Risperidone acts on hypothalamic MC4Rs/Mc4r-expressing neurons to cause weight gain. (A) Body weight of Mc4rSim1-KO mice fed the control (C), risperidone (R), or olanzapine (O) diet; n = 14 or 15; two-way ANOVA; F(22, 427) = 2.12; P = 0.46. (B) Body composition of mice in A after 10-wk treatment of the C, R, or O diet; n = 14 or 15; two-way ANOVA; F(1, 54) = 0.4843; P = 0.49. (C) Daily food intake in the first 28 d of treatment with the C, R, or O diet; n = 4 or 5; two-way ANOVA; F(30, 240) = 1.022; P = 0.44. (D) Fast-induced refeeding in risperidone-fed Mc4rSim1-KO mice; n = 5; one-way ANOVA; F(2, 12) = 0.3575; ***, P < 0.001. (E) Bright-field, fluorescent illumination (TRITC [tetramethylrhodamine isothiocyanate] for Mc4r-T2A-Cre::tdTomato; FITC for Alexa Fluor 488) and the merged image of a targeted MC4RPVH neuron for whole-cell patch-clamp experiments. Arrows indicate the targeted cell. Scale bars are 10 µm. (F) Acute effects of RISP (10 µM) on MC4RPVH neurons. (G) Acute effects of RISP in the presence of tetrodotoxin (TTX; 0.5 µM), kynurenic acid (1 mM), and picrotoxin (50 µM). SB, synaptic blocker. (H) Voltage responses to hyperpolarizing current steps (from −25 pA to 0 pA, applied as indicated by arrows in G. (I) Current-voltage relationship demonstrates RISP-induced decreases of input resistance. Erev = reversal potential. (J) Pretreatment with JKC-363 (20 nM, an MC4R antagonist) blocked the acute effects of RISP. (K) Co-treatment with setmelanotide (100 nM, an MC4R agonist) blocked the acute effects of RISP. (L) Bar graphs summarize the acute effects of RISP. The dashed line in F, G, J, and K indicates resting membrane potential. Data are presented as mean ± SEM. ****, P < 0.0001. One-way ANOVA with Sidak’s post hoc tests. All data were verified in at least two independent experiments.
Figure 3.

Risperidone acts on hypothalamic MC4Rs/Mc4r-expressing neurons to cause weight gain. (A) Body weight of Mc4rSim1-KO mice fed the control (C), risperidone (R), or olanzapine (O) diet; n = 14 or 15; two-way ANOVA; F(22, 427) = 2.12; P = 0.46. (B) Body composition of mice in A after 10-wk treatment of the C, R, or O diet; n = 14 or 15; two-way ANOVA; F(1, 54) = 0.4843; P = 0.49. (C) Daily food intake in the first 28 d of treatment with the C, R, or O diet; n = 4 or 5; two-way ANOVA; F(30, 240) = 1.022; P = 0.44. (D) Fast-induced refeeding in risperidone-fed Mc4rSim1-KO mice; n = 5; one-way ANOVA; F(2, 12) = 0.3575; ***, P < 0.001. (E) Bright-field, fluorescent illumination (TRITC [tetramethylrhodamine isothiocyanate] for Mc4r-T2A-Cre::tdTomato; FITC for Alexa Fluor 488) and the merged image of a targeted MC4RPVH neuron for whole-cell patch-clamp experiments. Arrows indicate the targeted cell. Scale bars are 10 µm. (F) Acute effects of RISP (10 µM) on MC4RPVH neurons. (G) Acute effects of RISP in the presence of tetrodotoxin (TTX; 0.5 µM), kynurenic acid (1 mM), and picrotoxin (50 µM). SB, synaptic blocker. (H) Voltage responses to hyperpolarizing current steps (from −25 pA to 0 pA, applied as indicated by arrows in G. (I) Current-voltage relationship demonstrates RISP-induced decreases of input resistance. Erev = reversal potential. (J) Pretreatment with JKC-363 (20 nM, an MC4R antagonist) blocked the acute effects of RISP. (K) Co-treatment with setmelanotide (100 nM, an MC4R agonist) blocked the acute effects of RISP. (L) Bar graphs summarize the acute effects of RISP. The dashed line in F, G, J, and K indicates resting membrane potential. Data are presented as mean ± SEM. ****, P < 0.0001. One-way ANOVA with Sidak’s post hoc tests. All data were verified in at least two independent experiments.

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