Oxytocin: A Potential Therapeutic for Obesity

Abstract

Oxytocin is a neuropeptide involved in the homeostasis of food consumption and energy; it affects hedonic eating. Studies in obese or binge-eating patients reported the hypophagic effect of oxytocin, which reduced caloric intake after administration. Several studies have demonstrated the effect of oxytocin’s increasing energy intake, decreasing food consumption, and contributing to weight loss. Oxytocin’s effects on food intake and metabolism suggest its therapeutic potential for treating obesity and binge eating.

INTRODUCTION

Oxytocin is a hormone produced in the hypothalamus and secreted by the posterior pituitary gland.¹ The hormone is involved in childbirth and breastfeeding and affects emotions such as love and affection, social behavior, and metabolic processes.² Several studies have demonstrated the effects of oxytocin on increasing energy consumption and decreasing food consumption, leading to weight loss. Oxytocin’s effects on food intake and metabolism suggest its potential for treating obesity and binge-eating.

PHYSIOLOGICAL PROPERTIES OF OXYTOCIN

Oxytocin is a peptide comprising nine amino acids produced in the brain and peripheral organs. It binds to the oxytocin receptor, which is a member of the G protein-coupled receptor (GPCR) family.³ Oxytocin is synthesized in the supraoptic nucleus and paraventricular nucleus (PVN) of the hypothalamus.^4-6 It regulates eating behaviors and the metabolism.¹ Magnocellular neuroendocrine neurons in two nuclei extend axonal connections into the posterior pituitary gland. The hormone is secreted into the peripheral blood circulation⁷ and does not cross back through the blood-brain barrier.^8-12 Other axonal connections exist between the PVN oxytocin neurons and regions of the brain. The PVN contains parvocellular oxytocin neurons, which protrude into the central nervous system structures including the brainstem and spinal cord.¹³ Parvocellular oxytocin neurons in the PVN connect to the nuclear bed of the stria terminalis, the ventral tegmental area, and the nucleus accumbens and are involved in reward behavior and eating behavior regulation.^14-18 GPCRs bound by oxytocin are expressed throughout the brain¹⁹ in structures such as the olfactory nucleus, hypothalamus, amygdala, and anterior cingulate cortex limbic system.²⁰ Oxytocin interacts with other neurotransmitters, and serotonin has been reported to increase oxytocin concentrations.³ Dopamine interacts with oxytocin to regulate the activity of the reward circuitry in the brain (Fig. 1).^21,22 Oxytocin is synthesized in such organs as the placenta, heart, kidneys, uterus, ovaries, testis, blood vessels, and skin.^19,23 Oxytocin receptors are present on myoepithelial cells, the pancreas, heart, blood vessels, kidneys, thymus, adipocytes, and macrophages.^24,25 Oxytocin receptors are involved in nitric oxide production, uterine contractions, and lipolysis through G protein coupling and C-beta pathway activation.^26-29 The production and secretion of oxytocin in the gastrointestinal tract⁷ are associated with autocrine and paracrine effects.^30,31 Positive feedback effects have been reported from the central or peripheral administration of oxytocin, stimulating auto-receptors in the magnocellular supraoptic neurons.^32,33 Oxytocin receptors are found throughout the central nervous system and peripheral regions, providing a clue for the regulation of food consumption and metabolism. In addition to the anterior pituitary gland, oxytocin receptors have been observed in the pancreas, adipocytes, and gastrointestinal tract, and studies have reported their association with eating behaviors (Fig. 2).^19,30,34-43

Figure. 1.

Oxytocin production and secretion in the central nervous system. SON, supraoptic nucleus; PVN, paraventricular nucleus.

Figure. 2.

The effect of oxytocin on eating behavior and metabolism.

REGULATION OF ENERGY BALANCE AND METABOLISM OF OXYTOCIN

Oxytocin affects appetite by decreasing intake and promoting lipolysis and the oxidation of fats. It also lowers body temperature and visceral fat while increasing thermoregulation and energy consumption. Furthermore, it plays a role in glucose and metabolic homeostasis, improving insulin sensitivity.^1,44 An increase in oxytocin sends signals to reduce calorie consumption and raise energy intake. Dysfunction in oxytocin signaling can cause weight gain. Variations in the oxytocin receptor gene have been linked to obesity.⁴⁵ Oxytocin decreases food intake by affecting feeding behavior and causes satiety signaling in the brain. A positive relationship was found between oxytocin levels and body mass index,⁴⁶ and oxytocin levels correlate with visceral fat mass. In addition, a positive association was demonstrated between oxytocin levels and obesity and metabolic syndrome.^47,48 Oxytocin has been shown to decrease weight and body fat via fat oxidation and lipolysis independent of its effects on food intake.^11,33,49,50 Decreases in visceral fat and liver fat related to oxytocin⁴⁹ are particularly noteworthy because they are metabolically important fat types associated with a higher risk of cardiovascular disease and metabolic syndrome.⁵¹

