The neutral cannabinoid CB₁ receptor antagonist AM4113 regulates body weight through changes in energy intake in the rat

Abstract

The aim of this study was to determine if the neutral cannabinoid CB₁ receptor antagonist, AM4113, regulates body weight in the rat via changes in food intake. We confirmed that the AM4113-induced reduction in food intake is mediated by CB₁ receptors using CB₁ receptor knockout mice. In rats, intraperitoneally administered AM4113 (2, 10 mg kg⁻¹) had a transient inhibitory effect on food intake, while body weight gain was suppressed for the duration of the study. AM4113-induced hypophagia was no longer observed once the inhibitory effect of AM4113 on body weight stabilized, at which time rats gained weight at a similar rate to vehicle-treated animals, yet at a lower magnitude. Pair-feeding produced similar effects to treatment with AM4113. Food intake and body weight gain were also inhibited in rats by oral administration of AM4113 (50 mg kg⁻¹). Dual energy x-ray absorptiometry (DEXA) was used to measure lean and fat mass. The AM4113 treated group had 29.3±11.4% lower fat mass than vehicle-treated rats; this trend did not reach statistical significance. There were no differences in circulating levels of the endogenous cannabinoid 2-arachidonoyl glycerol (2-AG), glucose, triglycerides, or cholesterol observed between treatment groups. Similarly, 2-AG hypothalamic levels were not modified by AM4113 treatment. These data suggest that blockade of an endocannabinoid tone acting at CB₁ receptors induces an initial, transient reduction in food intake which results in long-term reduction of body weight gain.

Figure 1

The effect of AM4113 (10 mg kg⁻¹; i.p.) on food intake compared to vehicle (4% DMSO; 1% Tween 80; 95% saline; i.p.) treated animals in wildtype (A) and CB₁ receptor knockout mice (B). Bars represent the mean ± S.E.M, n = 5–6 per group. * p < 0.05 and ** p<0.01 represent a significant difference to vehicle treatment analyzed by 2-way ANOVA followed by Bonferroni’s post hoc test.

Figure 2

The effect of daily AM4113 (2 or 10 mg kg⁻¹; i.p.) administration, over 14 d, on food intake (A), body weight (B) and weight change (C) in rats compared to vehicle (4% DMSO; 1% Tween 80; 95% saline; i.p.)and rats pair -fed to the 10 mg kg⁻¹ treated group. The effect of AM4113 (2 or 10 mg kg⁻¹), vehicle or being pair-fed on lean mass (D), fat mass (E) and the lean: fat mass ratio (F). Data points or bars represent the mean ± S.E.M, n = 5–6 per group. * p <0.05, ** p<0.01 and *** p < 0.001 represent a significant difference to vehicle treatment analyzed by 2-way ANOVA (A, B, C) or 1-way ANOVA (D, E, F) followed by Bonferroni’s post hoc test.

Figure 3

The effect of daily AM4113 (50 mg kg⁻¹; p.o.) administration, over 7 d (treatments days denoted by the black horizontal bar) on food intake (A), body weight (B) and weight change(C) in rats compared to vehicle (4% DMSO; 96% olive oil; p.o.) and rats pair-fed to the 50 mg kg⁻¹ treated group. Data points represent the mean ±S.E.M, n = 4–5 per group. * p <0.05 represents a significant difference to vehicle treatment analyzed by 2-way ANOVA followed by Bonferroni’s post hoc test.