Chronic hindbrain administration of oxytocin is sufficient to elicit weight loss in diet-induced obese rats

Abstract

Oxytocin (OT) administration elicits weight loss in diet-induced obese (DIO) rodents, nonhuman primates, and humans by reducing energy intake and increasing energy expenditure. Although the neurocircuitry underlying these effects remains uncertain, OT neurons in the paraventricular nucleus are positioned to control both energy intake and sympathetic nervous system outflow to interscapular brown adipose tissue (BAT) through projections to the hindbrain nucleus of the solitary tract and spinal cord. The current work was undertaken to examine whether central OT increases BAT thermogenesis, whether this effect involves hindbrain OT receptors (OTRs), and whether such effects are associated with sustained weight loss following chronic administration. To assess OT-elicited changes in BAT thermogenesis, we measured the effects of intracerebroventricular administration of OT on interscapular BAT temperature in rats and mice. Because fourth ventricular (4V) infusion targets hindbrain OTRs, whereas third ventricular (3V) administration targets both forebrain and hindbrain OTRs, we compared responses to OT following chronic 3V infusion in DIO rats and mice and chronic 4V infusion in DIO rats. We report that chronic 4V infusion of OT into two distinct rat models recapitulates the effects of 3V OT to ameliorate DIO by reducing fat mass. While reduced food intake contributes to this effect, our finding that 4V OT also increases BAT thermogenesis suggests that increased energy expenditure may contribute as well. Collectively, these findings support the hypothesis that, in DIO rats, OT action in the hindbrain evokes sustained weight loss by reducing energy intake and increasing BAT thermogenesis.

The Anorexigenic Neural Pathways of Oxytocin and Their Clinical Implication

“…In HFDinduced obese male and female mice (body fat mass: 36%), 10 days of oxytocin treatment decreased abdominal and subcutaneous fat up to 15-20% without reducing muscle mass [39]. Similar effects of oxytocin on fat mass are found in other studies using HFD-induced obese mice/rats [25,29,31,32] and genetically obese models such as db/db [131] and ob/ob mice [37]. This suggests that the cause of decreased BW induced by oxytocin treatment depends not only on the decreased food intake, but also on the stimulation of lipolysis.…”

“…The RQ decrease by oxytocin treatment was also confirmed in rats, monkeys, and humans [25,32,34,35,135]. This reduction of BW by oxytocin may also be mediated by the induction of diet-induced thermogenesis [31,47]. Other factors related to the metabolic disorder were also found to be affected by the oxytocin treatment.…”

Role of oxytocin in the control of stress and food intake

“…130,146,159,160 Oxytocin administration has been shown to reduce food intake in laboratory animals and humans. 164 However, a meta-analysis revealed that the anorexigenic effect of oxytocin administration is not statistically significant in humans. 164 However, a meta-analysis revealed that the anorexigenic effect of oxytocin administration is not statistically significant in humans.…”

“…[161][162][163] The anorexigenic effect of oxytocin has been shown to be stronger in diet-induced obese rodents. 164 However, a meta-analysis revealed that the anorexigenic effect of oxytocin administration is not statistically significant in humans. 161 SNPs of the gene encoding the oxytocin receptor have been shown to be associated with eating disorders including anorexia nervosa and bulimia nervosa.…”

The role of oxytocin in regulation of appetitive behaviour, body weight and glucose homeostasis

“…and into the lateral, third (3V) and fourth ventricle (4V; as a strategy to more specifically target hindbrain OXTRs). Considering the debate over whether peripherally administered OXT crosses the blood‐brain barrier (BBB) and enters the brain in rodents, pigs, sheep, non‐human primates and humans, both the central and peripheral pools of the OXT receptor have been implicated in mediating OXT‐driven hypophagia . In addition, it has been suggested that peripheral OXT may also act, in part, via hindbrain OXTRs: 4V pre‐treatment with an OXTR antagonist attenuated the effects of i.p.…”