Oxytocin receptors bind G protein activated adenylate cyclase to increase cyclic adenosine monophosphate production, resulting in lipolysis.^26,28,52 The mechanism of energy expenditure facilitated by oxytocin has not been established. However, oxytocin generates thermogenesis by activating brown fat and converting white adipose tissue to beige fat.⁵³ Unlike a single dose of oxytocin, chronic oxytocin exposure has been shown to affect energy consumption.⁵⁴ Oxytocin affects metabolism directly and also down-regulates the hypothalamic-pituitary-adrenal axis. Oxytocin was reported to decrease adrenocorticotropic hormone and cortisol release from the anterior pituitary gland and adrenal glands through oxytocin receptors, mitigating the negative metabolic effects of cortisol.^43,55-60

Oxytocin receptors are also found on pancreatic α and β islet cells.⁴² Conflicting responses of oxytocin to insulin and blood glucose have been reported in human studies. Oxytocin caused different effects depending upon the dose or route of administration such as whether the injections were intravenous or intranasal and whether they were delivered in a bolus or by continuous infusion. One study showed a sharp drop in postprandial 3-hour blood sugar following the administration of an intravenous bolus of 10 MIU/kg oxytocin to postpartum women.⁶¹

In another study, 10 IU of oxytocin was administered to postpartum women intravenously, but there was no change in blood glucose or insulin levels.⁶² In men, 6 IU of oxytocin, but not 3 IU, increased insulin levels with no change in blood glucose, glucagon, growth hormone, or cortisol levels.⁶³ In another study, healthy men in their 20s were administered oxytocin at 0.2 IU/min over 60 minutes in a continuous intravenous infusion, which caused hyperglycemia; elevated insulin, glucagon, and adrenaline levels; and decreased cortisol levels. The same results were seen in insulin-induced hypoglycemia.⁶⁴ This suggests that oxytocin affects glucose homeostasis but does not consistently raise or lower blood glucose. Oxytocin improved pancreatic β cell responsiveness and insulin sensitivity to a glucose challenge.⁶⁵

Diabetic patients showed high blood glucose, insulin, and glycosylated hemoglobin levels and a high homeostatic model assessment of insulin resistance with low levels of oxytocin.^66,67 Oxytocin administration increased the expression of glucose transporter type 4, an insulin-dependent glucose transporter.⁶⁸ Oxytocin directly facilitated insulin secretion from β cells of the pancreas through the turnover of phosphoinositide and the activation of protein kinase C, and by indirectly affecting vagal cholinergic neurons.^69,70

STUDIES ON THE ROLE OF OXYTOCIN IN EATING BEHAVIORS

Many studies have investigated the impact of oxytocin on the eating habits of rats. Oxytocin suppressed the appetites of mice for sugar and carbohydrates rather than for fat. Oxytocin receptor-knockout mice consumed more sweet solutions, sweetened food, and carbohydrates than wild-type mice^71-73 and progressed to late-onset obesity.⁷⁴ Wild-type mice injected with an oxytocin receptor antagonist consumed more sucrose than fat.⁷⁵ Oxytocin expression was reduced in rats with long-term exposure to sugar.⁷⁶ Single-minded 1 gene deletions⁷⁷ and the loss of hypothalamic oxytocin neurons,⁷⁸ which control appetite and weight, have been associated with obesity. Diet-induced obese mice showed dysfunctions in their oxytocin systems.⁷⁹

Injections of oxytocin decreased the feeding and drinking of rats of both sexes in a dose-dependent manner.⁸⁰ Oxytocin administration resulted in greater reductions in food intake in obese rats than in slim rats.⁸¹ Intraventricular injections demonstrated better effects on the regulation of food consumption than did intraperitoneal injections.⁸² However, peripheral oxytocin administration also improved obesity by decreasing food consumption and visceral fat.⁴⁹ Maejima et al.⁴⁹ showed that both intraperitoneal and subcutaneous (SC) oxytocin injections decreased food consumption and the effects were better in obese mice than in normal-weight mice. Daily SC oxytocin injections decreased food intake and body weight. Chronic oxytocin injections delivered via a pump decreased food consumption, total body weight, and visceral fat. There was no rebound weight recovery. Chronic oxytocin infusions promoted fat usage and improved glucose tolerance.⁴⁹ However, discrepant results of oxytocin effects have been reported.

