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Representative scheme of the oxytocin neuronal circuits controlling food intake. Leptin, through the leptin receptor (LepR), activates oxytocin (Oxt) neurons in the hypothalamic paraventricular nucleus (PVN) and POMC/CART neurons in the hypothalamic arcuate nucleus (ARC), whereas it inhibits AgRP/NPY neurons in the ARC. Once oxytocin neurons are activated, they are innervating and activating POMC/CART neurons in the hypothalamic ARC nucleus and the hindbrain NTS nucleus (which is receiving also innervation from the gut), leading to a decrease in food intake. Moreover, activation of oxytocin neurons also triggers a negative feedback loop as PVN oxytocin neurons innervate AgRP/NPY neurons in the ARC nucleus, which inhibit oxytocin neurons in the PVN. At last, oxytocin neurons innervate the posterior pituitary and their activation leads to the secretion of oxytocin into the circulation, a way by which oxytocin can reach its target tissues, such as white adipose tissue. Arrow-headed lines and bar-headed lines indicate activation and inhibition, respectively. Oxytocin neurons and innervations are drawn in red, POMC/CART neurons in green, AgRP/NPY neurons in blue, leptin protein in purple circles, and oxytocin protein in red circles. Abbreviations: Oxt, oxytocin; POMC, pro-opiomelanocortin; CART, cocaine- and amphetamine-regulated transcript; AgRP, agouti-related protein; NPY, neuropeptide Y; CCK, cholecystokinin; LepR, leptin receptor; OxtR, oxytocin receptor; ARC, arcuate nucleus; PVN, paraventricular nucleus; NTS, nucleus of the solitary tract.
Source publication
This review summarizes the existing literature on the effects of oxytocin administration in the treatment of obesity in different animal models and in humans, focusing on the central control of food intake, the oxytocin effects on adipose tissue, and the relationships between oxytocin and leptin. Oxytocin is a hypothalamic nonapeptide synthesized m...
Citations
... Oxytocin neurons in caudal regions of the PVH coordinate various aspects of ingestive behavior and autonomic regulation (15)(16)(17)(18)(19)(20)(21)(22)(23). Oxytocin neural circuits mature relatively late in development, as mature oxytocin peptide is not detected until after birth, and axon outgrowth progressively increases during the first few weeks of postnatal life (24)(25)(26). ...
... This observation suggests an indirect mechanism of leptin action on neural development, perhaps through activity-dependent activation of axon targeting. Thus, leptin signaling appears to function indirectly during postnatal life to alter development of PVH oxytocin neurons, in contrast to its regulatory actions documented previously in adult rodents(16,22,(56)(57)(58).Neuronal activity has not been shown previously to impact development of hypothalamic circuits, however, activity-dependent axonal targeting has been well documented in otherneural systems. Studies in the visual system of multiple species have demonstrated that neural activity, either spontaneous or patterned, is required for normal development of central projections (10, 59, 60). ...
During postnatal life, the adipocyte-derived hormone leptin is required for proper targeting of neural inputs to the paraventricular nucleus of the hypothalamus (PVH) and impacts the activity of neurons containing agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus. Activity-dependent developmental mechanisms are known to play a defining role during postnatal organization of neural circuits, but whether leptin-mediated postnatal neuronal activity specifies neural projections to the PVH or impacts downstream connectivity is largely unexplored. Here, we blocked neuronal activity of AgRP neurons during a discrete postnatal period and evaluated development of AgRP inputs to defined regions in the PVH, as well as descending projections from PVH oxytocin neurons to the dorsal vagal complex (DVC) and assessed their dependence on leptin or postnatal AgRP neuronal activity. In leptin-deficient mice, AgRP inputs to PVH neurons were significantly reduced, as well as oxytocin-specific neuronal targeting by AgRP. Moreover, downstream oxytocin projections from the PVH to the DVC were also impaired, despite the lack of leptin receptors found on PVH oxytocin neurons. Blocking AgRP neuron activity specifically during early postnatal life reduced the density of AgRP inputs to the PVH, as well as the density of projections from PVH oxytocin neurons to the DVC, and these innervation deficits were associated with dysregulated autonomic function. These findings suggest that postnatal targeting of descending PVH oxytocin projections to the DVC requires leptin-mediated AgRP neuronal activity, and represents a novel activity-dependent mechanism for hypothalamic specification of metabolic circuitry, with consequences for autonomic regulation.
Significance statement
Hypothalamic neural circuits maintain homeostasis by coordinating endocrine signals with autonomic responses and behavioral outputs to ensure that physiological responses remain in tune with environmental demands. The paraventricular nucleus of the hypothalamus (PVH) plays a central role in metabolic regulation, and the architecture of its neural inputs and axonal projections is a defining feature of how it receives and conveys neuroendocrine information. In adults, leptin regulates multiple aspects of metabolic physiology, but it also functions during development to direct formation of circuits controlling homeostatic functions. Here we demonstrate that leptin acts to specify the input-output architecture of PVH circuits through an activity-dependent, transsynaptic mechanism, which represents a novel means of sculpting neuroendocrine circuitry, with lasting effects on how the brain controls energy balance.
