Extended Data Fig. 8: NNC-711 in the lOFC restores devaluation in obesity.

a) Weights of lean and obese mice following long-term exposure to either the 10% low fat (lean n = 14) or 60% high-fat (obese n = 16) diet in the devaluation by selective satiety task. Unpaired T-test: t ₍₂₈₎ =7.818, p < 0.0001****. Data are presented as mean values + /− SEM. b) Number of lever presses performed on the last two days of RR5, RR10, RR20 training prior to behavioral testing for selective satiety devaluation of lean (n = 14) and obese (n = 16) mice. Two-way RM ANOVA: Diet effect: F (1, 28) = 24.80, P < 0.0001****, training schedule effect: F (1.441, 40.35) = 11.45, p = 0.0005***, diet × training schedule interaction: F (2, 56) = 3.103, p = 0.0527. We expected that both lean and obese mice would escalate their lever presses. Dunnett’s multiple comparison: lean RR5 vs RR10 p = 0.4182, lean RR5 vs RR20 p = 0.0171*, obese RR5 vs RR10 p = 0.0554, obese RR5 vs RR20 p = 0.0102*. Data are presented as mean values + /− SEM. c) Sucrose presconsumption of lean vehicle mice (n = 12), lean NNC mice (n = 12), and obese vehicle mice (n = 14) and obese NNC mice (n = 15). Two-way RM ANOVA mixed effects model: Interaction: F (1, 21) = 0.03347, p = 0.8566, diet effect: F (1, 28) = 0.5022, p = 0.4844, Drug effect: F (1, 21) = 0.007126, p = 0.9335. Data are presented as mean values + /− SEM. d) Total distance traveled (m) of lean (n = 7) and obese (n = 6) mice in a one-hour open field test immediately following lOFC infusions of either vehicle or NNC-711 (NNC-711 10 µM). Two-way RM ANOVA: Interaction: F (1, 11) = 0.1175, p = 0.7383, vehicle vs. NNC-711 effect: F (1, 11) = 0.7986, p = 0.3906, diet effect: F (1, 11) = 16.76, p = 0.0018*. Based on previous literature and because there was a diet effect, we expected that obese mice would travel less distance than lean mice. Sidaks multiple comparison test: vehicle lean vs obese p = 0.0172*, NNC-711 lean vs obese p = 0.0061**. Data are presented as mean values + /− SEM.

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