A meta-analysis by Leslie et al.⁸³ reported different results according to sex and the oxytocin administration period. Oxytocin decreased food consumption more in male rats than in female rats, with food intake decreasing over time. A short-term oxytocin treatment delivered as a single dose either by a central or peripheral route reduced food consumption, whereas chronic, long-term administration did not.⁸³ Altirriba et al.³⁹ reported the dose-dependent effects of oxytocin on 1-week reductions in weight and food consumption in obese, diabetic mice. Oxytocin had a smaller effect in thin rats. After 2 weeks, weight gain in the oxytocin-administered group and the saline-administered group was similar. In the higher oxytocin receptor specificity group, the short-term administration of oxytocin produced a small weight gain without any change in food consumption. This suggests that the effect of oxytocin on weight loss was due to decreased food intake as well as increased fat metabolism.³⁹

The mechanism by which oxytocin reduces food intake has not been established. However, one hypothesized mechanism of the effects of oxytocin on caloric intake involves the action of oxytocin on homeostatic, reward, and impulse control brain circuitry, which could reduce calorie consumption, particularly of more appetizing foods in response to peripheral signals indicating energy availability.¹

Several studies on oxytocin and obesity in humans have been conducted. An association between variants of the oxytocin receptor gene, which encodes GPCRs, and childhood obesity was reported.⁴⁵ Single-minded 1 gene variants are also associated with obesity in humans.^84,85 Reduced numbers and sizes of PVN oxytocin neurons have been reported in Prader-Willi syndrome patients.⁸⁶

One study observed changes on functional magnetic resonance imaging after intranasal administration of 24 IU of oxytocin in 15 normal-weight men. Activity in the ventrolateral prefrontal cortices, ventromedial prefrontal cortex, anterior cingulate, and supplementary motor area increased when the subjects were viewed food images after oxytocin administration.⁸⁷

A randomized controlled trial was performed in Korean women by treating anorexia nervosa, bulimia nervosa, and control groups with 40 IU of intranasal oxytocin.⁸⁸ The administration of oxytocin reduced 24-hour caloric intake in patients with bulimia nervosa. However, intake by women in the anorexia nervosa or control groups was not changed.⁸⁸ Studies have also looked at the central oxytocin effect produced by the administration of 24 IU of intranasal oxytocin in men. In one study, total calorie and fat consumption but not carbohydrates or protein were decreased when oxytocin was administered to 25 men.⁵⁴ In another study, total caloric intake was not decreased after oxytocin was administered in 20 men, but chocolate cookie consumption was reduced by 25%.⁸⁹ In another study, the administration of oxytocin in normal-weight men (20 men) and obese men (18 men) reduced snack consumption. However, the total amount of food consumed was reduced only in obese men.⁹⁰

Single-dose administration of oxytocin showed calorie and weight loss effects, and some studies analyzed the results of chronic oxytocin administration. In a study where 24 IU of oxytocin was administered intranasally four times a day for eight weeks, the participants lost an average of 4.6 kg after four weeks and an average of 8.9 kg after eight weeks. More weight was lost by the more obese participants.⁹¹ A meta-analysis⁸³ reported greater decreases in food consumption because of oxytocin in males compared to females, in the satiated state compared to the fasting state, and in more obese subjects compared to less.⁸³

THERAPEUTIC POTENTIAL OF OXYTOCIN IN TREATING OBESITY

In previous studies,^54,89 intranasal treatment with oxytocin reduced the intake of tasty food such as those high in fats and carbohydrates, resulting in weight loss. Oxytocin decreased food intake by controlling compensatory hedonic eating.⁹² Oxytocin’s inhibition of reward-related food motivation¹ was associated with satiety signals and inhibited activity of the food-related reward pathway.¹⁵

More research is needed before oxytocin can be used to treat obesity. Studies investigating the side effects of oxytocin in humans reported that intranasal oxytocin administration (1) resulted in no detectable subjective changes in the recipients, (2) caused no consistent side effects, and (3) was not associated with adverse outcomes when given short term in doses of 18–40 IU in controlled research settings.⁹³ Oxytocin can modify the heart rate and cause cardiovascular effects,^94,95 and people with heart and cardiovascular conditions may be more vulnerable to these effects. Susceptible subjects should be selected with consideration of dose and route, treatment effects, and side effects. Nonetheless, we found that oxytocin had beneficial effects, inducing early satiation, reducing reward-driven food intake,⁸⁹ and improving glucose homeostasis. Pharmacological studies should be conducted to develop strategies for using oxytocin as a new obesity treatment. Integrated behavioral and metabolic approaches to treating obesity should also be developed.

CONCLUSION

Several studies have shown that oxytocin reduced food consumption, increased energy consumption, and caused weight loss in animals and humans. Oxytocin reduced the consumption of appetizing foods such as fats and carbohydrates, resulting in weight loss. Oxytocin was also shown to affect the metabolism of glucose and lipids in humans. These effects can result in weight loss through homeostatic pathways, reward processing, and cognitive control, especially in obese patients.⁹⁶ The administration of oxytocin had a positive effect on excessive appetite by producing satiety and reducing visceral fat. Thus, we suggest that oxytocin may be a beneficial new treatment option for obesity.