The nutrient sensor OGT in PVN neurons regulates feeding

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The nutrient sensor OGT in PVN neurons regulates feeding by Olof Lagerlöf, Julia E. Slocomb, Ingie Hong, Yeka Aponte, Seth Blackshaw, Gerald W. Hart, and Richard L. Huganir Science Volume 351(6279):1293-1296 March 18, 2016 Published by AAAS

Fig. 1 Acute deletion of OGT in αCaMKII-positive neurons causes hyperphagia-dependent obesity. Acute deletion of OGT in αCaMKII-positive neurons causes hyperphagia-dependent obesity. (A) Photo of mice 4 weeks after OGT deletion. (B) Body weight time course [n = 8 WT mice, n = 8 OGT knockout mice; repeated-measures two-way analysis of variance (ANOVA) with post hoc Bonferroni test, P < 0.05]. (C) Daily food intake time course (n = 6 WT mice, n = 6 OGT knockout mice; repeated-measures two-way ANOVA with post hoc Bonferroni test, P < 0.05). (D) Body weight time course upon pair-feeding (n = 4 free mice, n = 4 restricted mice, n = 3 WT mice). (E) Food intake every 15 min from sample mice. Quantifications represent mean ± SEM. Olof Lagerlöf et al. Science 2016;351:1293-1296 Published by AAAS

Fig. 2 OGT-mediated hyperphagia is associated with feeding circuitry function in the PVN. OGT-mediated hyperphagia is associated with feeding circuitry function in the PVN. (A) αCaMKII expression within feeding circuitry (schematized from fig. S5A). (B) TRH expression. (Left) Image of probe staining. (Right) Quantification (n = 4 WT mice, n = 4 OGT knockout mice; two-tailed t test: P < 0.05). (C) (Left) GFP and O-GlcNAc in the PVN. (Right) Quantification of O-GlcNAc intensity in GFP-positive cells (1 mM, n = 360 cells, 5 mM, n = 330 cells; two-tailed t test: P < 0.05). Quantifications represent mean ± SEM. Olof Lagerlöf et al. Science 2016;351:1293-1296 Published by AAAS

Fig. 3 OGT regulates excitatory synaptic function in αCaMKII PVN neurons. OGT regulates excitatory synaptic function in αCaMKII PVN neurons. (A) Sample traces from WT and OGT knockout cells. (B) mEPSC frequency and (C) amplitude in αCaMKII-positive PVN neurons (n = 6 WT cells, n = 6 OGT knockout cells; two-tailed t test, P < 0.05). Quantifications represent mean ± SEM. Olof Lagerlöf et al. Science 2016;351:1293-1296 Published by AAAS

Fig. 4 OGT regulates feeding behavior in αCaMKII neurons of the PVN. OGT regulates feeding behavior in αCaMKII neurons of the PVN. (A) (Top) Schematic of stereotactic PVN injection. (Bottom) GFP expression in the PVN after stereotactic injection. (B) Body weight and (C) daily food intake time course (n = 5 WT mice, n = 7 OGT knockout mice; repeated-measures two-way ANOVA with post hoc Bonferroni test, P < 0.05). (D) Schematic of optogenetic setup with αCaMKII-driven expression of channelrhodopsin-2 in the PVN with the abutting laser. (E and F) Food intake after optogenetic stimulation. (E) 24 hours cumulative food intake. Bars represent average intake over all mice, and lines represent average intake per individual mouse (baseline, n = 11 experiments (5 mice); stimulation, n = 11 experiments (5 mice); two-tailed t test, P < 0.05). (F) Average meal size (baseline, n = 125 meals (5 mice); stimulation, n = 110 meals (5 mice); two-tailed t test, P < 0.05). (G) Model of OGT-dependent hyperphagia. Quantifications represent mean ± SEM. Olof Lagerlöf et al. Science 2016;351:1293-1296 Published by AAAS