... Oxytocin, a neuropeptide synthesized in the hypothalamus and secreted by the posterior pituitary gland, is traditionally associated with childbirth, lactation, and social bonding behaviors [1,2]. However, recent studies have expanded our understanding of oxytocin's roles, suggesting its involvement in a myriad of physiological processes, including metabolism and energy homeostasis [3][4][5]. This peptide hormone acts through the oxytocin receptor, which is expressed not only in the central nervous system but also in peripheral tissues, including the heart, pancreas, and adipose tissue, indicating its systemic influence [6,7]. ...
Oxytocin, traditionally recognized for its roles in social bonding and reproductive behaviors, is emerging as a crucial regulator of mitochondrial metabolism and energy homeostasis. This review synthesizes current research illustrating how oxytocin influences cellular energy processes, particularly within the context of metabolic disorders. By interacting with oxytocin receptors in key metabolic organs, oxytocin modulates mitochondrial biogenesis, enhances glucose uptake, and optimizes energy utilization, thereby contributing to overall metabolic stability. Recent studies in rodent models highlight the potential of oxytocin analogs in ameliorating symptoms of metabolic syndromes, such as obesity and diabetes, by improving mitochondrial function and energy expenditure. This review aims to consolidate these findings, propose mechanisms of action, and discuss the therapeutic prospects of oxytocin in managing metabolic diseases. The implications of oxytocin’s metabolic effects extend beyond traditional reproductive and social domains, suggesting a multifaceted hormone with significant potential for addressing public health challenges related to metabolic disorders.
... OXT is also implicated in the control of control of energy balance. It has turned out to be a downstream mediator of the effects of leptin, an anorexigenic product of white fat cells that signals to the brain how much energy is stored as body fat (Altirriba et al., 2015) Moreover leptin has been shown to target a specific subpopulation of OXT neurons in paraventricular nucleus (PVN), and its effects are important for leptin's ability to reduce body weight in both control and obese rats (Perello and Raingo, 2013). Secretion of OXT from a descending PVN to nucleus of the solitary tract pathway contributes to leptin's attenuation of food intake by a mechanism that involves the activation of paraventricular nucleus oxytocin neurons by leptin, resulting in increased sensitivity of nucleus of the solitary tract neurons to satiety signals (Blevins et al., 2004). ...
... Therefore, it is postulated that a decrease in circulating oxytocin levels may serve as a potential risk factor linked to obesity. A recent study has additionally demonstrated the potential of oxytocin administration as a therapeutic intervention for addressing leptin resistance in individuals with obesity (25). Oxytocin has been found to have various effects on body weight, primarily characterized by a reduction in food consumption, an increase in energy expenditure, and an enhancement of lipolysis (24,26). ...
Introduction and Aim: Obesity is a serious, life-threatening health condition that is prevalent in Iraq and the world as a whole. Since Leptin, irisin, oxytocin and insulin are proposed to play main roles in energy expenditure, glucose homeostasis, regulating body weight, reducing obesity and improving life expectancy so the aim of this study was to evaluate the concentrations of these anti-obesity hormones plus insulin resistance Materials and Methods: The study was conducted on 100 obese young men with a mean age of 29.95 years and fifty normal weight young men with a mean age of 28.44. Results: In obese men, the mean leptin concentration was 24.08±9.91 ng/ml which was significantly higher than in normal weight men 5.48 ng/ml. Serum irisin levels in obese men and normal weight were 8.9 ng/ml, 2.4 ng/ml respectively, and it was significantly higher in obese group in comparison to the normal weight group. The mean serum oxytocin concentration was significantly lower in obese group 6.41pg/ml in comparison to normal weight 29.55 pg/ml. Serum insulin levels in obese and normal weight were 19.55±5.56 and 3.64 micro lU/ml respectively and it was significantly higher in obese men. The mean fasting blood glucose concentration in obese men was 98.67mg/dl and it was significantly higher than in normal weight 84±9.85 mg/ml. Insulin resistance (HOMA IR) was significantly higher in obese men 6.6 than in normal weight 0.68. Conclusion: Serum levels of leptin, irisin, insulin, and insulin resistance are higher in obese young men, while oxytocin levels were noticeably low. Our study also shows that obesity increases the likelihood of insulin resistance.
... This response contributed to DOHaD. In other words, if the variation in the oxytocin downstream of leptin is clarified, it could play a significant role in clarifying DOHaD [24,25]. ...
