Oxytocin Administration Alleviates Acute but Not Chronic Leptin Resistance of Diet-Induced Obese Mice

Abstract

Whereas leptin administration only has a negligible effect on the treatment of obesity, it has been demonstrated that its action can be improved by co-administration of leptin and one of its sensitizers. Considering that oxytocin treatment decreases body weight in obese animals and humans, we investigated the effects of oxytocin and leptin cotreatment. First, lean and diet-induced obese (DIO) mice were treated with oxytocin for 2 weeks and we measured the acute leptin response. Second, DIO mice were treated for 2 weeks with saline, oxytocin (50 μg/day), leptin (20 or 40 µg/day) or oxytocin plus leptin. Oxytocin pre-treatment restored a normal acute leptin response, decreasing food intake and body weight gain. Chronic continuous administration of oxytocin or leptin at 40 µg/day decreased body weight in the presence (leptin) or in the absence (oxytocin) of cumulative differences in food intake. Saline or leptin treatment at 20 µg/day had no impact on body weight. Oxytocin and leptin cotreatments had no additional effects compared with single treatments. These results point to the fact that chronic oxytocin treatment improves the acute, but not the chronic leptin response, suggesting that this treatment could be used to improve the short-term satiety effect of leptin.

Keywords: food intake; leptin; obesity; oxytocin.

Figure 1

Acute leptin effects on food intake. (A) Experimental design described in Material and Methods. Mice were fed a chow diet (CD) or a high fat diet (HFD) during 10 weeks. The last two weeks, mice were infused subcutaneously with the vehicle (saline, Sal) or oxytocin (Oxt, 50 μg/day). At days 10–13, they were IP injected twice per day (7:00 and 19:00) with saline (days 10–11) and leptin (days 12–13). (B–E) Cumulative food intake at the indicated timings in the different groups. White bars, saline; black bars, leptin (1.5 mg/kg). Statistical significance was analyzed by two-way repeated measures ANOVA with an FDR Benjamini and Hochberg’s post-hoc test, * p < 0.05, ** p < 0.01, *** p < 0.001.

Figure 2

Effects of chronic oxytocin and leptin treatment on body weight and food intake. (A,B) Delta body weight of HFD mice treated subcutaneously with minipumps infusing saline, oxytocin (50 μg/day), leptin (20 µg/day) (A) or (40 µg/day) (B), leptin plus oxytocin (20 μg/day and 50 µg/day, respectively) (A) or (40 μg/day and 50 µg/day) (B). (C) Delta body weight at the end of the treatment for the indicated groups. (D–F) Daily (D,E) and cumulative (F) food intake for the indicated groups. For (A,B) and (D,E), statistical significance was analyzed by two way repeated measures ANOVA with a FDR Benjamini and Hochberg’s post-hoc test. For (C) and (F), statistical significance was analyzed by one-way ANOVA with a FDR Benjamini and Hochberg’s post-hoc test. For (A,B) and (D,E): n = 6–8, * p < 0.05, Sal vs. Oxt; # p < 0.05, Sal vs. Lep; $ p < 0.05, Sal vs. Lep+Oxt; and p < 0.05, Oxt vs. Lep+Oxt; + p < 0.05, Lep vs. Lep+Oxt; % p < 0.05, Lep vs. Oxt. For (C,F), n = 6–16, a, p < 0.05 vs. Sal; b, p < 0.05 vs. Lep 20 µg/day; c, p < 0.05 vs. oxytocin.