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. 2018 Jun;12:98-106.
doi: 10.1016/j.molmet.2018.04.002. Epub 2018 Apr 13.

mTORC1-dependent Increase in Oxidative Metabolism in POMC Neurons Regulates Food Intake and Action of Leptin

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Free PMC article

mTORC1-dependent Increase in Oxidative Metabolism in POMC Neurons Regulates Food Intake and Action of Leptin

Magalie Haissaguerre et al. Mol Metab. .
Free PMC article

Abstract

Objective: Nutrient availability modulates reactive oxygen species (ROS) production in the hypothalamus. In turn, ROS regulate hypothalamic neuronal activity and feeding behavior. The mechanistic target of rapamycin complex 1 (mTORC1) pathway is an important cellular integrator of the action of nutrients and hormones. Here we tested the hypothesis that modulation of mTORC1 activity, particularly in Proopiomelanocortin (POMC)-expressing neurons, mediates the cellular and behavioral effects of ROS.

Methods: C57BL/6J mice or controls and their knockout (KO) littermates deficient either for the mTORC1 downstream target 70-kDa ribosomal protein S6 kinase 1 (S6K1) or for the mTORC1 component Rptor specifically in POMC neurons (POMC-rptor-KO) were treated with an intracerebroventricular (icv) injection of the ROS hydrogen peroxide (H2O2) or the ROS scavenger honokiol, alone or, respectively, in combination with the mTORC1 inhibitor rapamycin or the mTORC1 activator leptin. Oxidant-related signal in POMC neurons was assessed using dihydroethidium (DHE) fluorescence.

Results: Icv administration of H2O2 decreased food intake, while co-administration of rapamycin, whole-body deletion of S6K1, or deletion of rptor in POMC neurons impeded the anorectic action of H2O2. H2O2 also increased oxidant levels in POMC neurons, an effect that hinged on functional mTORC1 in these neurons. Finally, scavenging ROS prevented the hypophagic action of leptin, which in turn required mTORC1 to increase oxidant levels in POMC neurons and to inhibit food intake.

Conclusions: Our results demonstrate that ROS and leptin require mTORC1 pathway activity in POMC neurons to increase oxidant levels in POMC neurons and consequently decrease food intake.

Keywords: Food intake; Hypothalamus; Leptin; POMC; Reactive oxygen species; mTORC1.

Figures

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Figure 1
Figure 1
Central administration of the ROS H2O2 engages mTORC1 signaling to decrease food intake. (A) Acute icv co-administration of the mTORC1 inhibitor rapamycin with H2O2 blunts the effect of H2O2 on food intake (Repeated measures ANOVA: treatment effect F(2,15) = 6.39, P < 0.01; time effect F(3,45) = 141.33, P < 0.0001; treatment × time interaction F(6,45) = 4.59, P < 0.01, n = 5–7 mice per group) and (B) 24h body weight (BW) change (One-way ANOVA: treatment effect F(2,15) = 9.37, P < 0.005, n = 5–7 mice per group) in C57BL/6J mice. (C) Effect of an acute icv administration of H2O2 on food intake (Repeated measures ANOVA: treatment effect F(1,40) = 7.94, P < 0.01; genotype effect F(1,40) = 11.24, P < 0.005; treatment × genotype interaction F(1,40) = 6.18, P < 0.05; time effect F(3,120) = 892.17, P < 0.0001; treatment x genotype × time interaction F(3,120) = 7.58, P < 0.0005, n = 10–12 mice per group) and (D) 24h BW change (two-way ANOVA: treatment effect F(1,40) = 5.71, P < 0.05; genotype effect F(1,40) = 4.37, P < 0.05; treatment × genotype interaction F(1,40) = 9.81, P < 0.005, n = 10–12 mice per group) in WT and S6K1-KO littermates. Data are mean ± SEM. *P < 0.05, **P < 0.005, ***P < 0.0005.
Figure 2
Figure 2
H2O2 requires activity of mTORC1 in POMC neurons to modulate food intake and intracellular oxidant levels. (A) Effect of an acute icv administration of H2O2 on food intake (Repeated measures ANOVA: treatment effect F(1,25) = 3.99, P = 0.05; genotype effect F(1,25) = 1.25, P = 0.31; treatment × genotype interaction F(1,25) = 4.73, P < 0.05; time effect F(3,75) = 624.43, P < 0.0001; treatment x genotype × time interaction F(3,75) = 6.63, P < 0.0005, n = 7–8 mice per group) and (B) 24h BW change (Two-way ANOVA: treatment effect F(1,25) = 1.04, P = 0.31; genotype effect F(1,25) = 0.33, P = 0.56; treatment × genotype interaction F(1,25) = 6.07, P < 0.05, n = 7–8 mice per group) in POMCCre−/-::Rptorflox/flox control and POMC-rptor-KO littermates. (C) Representative images of DHE-associated fluorescence in POMC neurons of control and POMC-rptor-KO littermates after icv administration of H2O2 and (D) related quantification (Two-way ANOVA: treatment effect F(1,8) = 1.70, P = 0.22; genotype effect F(1,8) = 2.44, P = 0.1; treatment × genotype interaction F(1,8) = 5.9, P < 0.05, n = 3 mice per group). Data are mean ± SEM. *P < 0.05, **P < 0.005. Scale bar: 10 μm.
Figure 3
Figure 3
Leptin needs ROS formation to modulate food intake. (A) Representative images of DHE-related fluorescence in POMC neurons after icv administration of leptin in C57BL/6J mice and (B) related quantification (Unpaired t-test, one-tailed: t(9) = 1.94, P < 0.05, n = 5–6 mice per group). (C) Effect of an acute ip administration of leptin combined with icv administration of the ROS scavenger honokiol on 2h food intake in C57BL/6J mice (Two-way ANOVA: honokiol effect F(1,27) = 0.80, P = 0.38; leptin effect F(1,27) = 5.33, P < 0.05; honokiol × leptin interaction F(1,27) = 4.53, P < 0.05, n = 7–9 mice per group). Data are mean ± SEM. *P < 0.05, **P < 0.005. Scale bar: 10 μm.
Figure 4
Figure 4
Leptin requires activity of mTORC1 in POMC neurons to modulate food intake and intracellular oxidant levels. (A) Effect of an acute icv administration of leptin on food intake (Repeated measures ANOVA: treatment effect F(1,27) = 11.1, P < 0.005; genotype effect F(1,27) = 0.50, P = 0.49; treatment × genotype interaction F(1,27) = 3.79, P = 0.06; time effect F(3,81) = 314.54, P < 0.0001; treatment x genotype × time interaction F(3,81) = 7.44, P < 0.0005, n = 7–9 mice per group) and (B) 24h BW change (Two-way ANOVA: treatment effect F(1,27) = 6.01, P < 0.05; genotype effect F(1,27) = 2.91, P = 0.10; treatment × genotype interaction F(1,27) = 3.2, P = 0.08, n = 7–9 mice per group) in POMCCre−/-::Rptorflox/flox control and POMC-rptor-KO littermates. (C) Representative images of DHE-related fluorescence in POMC neurons of control and POMC-rptor-KO littermates after icv administration of leptin and (D) related quantification (Two-way ANOVA: treatment effect F(1,12) = 5.04, P < 0.05; genotype effect F(1,12) = 15.79, P < 0.005; treatment × genotype interaction F(1,12) = 6.51, P < 0.05, n = 3–5 mice per group). Data are mean ± SEM. *P < 0.05, **P < 0.005, ***P < 0.0005. Scale bar: 10 μm.

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