Tanycytes as gatekeepers of the Metabolic Brain
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1 Tanycytes as gatekeepers of the Metabolic Brain Vincent Prevot Inserm team Development and Plasticity of the Postnatal Brain Jean-Pierre Aubert Research Centre, U837, Lille France
2 Metabolic signals and energy homeostasis CNS: hypothalamus Ghrelin Leptin Stomach Adipocytes
3 Metabolic signals and energy homeostasis P12 Reduce/promote food intake Increase energy expenditure P12 NPY/AgRP POMC/CART Ghrelin Leptin Stomach Adipocytes
4 Do circulating metabolic signals have direct access to the arcuate nucleus of the hypothalamus (ARH)? DMH VMH ARH Circulating metabolic signals Tanycytic processes 3V Median Eminence
5 Do circulating metabolic signals have direct access to the arcuate nucleus of the hypothalamus (ARH)? DMH VMH ARH Circulating metabolic signals Tanycytic processes 3V Tight junctions Median Eminence
6 Do circulating metabolic signals have direct access to the arcuate nucleus of the hypothalamus (ARH)? DMH VMH ARH Circulating metabolic signals Tanycytic processes Fenestrated blood vessels 3V Tight junctions Median Eminence
7 Do circulating metabolic signals have direct access to the arcuate nucleus of the hypothalamus (ARH)? Nerve Terminal DMH Endothelial cell nucleus VMH ARH 3V Tight junctions Tanycytic processes Fenestrated blood vessels Median Eminence
8 Median eminence fenestrated capillaries are permeable to circulating metabolic signals Nerve Terminal Endothelial cell nucleus Schaeffer et al, PNAS 110: , 2013
9 Median eminence fenestrated capillaries are permeable to circulating metabolic signals, however, Intravenous infusion of an inert dye e.g., Evans blue (1 kda) DMH VMH Tight junctions ARH 3V Median Eminence Fenestrated blood vessels
10 Median eminence fenestrated capillaries are permeable to circulating metabolic signals, however, their diffusion appears to be restricted to the median eminence Intravenous infusion of an inert dye e.g., Evans blue (1 kda) DMH VMH ARH 3V Median Eminence Mullier et al, J Comp Neurol 518:943, 2010
11 Does nutritional status regulate this blood-hypothalamus barrier composed of tanycytes and fenestrated endothelial cells?
12 Fasting induces Plasticity of the Blood-Hypothalamus Barrier Langlet et al., Cell Metab, 17: , 2013
13 Fasting induces Plasticity of the Blood-Hypothalamus Barrier Langlet et al., Cell Metab, 17: , 2013
14 Glucose deprivation mediates Fasting-induced Plasticity at the Blood- Hypothalamus Barrier Fenestrated vessels in the ARH Organized tight junctions in ARH tanycytes Langlet et al., Cell Metab, 17: , 2013
15 Fasting and Glucoprivation require VEGF Signaling to promote Plasticity at the Blood-Hypothalamus Barrier Langlet et al., Cell Metab, 17: , 2013
16 Fasting requires VEGF-A expression in tanycytes to promote Plasticity at the Blood-Hypothalamus Barrier Fenestrated vessels in the ARH Organized tight junctions in ARH tanycytes Langlet et al., Cell Metab, 17: , 2013
17 Do Tanycytes, which were recently shown to be Glucosensing Cells play a dynamic role in Fasting-induced Brain-Hypothalamus Barrier Plasticity? Bolborea and Dale, TINS, 36:91-100, 2012
18 TAT-Cre recombinant protein infusion into the third ventricle selectively targets tanycytes tat-cre intracerebrobentricular infusion in tdtomato loxp/+ mice Langlet et al., Cell Metab, 17: , 2013
19 Real time-pcr analysis of gene expression in tanycytes in vivo Langlet et al., Cell Metab, 17: , 2013
20 Fasting promotes VEGF-A expression in tanycytes Langlet et al., Cell Metab, 17: , 2013
21 Fasting-induced Blood-Hypothalamus Barrier Plasticity Requires Tanycytic VEGF-A expression Fenestrated vessels in the ARH Organized tight junctions in ARH tanycytes Langlet et al., Cell Metab, 17: , 2013
22 Blood-Hypothalamus Barrier Plasticity Modulates Access of Blood-Borne Factors to the ventromedial Arcuate Nucleus (vmarh) Intravenous injection of Evans blue Langlet et al., Cell Metab, 17: , 2013
23 Blood-Hypothalamus Barrier Plasticity Modulates Access of Blood-Borne metabolic Factors to the ventromedial Arcuate Nucleus (vmarh) Intravenous injection of fluorescently labeled grhelin Control Fasting Refeeding Schaeffer et al, PNAS 110: , 2013
24 Blood-Hypothalamus Barrier Plasticity Modulates Feeding Langlet et al., Cell Metab, 17: , 2013
25 Conclusion Fasting induces the plasticity of brain barriers in hypothalamic feeding regions Central neuroglucopenia triggers bloodhypothalamus barrier plasticity Fasting-induced brain barrier plasticity requires VEGF-A expression in tanycytes The tanycytic barrier modulates bloodborne signals access to CNS feeding circuits Mullier et al, J Comp Neurol 518:943, 2010 Langlet et al., Cell Metab, 17: , 2013 Schaeffer et al, PNAS 110: , 2013
26 Acknowledgments Fanny Langlet Bénédicte Dehouck Collaborators Cisbio Bioassays - Eric Trinquet IGF, Montpellier - Patrice Mollard - Marie Schaeffer VIB, Leuven, Belgium -Massimiliano Mazzone - Peter Carmeliet
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