Oxytocin in the ventromedial hypothalamic nucleus reduces feeding and acutely increases energy expenditure

Abstract

Noble EE, Billington CJ, Kotz CM, Wang C. Oxytocin in the ventromedial hypothalamic nucleus reduces feeding and acutely increases energy expenditure. Am J Physiol Regul Integr Comp Physiol 307: R737-R745, 2014. First published July 2, 2014; doi:10.1152/ajpregu.00118.2014.-Central oxytocin reduces food intake and increases energy expenditure. The ventromedial hypothalamic nucleus (VMN) is associated with energy balance and contains a high density of oxytocin receptors. We hypothesized that oxytocin in the VMN is a negative regulator of energy balance acting to reduce feeding and increase energy expenditure. To test this idea, oxytocin or vehicle was injected directly into the VMN of Sprague-Dawley rats during fasted and nonfasted conditions. Energy expenditure (via indirect calorimetry) and spontaneous physical activity (SPA) were recorded simultaneously. Animals were also exposed to a conditioned taste aversion test, to determine whether oxytocin's effects on food intake were associated with malaise. When food was available during testing, oxytocin-induced elevations in energy expenditure lasted for 1 h, after which overall energy expenditure was reduced. In the absence of food during the testing period, oxytocin similarly increased energy expenditure during the first hour, but differences in 12-h energy expenditure were eliminated, implying that the differences may have been due to the thermic effects of feeding (digestion, absorption, and metabolic processing). Oxytocin acutely elevated SPA and reduced feeding at doses that did not cause a conditioned taste aversion during both the fed and fasted states. Together, these data suggest that oxytocin in the VMN promotes satiety and acutely elevates energy expenditure and SPA and implicates the VMN as a relevant site for the antiobesity effects of oxytocin. oxytocin; ventromedial hypothalamus; energy expenditure; obesity; feeding OXYTOCIN HAS ANTIOBESITY EFFECTS and is currently being tested clinically for use in the treatment of obesity and Type 2 diabetes (34, 65). Although the mechanism for oxytocin's effects have not been fully characterized, an extensive body of work has demonstrated antiobesity effects of oxytocin in rodents (11,26,30,64,65), as well as humans (65). Behaviorally, central oxytocin has been reported to delay meal onset (2) and reduce intake of sweet foods (22,27,33). Additionally, previous studies implicate a physiological role for endogenous oxytocin in reducing meal size (7, 62). In addition to feeding effects, central oxytocin has potent effects on energy metabolism. For example, low doses of intracerebroventricular oxytocin promote weight loss in rats without affecting feeding by elevating fat oxidation in adipose tissue, whereas higher doses of intracerebroventricular oxytocin both reduce feeding and increase lipolysis (11). Conversely, animals deficient in either oxytocin or its receptor show reduced energy expenditure, in some cases with normal feeding (1, 9, 19, 51).The main sources of oxytocin in the brain are the magnocellular and par...

Chronic CNS oxytocin signaling preferentially induces fat loss in high-fat diet-fed rats by enhancing satiety responses and increasing lipid utilization

“…Overall, the data indicate that chronic subcutaneous administration of oxytocin, at doses that reduce weight gain and food intake in chow-fed rats, is unlikely to elicit nausea. These findings extend other reports showing that acute bolus injections of oxytocin into the CNS or periphery fail to increase kaolin intake (103) or elicit a conditioned taste aversion (42,63,103).…”

“…The mechanism underlying these effects may involve outgoing polysynaptic sympathetic nervous system projections from PVN oxytocin neurons to both inguinal (86) and epididymal white adipose tissue (86,89). With respect to the question of which receptor populations contribute to the effects of oxytocin to impact energy expenditure, acute microinjection of oxytocin into the median raphe increases both heart rate and body temperature in mice (102), and oxytocin administration into the VMH increases short-term energy expenditure in rats (63). Evidence that adeno-associated viral expression of OTRs into the VMH/DMH of OTR null mice restores impairments in cold-induced thermogenesis (45) and corrects defects in ␤3-and ␣2-adrenceptor mRNA expression in interscapular brown adipose tissue, strengthens the link between OTRs in these areas and control of energy expenditure.…”

“…Recent studies indicate that in addition to suppressing food intake, oxytocin may also reduce body weight in rodents and nonhuman primates by increasing energy expenditure (10,63,90,99,(102)(103)(104). Conversely, animals with either partial or complete loss in oxytocin signaling show decreased energy expenditure (18,45,93,99,104) and brown adipose tissue thermogenesis (18,45,93).…”

Region-specific associations between sex, social status, and oxytocin receptor density in the brains of eusocial rodents

“…OTR in this region appears to be a common feature of hystricognath rodents measured to date, including guinea pigs and tuco-tucos as well as mole-rats, while its presence may be more variable and species-specific in myomorphic rodents (Tribollet et al, 1992;Beery et al, 2008). Oxytocin in the VMH decreases feeding and promotes activity in rats (Noble et al, 2014). While it remains to be tested whether oxytocin in the VMH has these effects in naked mole-rats, they might be beneficial to species that rely on subterranean group foraging for survival (Brett, 1991b).…”

The Anorexigenic Neural Pathways of Oxytocin and Their Clinical Implication

“…We found that mice showed increased energy expenditure with decreased respiratory quotient (RQ) during the light phase of the treatment period [23]. 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].…”