Introduction
Oxytocin, a neuropeptide synthesized in the hypothalamus and secreted by the posterior pituitary gland, plays a crucial role in various physiological processes, including childbirth, breastfeeding, emotional regulation (love and affection), social behavior, and metabolic functions. Several studies have explored the effects of oxytocin on energy consumption, food intake, and weight management, revealing its potential as a therapeutic target for obesity and related metabolic disorders. This article delves into the existing research on oxytocin and weight loss, examining its mechanisms of action, effects on eating behavior, and potential clinical applications.
The Role of Oxytocin in Food Consumption and Energy Homeostasis
Oxytocin is a peptide comprising nine amino acids produced in the brain and peripheral organs. It binds to the oxytocin receptor, a member of the G protein-coupled receptor (GPCR) family. Synthesized in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus, oxytocin regulates eating behaviors and metabolism.
Magnocellular neuroendocrine neurons in these nuclei extend axonal connections into the posterior pituitary gland, where the hormone is secreted into the peripheral blood circulation. Notably, oxytocin does not readily cross back through the blood-brain barrier.
Parvocellular oxytocin neurons in the PVN connect to central nervous system structures, including the brainstem and spinal cord. These neurons also project to the nuclear bed of the stria terminalis, the ventral tegmental area, and the nucleus accumbens, influencing reward and eating behavior regulation.
GPCRs bound by oxytocin are expressed throughout the brain, particularly in structures like the olfactory nucleus, hypothalamus, amygdala, and anterior cingulate cortex limbic system. Oxytocin interacts with other neurotransmitters, with serotonin increasing oxytocin concentrations and dopamine working together to regulate the brain's reward circuitry.
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Oxytocin is synthesized in various organs, including the placenta, heart, kidneys, uterus, ovaries, testis, blood vessels, and skin. Oxytocin receptors are present on myoepithelial cells, the pancreas, heart, blood vessels, kidneys, thymus, adipocytes, and macrophages, where they influence nitric oxide production, uterine contractions, and lipolysis through G protein coupling and C-beta pathway activation. The production and secretion of oxytocin in the gastrointestinal tract are associated with autocrine and paracrine effects. Positive feedback effects have been reported from central or peripheral administration of oxytocin, stimulating auto-receptors in the magnocellular supraoptic neurons.
The widespread distribution of oxytocin receptors throughout the central nervous system and peripheral regions suggests its involvement in regulating food consumption and metabolism. In addition to the anterior pituitary gland, oxytocin receptors have been observed in the pancreas, adipocytes, and gastrointestinal tract, with studies reporting their association with eating behaviors.
Oxytocin's Impact on Appetite and Metabolic Processes
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. 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. 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, and oxytocin levels correlate with visceral fat mass.
Oxytocin receptors bind G protein activated adenylate cyclase to increase cyclic adenosine monophosphate production, resulting in lipolysis. 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. Unlike a single dose of oxytocin, chronic oxytocin exposure has been shown to affect energy consumption.
Oxytocin affects metabolism directly and also down-regulates the hypothalamic-pituitary-adrenal axis. Oxytocin receptors are also found on pancreatic α and β islet cells. 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. In another study, 10 IU of oxytocin was administered to postpartum women intravenously, but there was no change in blood glucose or insulin levels. 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. 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. This suggests that oxytocin affects glucose homeostasis but does not consistently raise or lower blood glucose.
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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 and progressed to late-onset obesity. Wild-type mice injected with an oxytocin receptor antagonist consumed more sucrose than fat. Oxytocin expression was reduced in rats with long-term exposure to sugar. Single-minded 1 gene deletions and the loss of hypothalamic oxytocin neurons, which control appetite and weight, have been associated with obesity. Injections of oxytocin decreased the feeding and drinking of rats of both sexes in a dose-dependent manner. Oxytocin administration resulted in greater reductions in food intake in obese rats than in slim rats. Intraventricular injections demonstrated better effects on the regulation of food consumption than did intraperitoneal injections. However, peripheral oxytocin administration also improved obesity by decreasing food consumption and visceral fat. Maejima et al. 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. A meta-analysis by Leslie et al. 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. Altirriba et al. 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. The mechanism by which oxytocin reduces food intake has not been established.
Human Studies on Oxytocin and Obesity
Several studies on oxytocin and obesity in humans have been conducted. One study observed changes on functional magnetic resonance imaging after intranasal administration of 24 IU of oxytocin in 15 normal-weight men. A randomized controlled trial was performed in Korean women by treating anorexia nervosa, bulimia nervosa, and control groups with 40 IU of intranasal oxytocin. 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. 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. In another study, total caloric intake was not decreased after oxytocin was administered in 20 men, but chocolate cookie consumption was reduced by 25%. In another study, the administration of oxytocin in normal-weight men (20 men) and obese men (18 men) reduced snack consumption. 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. In previous studies, intranasal treatment with oxytocin reduced the intake of tasty food such as those high in fats and carbohydrates, resulting in weight loss.
Considerations and Future Directions
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. Oxytocin can modify the heart rate and cause cardiovascular effects, 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, and improving glucose homeostasis. Pharmacological studies should be conducted to develop strategies for using oxytocin as a new obesity treatment.
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