Francesco Longo

Objectives Oxytocin (OT) has a well‐established role in reproductive behaviours; however, it recently emerged as an important regulator of energy homeostasis. In addition to central nervous system (CNS), OT is found in the plasma and OT receptors (OT‐R) are found in peripheral tissues relevant to energy balance regulation. Here, we aim to determine whether peripheral OT‐R activation is sufficient to alter energy intake and expenditure. Methods and Results We first show that systemic OT potently reduced food intake and food‐motivated behaviour for a high‐fat reward in male and female rats. As it is plausible that peripherally, intraperitoneally (IP) injected OT crosses the blood‐brain barrier (BBB) to produce some of the metabolic effects within the CNS, we screened, with a novel fluorescently labelled‐OT ( f AF546‐OT, Roxy), for the presence of IP‐injected Roxy in CNS tissue relevant to feeding control and compared such with BBB‐impermeable fluorescent OT‐B 12 ( f Cy5‐OT‐B 12; BRoxy). While Roxy did penetrate the CNS, BRoxy did not. To evaluate the behavioural and thermoregulatory impact of exclusive activation of peripheral OT‐R, we generated a novel BBB‐impermeable OT (OT‐B 12 ), with equipotent binding at OT‐R in vitro. In vivo, IP‐injected OT and OT‐B 12 were equipotent at food intake suppression in rats of both sexes, suggesting that peripheral OT acts on peripheral OT‐R to reduce feeding behaviour. Importantly, OT induced a potent conditioned taste avoidance, indistinguishable from that induced by LiCl, when applied peripherally. Remarkably, and in contrast to OT, OT‐B 12 did not induce any conditioned taste avoidance. Limiting the CNS entry of OT also resulted in a dose‐dependent reduction of emesis in male shrews. While both OT and OT‐B 12 proved to have similar effects on body temperature, only OT resulted in home‐cage locomotor depression. Conclusions Together our data indicate that limiting systemic OT CNS penetrance preserves the anorexic effects of the peptide and reduces the clinically undesired side effects of OT: emesis, taste avoidance and locomotor depression. Thus, therapeutic targeting of peripheral OT‐R may be a viable strategy to achieve appetite suppression with better patient outcomes.