Peripherally restricted oxytocin is sufficient to reduce food intake and motivation, while CNS entry is required for locomotor and taste avoidance effects

Abstract

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 (fAF546-OT, Roxy), for the presence of IPinjected Roxy in CNS tissue relevant to feeding control and compared such with BBB-impermeable fluorescent OT-B 12 (fCy5-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 BBBimpermeable OT (OT-B 12 ), with equipotent binding at OT-R in vitro. In vivo, IPinjected 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.

Measuring oxytocin release in response to gavage: Computational modelling and assay validation

“…There is also evidence that oxytocin can suppress food intake by its peripheral actions. 31,39 The functional organisation of central projections of magnocellular oxytocin neurones, and the relative contribution of axons and dendrites to central oxytocin release, have yet to be fully defined, despite its potential importance for understanding central oxytocin signalling.…”

“…The central release of oxytocin appears to modulate the motivation to eat by its actions not only in the hypothalamus, but also in the amygdala 33 and at forebrain sites such as the nucleus accumbens 2,34–36 and the ventral tegmental area, 37,38 where it may be involved in food reward. There is also evidence that oxytocin can suppress food intake by its peripheral actions 31,39 …”

Treatment of hypothalamic obesity in people with hypothalamic injury: new drugs are on the horizon

“…Individuals with hypothalamic injury might lack the ability to respond to intranasal OXT because key hypothalamic nuclei that impact appetite and energy balance are missing. In animal models, however, administration of OXT outside the hypothalamus, in the hindbrain or peripherally, decreases weight gain via decrease in food intake and activation of catecholamine neurons in nucleus tractus solitarius (NTS, see Figure 1 ) ( 70 , 82 – 84 ).…”

Rapid, green disulphide bond formation in water using the corrin dicyanocobinamide

“…Finally, we confirmed functionality post Cbi oxidation by screening one of the peptides, OT, both free and after conjugation to B 12 at the oxytocin receptor with equipotent agonism recorded (K D = 4.39 and 4.63 nM, respectively). 43 In conclusion, Cbi is a powerful catalyst for the oxidation of cysteine residues in peptides synthesized via SPPS. Cbi can be synthesized from vitamin B 12 or purchased commercially.…”

“…Finally, we confirmed functionality post Cbi oxidation by screening one of the peptides, OT , both free and after conjugation to B 12 at the oxytocin receptor with equipotent agonism recorded ( K D = 4.39 and 4.63 nM, respectively). 43…”