BackgroundProgrammed cell death (PCD) plays essential roles in the regulation of survival and function of neural stem cells (NSCs). Abnormal regulation of this process is associated with developmental and degenerative neuronal disorders. However, the mechanisms underlying the PCD of NSCs remain largely unknown. Understanding the mechanisms of PCD in NSCs is crucial for exploring therapeutic strategies for the treatment of neurodegenerative diseases.ResultWe have previously reported that adult rat hippocampal neural stem (HCN) cells undergo autophagic cell death (ACD) following insulin withdrawal without apoptotic signs despite their normal apoptotic capabilities. It is unknown how interconnection between ACD and apoptosis is mediated in HCN cells. Valosin-containing protein (VCP) is known to be essential for autophagosome maturation in mammalian cells. VCP is abundantly expressed in HCN cells compared to hippocampal tissue and neurons. Pharmacological and genetic inhibition of VCP at basal state in the presence of insulin modestly impaired autophagic flux, consistent with its known role in autophagosome maturation. Of note, VCP inaction in insulin-deprived HCN cells significantly decreased ACD and down-regulated autophagy initiation signals with robust induction of apoptosis. Overall autophagy level was also substantially reduced, suggesting the novel roles of VCP at initial step of autophagy.ConclusionTaken together, these data demonstrate that VCP may play an essential role in the initiation of autophagy and mediation of crosstalk between ACD and apoptosis in HCN cells when autophagy level is high upon insulin withdrawal. This is the first report on the role of VCP in regulation of NSC cell death. Elucidating the mechanism by which VCP regulates the crosstalk of ACD and apoptosis will contribute to understanding the molecular mechanism of PCD in NSCs.
BackgroundInsulin plays diverse roles in the brain. Although insulin produced by pancreatic β-cells that crosses the blood–brain barrier is a major source of brain insulin, recent studies suggest that insulin is also produced locally within the brain. However, the mechanisms underlying the production of brain-derived insulin (BDI) are not yet known.ResultsHere, we examined the effect of Wnt3a on BDI production in a hypothalamic cell line and hypothalamic tissue. In N39 hypothalamic cells, Wnt3a treatment significantly increased the expression of the Ins2 gene, which encodes the insulin isoform predominant in the mouse brain, by activating Wnt/β-catenin signaling. The concentration of insulin was higher in culture medium of Wnt3a-treated cells than in that of untreated cells. Interestingly, neurogenic differentiation 1 (NeuroD1), a target of Wnt/β-catenin signaling and one of transcription factors for insulin, was also induced by Wnt3a treatment in a time- and dose-dependent manner. In addition, the treatment of BIO, a GSK3 inhibitor, also increased the expression of Ins2 and NeuroD1. Knockdown of NeuroD1 by lentiviral shRNAs reduced the basal expression of Ins2 and suppressed Wnt3a-induced Ins2 expression. To confirm the Wnt3a-induced increase in Ins2 expression in vivo, Wnt3a was injected into the hypothalamus of mice. Wnt3a increased the expression of NeuroD1 and Ins2 in the hypothalamus in a manner similar to that observed in vitro.ConclusionTaken together, these results suggest that BDI production is regulated by the Wnt/β-catenin/NeuroD1 pathway in the hypothalamus. Our findings will help to unravel the regulation of BDI production in the hypothalamus.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0207-5) contains supplementary material, which is available to authorized users.
Evidence has mounted that insulin can be synthesized in various brain regions, including the hypothalamus. However, the distribution and functions of insulin-expressing cells in the hypothalamus remain elusive. Herein, we show that in the mouse hypothalamus, the perikarya of insulin-positive neurons are located in the paraventricular nucleus (PVN) and their axons project to the median eminence; these findings define parvocellular neurosecretory PVN insulin neurons. Contrary to corticotropin-releasing hormone expression, insulin expression in the PVN was inhibited by restraint stress (RS) in both adult and young mice. Acute RS–induced inhibition of PVN insulin expression in adult mice decreased both pituitary growth hormone ( Gh ) mRNA level and serum GH concentration, which were attenuated by overexpression of PVN insulin. Notably, PVN insulin knockdown or chronic RS in young mice hindered normal growth via the downregulation of GH gene expression and secretion, whereas PVN insulin overexpression in young mice prevented chronic RS–induced growth retardation by elevating GH production. Our results suggest that in both normal and stressful conditions, insulin synthesized in the parvocellular PVN neurons plays an important role in the regulation of pituitary GH production and body length, unveiling a physiological function of brain-derived insulin.
Fibroblast growth factor 11 (FGF11) is a member of the intracellular fibroblast growth factor family. Here, we report the central role of FGF11 in the regulation of metabolism. Lentiviral injection of Fgf11 shRNA into the arcuate nucleus of the mouse hypothalamus decreased weight gain and fat mass, increased brown adipose tissue thermogenesis, and improved glucose and insulin intolerances under high-fat diet conditions. Fgf11 was expressed in the NPY–expressing neurons, and Fgf11 knockdown considerably decreased Npy expression and projection, leading to increased expression of tyrosine hydroxylase in the paraventricular nucleus. Mechanistically, FGF11 regulated Npy gene expression through the glycogen synthase kinase 3–cAMP response element-binding protein pathway. Our study defines the physiological significance of hypothalamic FGF11 in the regulation of metabolism in response to overnutrition such as high-fat diet.
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