ability to induce neurogenesis in the hypothalamus

The reestablishment of hypothalamic neuronal populations through neurogenesis has become a perspective for obesity control through mobilization of hypothalamic neural progenitor cells (NPCs). Evidence indicates that some cytokines may regulate the differentiation of NPCs in neurons. Interleukin 6 (IL-6) has several functions in the central nervous system, related to reduced apoptosis, neuronal differentiation and neuroprotection. However, there is no evidence of the influence of IL-6 on the proliferation and differentiation of hypothalamic NPCs. The aim of this work is to determine if IL-6 is able to act in stages of the process of hypothalamic neurogenesis (cell proliferation and / or differentiation). Murine models (Swiss albinus mice, IL-6 knockout mice (KOil6-/-), and C57BL6/J mice) were exposed to high fat diet, palmitate injections, and IL-6 injections in different times. In addition, cell cultures (strains and primary cultures) that were exposed to IL-6 at different times and concentrations were used. Tissues and cells were analyzed by real time polymerase chain reaction (qPCR) and immunofluorescence. Firstly, Swiss mice that ate a lower amount of high fat diet within 24 hours showed higher hypothalamic expression of Il-6 and Sox6 (neurogenic transcription factor). After one week of high fat diet, mice treated with intraperitoneal IL-6 showed lower food intake and weight gain. For mice challenged with central fatty acid injection, increased hypothalamic expression of Il6 was observed, followed by increased transcription factors Sox2 (proliferation-related), Sox6 and Ascl1 (expressed in neuronal progenitors). When treated with intraperitoneal IL-6, Swiss mice fed with chow diet showed hypothalamic increase of Il6, Sox2 and Sox6, as well as increased cell proliferation in arcuate nucleus. In the context of absence of IL-6, adult KOil6-/- mice showed higher weight, and reduced expression of proopiomelanocortin (Pomc) anorexigenic neuropeptide in the hypothalamus. In addition, one-week old KOil6-/- mice showed higher Gfap gene expression, astrocyte marker. In culture, neonatal KOil6-/- cells showed high proliferative ability, as well as anomalous expression of Pomc and the orexigenic neuropeptide Npy during differentiation. When treated with IL-6, KOil6-/- hypothalamic NPCs showed modulation of proliferation-related genes, and increased expression of doublecortin (Dcx) and NeuroD1. In addition, there was reduction of Pomc and Npy expression in IL-6 treated NPCs during differentiation. Our results suggest that IL-6 is related to weight gain control and expression of factors related to neurogenesis in the hypothalamus. The absence of IL-6 is related to differences in gene expression of neuropeptides and genes expressed in astrocytes and hypothalamic quiescent cells throughout development. Therefore, our data suggest that IL-6 induces neuronal differentiation by modulating the hypothalamic neurogenic niche (AU)