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

Mehdi Labyb,Françoise Rohner-Jeanrenaud,Chloé Chrétien,Aurélie Caillon,Jordi Altirriba

doi:10.3390/ijms20010088

Mehdi Labyb, Françoise Rohner-Jeanrenaud + Show 3 more

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https://doi.org/10.3390/ijms20010088

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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.

Highlights

While oxytocin was historically recognized for its peripheral role in parturition and lactation, we know that its central release influences various types of behaviors and participates in the regulation of energy balance [1]
We hypothesized that oxytocin could be such a candidate as: (1) oxytocin administration is able to decrease food intake and body fat gain in animal models of leptin resistance [1,2,3,4,5,6,7,8,9,10,11]; (2) oxytocin-expressing neurons are activated by leptin administration [23]; (3) intracerebroventricular injection of an oxytocin antagonist blunts the anorexigenic effect of leptin [23]
In keeping with these results, the leptin effect in decreasing body weight observed in the CD-Sal (−0.99 ± 0.4 g) or the CD-Oxt (−0.88 ± 0.3 g) group disappeared in HFD-Sal (−0.03 ± 0.2 g, p < 0.05 vs. CD-Sal), but was restored in HFD-fed mice that were treated with oxytocin (HFD-Oxt, −0.46 ± 0.2 g, p = n.s. vs. CD-Oxt) (Figure S2A,B)

Summary

Introduction

While oxytocin was historically recognized for its peripheral role in parturition and lactation, we know that its central release influences various types of behaviors and participates in the regulation of energy balance [1]. Initially described as a satiety hormone, has a profound impact on central circuits controlling body weight homeostasis, as well as glucose and lipid metabolism [12]. When it was discovered, leptin monotherapy was envisioned to cure the overwhelming worldwide epidemic of obesity and its metabolic comorbidities. Initial results obtained in obese subjects using very high doses of leptin indicated a tendency to decrease body weight Such high doses are not applicable for general use and lower concentrations were inefficient [13,14,15,16,17], being only applicable for leptin-deficient subjects [18,19]. We hypothesized that oxytocin could be such a candidate as: (1) oxytocin administration is able to decrease food intake and body fat gain in animal models of leptin resistance [1,2,3,4,5,6,7,8,9,10,11]; (2) oxytocin-expressing neurons are activated by leptin administration [23]; (3) intracerebroventricular injection of an oxytocin antagonist blunts the anorexigenic effect of leptin [23]

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