Hindbrain projections of oxytocin neurons in the parvocellular paraventricular nucleus (pPVN) are hypothesized to transmit leptin signaling from the hypothalamus to the nucleus of the solitary tract (NTS), where satiety signals from the gastrointestinal tract are received. Using immunocytochemistry, we found that an anorectic dose of leptin administered into the third ventricle (3V) increased twofold the number of pPVN oxytocin neurons that expressed Fos. Injections of fluorescent cholera toxin B into the NTS labeled a subset of pPVN oxytocin neurons that expressed Fos in response to 3V leptin. Moreover, 3V administration of an oxytocin receptor antagonist, [d-(CH2)5,Tyr(Me)2,Orn8]-vasotocin (OVT), attenuated the effect of leptin on food intake over a 0.5- to 4-h period ( P < 0.05). Furthermore, to determine whether oxytocin contributes to leptin's potentiation of Fos activation within NTS neurons in response to CCK, we counted the number of Fos-positive neurons in the medial NTS (mNTS) after 3V administration of OVT before 3V leptin and intraperitoneal CCK-8 administration. OVT resulted in a significant 37% decrease ( P < 0.05) in the potentiating effect of leptin on CCK activation of mNTS neuronal Fos expression. Furthermore, 4V OVT stimulated 2-h food intake by 43% ( P < 0.01), whereas 3V OVT at the same dose was ineffective. These findings suggest that release of oxytocin from a descending pPVN-to-NTS pathway contributes to leptin's attenuation of food intake by a mechanism that involves the activation of pPVN oxytocin neurons by leptin, resulting in increased sensitivity of NTS neurons to satiety signals.

Despite compelling evidence that oxytocin (OT) is effective in reducing body weight (BW) in diet-induced obese (DIO) rodents, studies of the effects of OT in humans and rhesus monkeys have primarily focused on noningestive behaviors. The goal of this study was to translate findings in DIO rodents to a preclinical translational model of DIO. We tested the hypothesis that increased OT signaling would reduce BW in DIO rhesus monkeys by inhibiting food intake and increasing energy expenditure (EE). Male DIO rhesus monkeys from the California National Primate Research Center were adapted to a 12-h fast and maintained on chow and a daily 15% fructose-sweetened beverage. Monkeys received 2× daily subcutaneous vehicle injections over 1 wk. We subsequently identified doses of OT (0.2 and 0.4 mg/kg) that reduced food intake and BW in the absence of nausea or diarrhea. Chronic administration of OT for 4 wk (0.2 mg/kg for 2 wk; 0.4 mg/kg for 2 wk) reduced BW relative to vehicle by 3.3 ± 0.4% (≈0.6 kg; P < 0.05). Moreover, the low dose of OT suppressed 12-h chow intake by 26 ± 7% (P < 0.05). The higher dose of OT reduced 12-h chow intake by 27 ± 5% (P < 0.05) and 8-h fructose-sweetened beverage intake by 18 ± 8% (P < 0.05). OT increased EE during the dark cycle by 14 ± 3% (P < 0.05) and was associated with elevations of free fatty acids and glycerol and reductions in triglycerides suggesting increased lipolysis. Together, these data suggest that OT reduces BW in DIO rhesus monkeys through decreased food intake as well as increased EE and lipolysis.

There is growing evidence that oxytocin (OXT), a hypothalamic hormone well recognized for its effects in inducing parturition and lactation, has important metabolic effects in both sexes. The purpose of this review is to summarize the physiologic effects of OXT on metabolism and to explore its therapeutic potential for metabolic disorders. In model systems, OXT promotes weight loss by decreasing energy intake. Pair-feeding studies suggest that OXT-induced weight loss may also be partly due to increased energy expenditure and/or lipolysis. In humans, OXT appears to modulate both homeostatic and reward-driven food intake, although the observed response depends on nutrient milieu (eg, obese vs. nonobese), clinical characteristics (eg, sex), and experimental paradigm. In animal models, OXT is anabolic to muscle and bone, which is consistent with OXT-induced weight loss occurring primarily via fat loss. In some human observational studies, circulating OXT concentrations are also positively associated with lean mass and bone mineral density. The impact of exogenous OXT on human obesity is the focus of ongoing investigation. Future randomized, placebo-controlled clinical trials in humans should include rigorous, standardized, and detailed assessments of adherence, adverse effects, pharmacokinetics/pharmacodynamics, and efficacy in the diverse populations that may benefit from OXT, in particular those in whom hypothalamic OXT signaling may be abnormal or impaired (eg, individuals with Sim1 deficiency, Prader–Willi syndrome, or craniopharyngioma). Future studies will also have the opportunity to investigate the characteristics of new OXT mimetic peptides and the obligation to consider long-term effects, especially when OXT is given to children and adolescents. (Endocrine Reviews XX: XX – XX, 2020) Graphical Abstract Open in new tab Download slide Graphical Abstract Open in new tab Download slide

Based largely on a number of short-term administration studies, growing evidence suggests that central oxytocin is important in the regulation of energy balance. The goal of the current work is to determine whether long-term third ventricular (3V) infusion of oxytocin into the central nervous system (CNS) is effective for obesity prevention and/or treatment in rat models. We found that chronic 3V oxytocin infusion between 21 and 26 days by osmotic minipumps both reduced weight gain associated with the progression of high-fat diet (HFD)-induced obesity and elicited a sustained reduction of fat mass with no decrease of lean mass in rats with established diet-induced obesity. We further demonstrated that these chronic oxytocin effects result from 1) maintenance of energy expenditure at preintervention levels despite ongoing weight loss, 2) a reduction in respiratory quotient, consistent with increased fat oxidation, and 3) an enhanced satiety response to cholecystokinin-8 and associated decrease of meal size. These weight-reducing effects persisted for approximately 10 days after termination of 3V oxytocin administration and occurred independently of whether sucrose was added to the HFD. We conclude that long-term 3V administration of oxytocin to rats can both prevent and treat diet-induced obesity.