| Abstract: | Experiments in animals suggest that the neuropeptide oxytocin acts as an anorexigenic signal in the central nervous control of food intake. In humans, however, research has almost exclusively focused on the involvement of oxytocin in the regulation of social behavior. We investigated the effect of intranasal oxytocin on ingestion and metabolic function in healthy men. Food intake in the fasted state was examined 45 min after neuropeptide administration, followed by the assessment of olfaction and reward-driven snack intake in the absence of hunger. Energy expenditure was registered by indirect calorimetry, and blood was repeatedly sampled to determine concentrations of blood glucose and hormones. Oxytocin markedly reduced snack consumption, restraining, in particular, the intake of chocolate cookies by 25%. Oxytocin, moreover, attenuated basal and postprandial levels of adrenocorticotropic hormone and cortisol and curbed the meal-related rise in plasma glucose. Energy expenditure and hunger-driven food intake as well as olfactory function were not affected. Our results indicate that oxytocin, beyond its role in social bonding, regulates nonhomeostatic, reward-related energy intake, hypothalamic-pituitary-adrenal axis activity, and the glucoregulatory response to food intake in humans. These effects can be assumed to converge with the psychosocial function of oxytocin and imply possible applications in the treatment of metabolic disorders.The hypothalamic nonapeptide oxytocin is released into the circulation by axonal terminals in the posterior pituitary and, moreover, acts directly on central nervous receptors. Oxytocin, which has been highly preserved during mammalian evolution, regulates physiological functions related to reproduction and mother-infant interaction, such as lactation, and in recent years, has been shown to modulate affiliative behavior (1). Research in humans has almost exclusively focused on the role of oxytocin in the regulation of prosocial behavior, including trust, attachment, and sexual behavior (2–5), largely ignoring potential effects of the neuropeptide on ingestive behavior and metabolism. In fact, evidence from rodent studies indicates that the neuropeptide acts as a strong inhibitor of food intake and affects energy expenditure and glucose homeostasis (6–9). Oxytocinergic neurons in the hypothalamic paraventricular nucleus are assumed to mediate the food intake–limiting effect of leptin, an adipokine that provides the brain with negative feedback on body fat stores and sensitizes caudal brainstem nuclei to satiety factors such as cholecystokinin (10). Hypothalamic oxytocin signaling, moreover, mediates anorexigenic effects of the satiety factor nesfatin-1 in a leptin-independent manner (11). Importantly, oxytocin reduces food intake not only in normal-weight rodents but also in animals with diet-induced obesity (8,12,13), so oxytocinergic pathways might be a promising target of clinical interventions in obese patients.The direct manipulation of neuropeptidergic central nervous signaling pathways can be achieved via the intranasal administration of peptides, which is known to bypass the blood–brain barrier and result in significant cerebrospinal fluid elevations in substance levels within 40 min, without the need for systemic infusion (14,15). This approach has been validated, among others, for vasopressin, a close homolog of oxytocin (14), and intranasal oxytocin administration has been shown to reliably modulate neuropsychological functions in a series of studies (2–5) in the absence of relevant side effects (16). Surprisingly, however, the effect of intranasal oxytocin on energy metabolism, including ingestive behavior, has not been investigated in humans so far. The assessment of respective effects of intravenous oxytocin (17) is hampered because peripheral oxytocin is not readily transported across the blood–brain barrier (18).In the present experiments, we studied the contribution of oxytocin signaling to the control of ingestive behavior and energy expenditure in normal-weight, healthy men, with a particular view to endocrine regulators of metabolism, such as ghrelin and insulin, as well as hypothalamic-pituitary-adrenal (HPA) axis secretory activity. Ingestive behavior is not only regulated homeostatically (i.e., by central nervous pathways that respond to energy depletion) but also by nonhomeostatic brain circuits that process the reward-related, “hedonic” qualities of food intake (19). Therefore, we applied a twofold assessment of food intake that relied, on the one hand, on a large breakfast buffet after an overnight fast to investigate homeostatic, primarily hunger-driven energy intake (20–22), and on the other hand, on a collection of snacks of varying palatability offered after breakfast intake for the measurement of reward-driven food intake (22–24). |
