Nociceptin receptor antagonist SB 612111 decreases high fat diet binge eating

Abstract

Binge eating is a dysregulated form of feeding behavior that occurs in multiple eating disorders including binge-eating disorder, the most common eating disorder. Feeding is a complex behavioral program supported through the function of multiple brain regions and influenced by a diverse array of receptor signaling pathways. Previous studies have shown the overexpression of the opioid neuropeptide nociceptin (orphanin FQ, N/OFQ) can induce hyperphagia, but the role of endogenous nociceptin receptor (NOP) in naturally occurring palatability-induced hyperphagia is unknown. In this study we adapted a simple, replicable form of binge eating of high fat food (HFD). We found that male and female C57BL/6J mice provided with daily one-hour access sessions to HFD eat significantly more during this period than those provided with continuous 24h access. This form of feeding is rapid and entrained. Chronic intermittent HFD binge eating produced hyperactivity and increased light zone exploration in the open field and light-dark assays respectively. Treatment with the potent and selective NOP antagonist SB 612111 resulted in a significant dose-dependent reduction in binge intake in both male and female mice, and, unlike treatment with the serotonin selective reuptake inhibitor fluoxetine, produced no change in total 24-h food intake. SB 612111 treatment also significantly decreased non-binge-like acute HFD consumption in male mice. These data are consistent with the hypothesis that high fat binge eating is modulated by NOP signaling and that the NOP system may represent a promising novel receptor to explore for the treatment of binge eating.

Keywords: Binge eating; Fluoxetine; High fat; Hyperphagia; Intermittent access; Nociceptin.

Figure 1. Intermittent daily access to HFD promotes large, rapid consumption

A. Schematic of home cage paradigm for continuous (left) vs intermittent (right) access to high fat food in C57BL6/J mice. Chow is ad libitum. Access to HFD was provided at 11 am. B. Normalized consumption (kCal/ g bodyweight) of the HFD during the one-hour access period for male (black) and female (red) mice under continuous (closed symbols) or intermittent (open symbols) access conditions over the first two weeks. Within both the male and female group, data were analyzed by RM two-way ANOVA (n for each group: I-HFD male = 35, C-HFD male = 20, I-HFD female = 12, C-HFD female = 12, see Results for details). The I-HFD group consumed significantly more food during this access period than the C-HFD group for both male and female mice. C. Normalized consumption of the home cage chow (kCal/ g bodyweight) for the male and female I-HFD groups over the first two weeks. Within both the male and female group, data were analyzed by RM one-way ANOVA (n for each group: I-HFD male = 35, I-HFD female = 12, see Results for details). D. Fractional intake of the HFD for the male and female HFD group (Binge Index) during the first two weeks. Within both the male and female group, data were analyzed by RM one-way ANOVA (n for each group: I-HFD male = 35, I-HFD female = 12, see Results for details). We observed a significant escalation in the Binge Index for both groups. E. Total caloric intake for male and female C-HFD and I-HFD groups. Data were analyzed by Unpaired student's t test(see Results for details). We observed a significant increase in caloric intake in both male and female C-HFD mice. F. After establishing a stable baseline of consumption in the I-HFD group, we decreased the access period length for the intermittent group from 60 min. to 30 min and 10 min. Within both the male and female group, data were analyzed by one-way ANOVA (n = 10 males and 12 females; see text for details). G. Percent change in bodyweight in males and females for I vs C mice. Continuous mice gain significantly more bodyweight than intermittent mice. Data were analyzed using an unpaired student's t test. H. Correlational analyses of binge HFD intake vs home cage chow intake in I-HFD mice. Male and Female animals were pooled. Data were fit using linear regression. Slope was significantly non-zero (F = 6.949, p = 0.0158). For all panels * = p < 0.05, ** = p < 0.01, *** = p < 0.001, and **** p < 0.0001.

Figure 2. Intermittent HFD binging effects on anxiety and psychomotor behavior

A. Open field apparatus. B. Distance traveled in the open field (cm) over 20 min. There is a significant overall effect of group and I mice travel significantly more than C mice. C. Time spent in the center of the open field. There is no significant effect on center time. D. Center entries. E. Light/Dark conflict box F. Time spent in the light side of the light/dark box. Significant overall group effect (see results) with a significant difference between I and C mice. G. Latency to enter the light side. No significant group difference H. Total number of entries into the light side. No significant group differences. I. Elevated Plus Maze (EPM). J. Distance traveled in the EPM. No significant group differences. K. % Open arm time in the EPM. No significant group differences. L. Probability of an open arm entry in the EPM. No significant group differences. For all measures, data were analyzed by one-way ANOVA with Sidak's multiple comparisons test. See Results for further information on the statistical analyses. n = 10/ group for each assay.

Figure 3. SB 612111 treatment reduces binge consumption, but not total 24 hour intake

A. Normalized binge intake in male mice treated with SB 612111 and 30 mg/kg fluoxetine (FLX). Drug Treatments were performed as described in the Methods. SB 612111 treatment produced a dose-dependent reduction in binge intake with 10 mg/kg SB 612111 producing a near 40% reduction in consumption intermittent mice (inset). There was no significant effect on continuous mice. B. Normalized binge intake in female mice treated with SB 612111 and 30 mg/kg FLX. SB 612111 produced a dose dependent reduction in binge intake with 10 mg/kg producing over 20% reduction in intake. There was no significant effect on continuous mice. C. Normalized 24 hour total intake in male mice treated with SB 612111 and 30 mg/kg fluoxetine (FLX). SB 612111 had no effect on total intake in either intermittent or continuous male mice. FLX produced a significant reduction in total intake in either group. D. Normalized 24 hour total intake in female mice treated with SB 612111 and 30 mg/kg fluoxetine (FLX). SB 612111 had no effect on total intake in either intermittent or continuous female mice. FLX produced a significant reduction in total intake in either group. For all panels, data were analyzed by a repeated measures two-way ANOVA with Dunnett's multiple comparison test to the baseline measurements of binge intake and total intake. E. HFD intake in first one-hour exposure to HFD in animals treated with vehicle or 10 mg/kg SB 612111 (n = 12/group). SB 612111 produced a highly significant reduction in HFD intake.