Neurogenesis in the Hypothalamus of Adult Mice: Potential Role in Energy Balance

Kokoeva, Maia V.; Yin, Han; Flier, Jeffrey S.

doi:10.1126/science.1115360

Cited by 630 publications

(756 citation statements)

References 38 publications

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“…β2‐tanycytes have been proposed as a neural stem cell population (Lee et al, 2012) and express Fgf10 (Haan et al, 2013). This potentially influences the birth of new neurons that modulate hypothalamic control of energy balance (Kokoeva et al, 2005; Lee et al, 2012; McNay et al, 2012). …”

Section: Discussionmentioning

confidence: 99%

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

Stoney

Helfer

Rodrigues

et al. 2015

Glia

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Thyroid hormone (TH) is essential for adult brain function and its actions include several key roles in the hypothalamus. Although TH controls gene expression via specific TH receptors of the nuclear receptor class, surprisingly few genes have been demonstrated to be directly regulated by TH in the hypothalamus, or the adult brain as a whole. This study explored the rapid induction by TH of retinaldehyde dehydrogenase 1 (Raldh1), encoding a retinoic acid (RA)‐synthesizing enzyme, as a gene specifically expressed in hypothalamic tanycytes, cells that mediate a number of actions of TH in the hypothalamus. The resulting increase in RA may then regulate gene expression via the RA receptors, also of the nuclear receptor class. In vivo exposure of the rat to TH led to a significant and rapid increase in hypothalamic Raldh1 within 4 hours. That this may lead to an in vivo increase in RA is suggested by the later induction by TH of the RA‐responsive gene Cyp26b1. To explore the actions of RA in the hypothalamus as a potential mediator of TH control of gene regulation, an ex vivo hypothalamic rat slice culture method was developed in which the Raldh1‐expressing tanycytes were maintained. These slice cultures confirmed that TH did not act on genes regulating energy balance but could induce Raldh1. RA has the potential to upregulate expression of genes involved in growth and appetite, Ghrh and Agrp. This regulation is acutely sensitive to epigenetic changes, as has been shown for TH action in vivo. These results indicate that sequential triggering of two nuclear receptor signalling systems has the capability to mediate some of the functions of TH in the hypothalamus. GLIA 2016;64:425–439

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Section: Discussionmentioning

confidence: 99%

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

Stoney

Helfer

Rodrigues

et al. 2015

Glia

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“…8 Further support for the physiological relevance of hypothalamic neuronal plasticity has come from recent studies using a neuronal growth factor, ciliary neurotrophic factor (CNTF). 9 Kokoeva et al showed that in adult mice, centrally administered CNTF induced cell proliferation in feeding centers of the murine hypothalamus and elimination of cell proliferation by co-administration of a mitotic blocker was associated with a loss of the long-term, but not the short-term, effects of CNTF on body weight. 9 The neurotrophins are a family of growth factors known to be involved in the development, maintenance and function of peripheral and central neurones and may be hypothesized to play an important role in mediating neuronal plasticity in the hypothalamus.…”

Section: Introductionmentioning

confidence: 99%

“…9 Kokoeva et al showed that in adult mice, centrally administered CNTF induced cell proliferation in feeding centers of the murine hypothalamus and elimination of cell proliferation by co-administration of a mitotic blocker was associated with a loss of the long-term, but not the short-term, effects of CNTF on body weight. 9 The neurotrophins are a family of growth factors known to be involved in the development, maintenance and function of peripheral and central neurones and may be hypothesized to play an important role in mediating neuronal plasticity in the hypothalamus. The neurotrophin receptor TrkB and its natural ligand, brain-derived neurotrophic factor (BDNF), have been implicated in the regulation of food intake and body weight.…”

Section: Introductionmentioning

confidence: 99%

Functional characterization of human NTRK2 mutations identified in patients with severe early-onset obesity

et al. 2006

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Objective: The neurotrophin receptor TrkB has been implicated in the regulation of energy homeostasis in rodents. We have previously identified four rare missense mutations in the gene encoding TrkB, NTRK2, in 198 severely obese children with developmental delay. We have now undertaken a more detailed analysis of the in vitro functional consequences of the mutations identified: I98V, P660L, T821A and Y722C. Design: Wild-type and mutant TrkB receptor constructs were stably transfected into PC12 cells and the signaling responses to the endogenous ligand, brain-derived neurotrophic factor (BDNF), were examined by Western blotting of cell lysates. In the case of Y722C, PC12 cells stably expressing this mutant were studied for their ability to respond to BDNF by promoting neurite outgrowth and cell survival. Results: Further functional characterization of the previously reported Y722C TrkB mutation reveals impaired activation of mitogen-activated protein kinase, phospholipase C-g and Akt, as well as reduced BDNF-induced neurite outgrowth and cell survival in stably transfected PC12 cell lines. However, the signaling properties of I98V, P660L and T821A were all indistinguishable from wild type. Conclusion: We provide further evidence for the impairment in signaling by Y722C and show that as well as a loss of signaling, this mutation affects the ability of TrkB to promote neurite outgrowth in response to BDNF. Thus, impaired hypothalamic neurogenesis may contribute to the severe hyperphagia and obesity seen in the individual harboring the Y722C variant. The other three rare TrkB variants do not show reduced autophosphorylation or impaired downstream signaling in vitro and, as yet, it is unclear whether these variants contribute to obesity in these patients.

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“…Other reports indicate that LIF signaling supports the maintenance/ self-renewal of cultured mouse embryonic NSCs (Shimazaki et al, 2001;Pitman et al, 2004;Bonaguidi et al, 2005;Gregg and Weiss, 2005), possibly by activating Notch signaling (Chojnacki et al, 2003). However, little is known about the influence of LIF signaling on NSCs and neurogenesis in vivo: gp130 regulates cellcycle reentry of embryonic cortical progenitors (Hatta et al, 2002), and exogenous CNTF enhances neurogenesis in the adult brain (Emsley and Hagg, 2003;Kokoeva et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Leukemia Inhibitory Factor Promotes Neural Stem Cell Self-Renewal in the Adult Brain

Bauer¹,

Patterson²

2006

J. Neurosci.

212

164

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Although neural stem cells (NSCs) persist in various areas of the adult brain, their contribution to brain repair after injury is very limited. Treatment with exogenous growth factors can mitigate this limitation, suggesting that the brain environment is normally deficient in permissive cues and that it may be possible to stimulate the latent regenerative potential of endogenous progenitors with appropriate signals. We analyzed the effects of overexpressing the cytokine leukemia inhibitory factor (LIF) on adult neurogenesis in the normal brain. We found that LIF reduces neurogenesis in the olfactory bulb and subventricular zone by acting directly on NSCs. LIF appears to promote NSC self-renewal, preventing the emergence of more differentiated cell types. This ultimately leads to an expansion of the NSC pool. Our results have implications for the development of therapeutic strategies for brain repair and suggest that LIF may be useful, in combination with other factors, in promoting regeneration in the adult brain.

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Neurogenesis in the Hypothalamus of Adult Mice: Potential Role in Energy Balance

Cited by 630 publications

References 38 publications

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

Functional characterization of human NTRK2 mutations identified in patients with severe early-onset obesity

Leukemia Inhibitory Factor Promotes Neural Stem Cell Self-Renewal in the Adult Brain

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