Setmelanotide mitigates hyperphagia and obesity in risperidone- and olanzapine-fed mice. (A) Refeeding after an i.p. dose of setmelanotide (SET; 2 mg/kg) or saline in Mc4r^fl/fl and Mc4r^Sim1-KO mice after an overnight fast; n = 6–14; two-way ANOVA; F(1, 36) = 4.651; P > 0.999. (B) Daily food intake in risperidone-fed wild-type mice treated with SET or saline (mini-pumps); n = 9 or 10; two-way ANOVA; F(1, 15) = 14.46; P = 0.002. (C) Changes in body weight before and after the 14-d treatment with SET or saline; n = 9; two-way ANOVA; F(2, 25) = 9.995; P < 0.001. (D) Body composition in risperidone-fed mice after the 14-d treatment with SET or saline; n = 9 or 10; two-way ANOVA; F(2, 50) = 4.215; P = 0.034. (E) GTT in risperidone-fed mice after the 14-d treatment with SET or saline; n = 10; F (18, 90) = 5.378; two-way ANOVA; P < 0.001. (F) Daily food intake in olanzapine-fed wild-type mice treated with SET or saline (mini-pumps); n = 8; two-way ANOVA; F(1, 14 = 7.734; P = 0.015. (G) Changes in body weight before and after the 14-d treatment with SET or saline; n = 8; two-way ANOVA; F(1, 14) = 14.17; P = 0.002. (H) Body composition in olanzapine-fed mice after the 14-d treatment with SET or saline; n = 8; two-way ANOVA; F(1, 14) = 16.70; P = 0.0011. (I) Open field test measuring amphetamine-induced hyperlocomotion in mice pretreated with saline, SET, RISP, or RISP + SET; n = 12; two-way ANOVA; F(357, 5236) = 1.683; P < 0.001. Saline versus RISP, P = 0.002; RISP versus RISP + SET, P > 0.999. *, P < 0.05; **, P < 0.01; ***, P < 0.001. Two-way ANOVA with Sidak’s post hoc tests. All data were verified in at least two independent experiments.