Changes in the activities of some metabolic factors have been suggested to increase the risk of conditions associated with the Developmental Origins of Health and Disease (DOHaD). We examined changes in oxytocin (OT), a metabolic factor, and OT receptor (OTR) mRNA levels throughout the developmental period in rats of intrauterine undernutrition. Pregnant rats were divided into two groups: a maternal normal nutrition (mNN) and maternal undernutrition (mUN) group. Serum OT concentrations and hypothalamic mRNA levels of OT and OTR were measured in both offspring at various postnatal stages. Both offspring showed significant increases in serum OT concentrations during the neonatal period, significant reductions around the pubertal period, and significant increases in adulthood. Hypothalamic OT mRNA expression levels gradually increased from the neonatal to pubertal period and decreased in adulthood in both offspring. In the pre-weaning period, hypothalamic OT mRNA expression levels were significantly lower in the mUN offspring than in the mNN offspring. In the mUN offspring, hypothalamic OTR mRNA expression levels transiently increased during the neonatal period, decreased around the pubertal period, and increased again in adulthood, whereas transient changes were not detected in mNN offspring. These changes could affect nutritional and metabolic regulation systems in later life and play a role in the mechanisms underlying DOHaD.
... En términos generales se considera que la Oxt reduce la ingesta de alimento y aumenta el gasto energético en animales saciados y en ayuno (Arletti et al, 1989;Noble, Billington, Kotz & Wang, 2014), mejora el metabolismo de la glucosa y disminuye el peso corporal y tejido adiposo en ratas obesas (Altirriba, Poher & Rohner-Jeanrenaud, 2015;Iwasa et al., 2019;Roberts et al., 2017), inhibe la ingesta de alimento en ratas macho y hembra (Liu et al., 2020). En contraste, el bloqueo farmacológico de los receptores de Oxt con antagonistas selectivos, aumenta la ingesta calórica y el peso corporal en ratones (Zhang & Cai, 2011). ...
El consumo intermitente de bebidas dulces y refrigerios (snacks) entre comidas contribuyen con el desarrollo de la obesidad. La frecuencia de consumo y el tamaño de los refrigerios (incluyendo bebidas) con una carga calórica alta, conducen al sobrepeso. Se reconoce la participación de la oxitocina en el control de la alimentación, pero su mecanismo de acción no se ha establecido totalmente. Por tanto, el objetivo de esta investigación fue evaluar el efecto del acceso intermitente a una solución de sacarosa, sobre la expresión de las neuronas del núcleo paraventricular (PVN) y del núcleo supraótico (SON) que producen oxitocina (Oxt), y caracterizar la microestructura de la conducta de beber en ratas saciadas. Se tuvieron tres grupos de ratas macho Wistar saciadas por 23 h, y en la primera hora al inicio del periodo de luz, el grupo Control tuvo agua, el grupo Restringido 5g de una solución de sacarosa al 20% y el grupo Ad libitum acceso libre a la solución de sacarosa. Los sujetos incrementaron el consumo de la solución de sacarosa a pesar de estar saciados, esto debido a la interrupción del estado de saciedad y la demora del proceso de satisfacción. La actividad de las neuronas de Oxt se incrementó en ambos núcleos, en el grupo Restringido la mayor expresión se observó en el SON y en el grupo Ad libitum en el PVN. No se encontró correlación entre la cantidad de bebida ingerida y la actividad de las neuronas Oxt, se discuten los posibles mecanismos participantes.
... Furthermore, in the paraventricular nucleus of the hypothalamus, leptin alters oxytocin levels and activates oxytocin neurons. On the other hand, increased oxytocin levels, could enhance leptin sensitivity and modulate leptin resistance state, a common condition observed in overweight/obese individuals [61]. Interestingly, some probiotic bacterial strains such as L. reuteri has been demonstrated to increase oxytocin gene expression [62]. ...
... Interestingly, some probiotic bacterial strains such as L. reuteri has been demonstrated to increase oxytocin gene expression [62]. This effect could subsequently lead to improving the body weight homeostasis regulation [61]. ...
Recent studies have demonstrated the effect of probiotics, prebiotics, and synbiotics on adiponectin and leptin levels; however, those findings remain contested. The present study aimed to explore the impact of probiotics/synbiotics on appetite-regulating hormones and the desire to eat.
Methods
A systematic review was conducted by searching the Medline (PubMed) and Scopus databases from inception to December 2021, using relevant keywords and MeSH terms, and appropriate randomized controlled trials (RCTs) were extracted. The standardized mean differences (SMD) and 95% confidence intervals (95%CIs) were calculated as part of the meta-analysis using a random-effect model to determine the mean effect sizes. Analysis of Galbraith plots and the Cochrane Chi-squared test were conducted to examine heterogeneity.
Results
Meta-analysis of data from a total of 26 RCTs (n = 1536) showed a significant decrease in serum/plasma leptin concentration following probiotic/synbiotic supplementation (SMD: -0.38, 95%CI= -0.638, -0.124); P-value= 0.004; I²= 69.4%; P heterogeneity <0.001). The leptin level decrease from probiotic/synbiotic supplementation was higher in patients with NAFLD than those with overweight/obesity or type 2 diabetes mellitus/ metabolic syndrome/ prediabetes. Probiotic/synbiotic supplementation was associated with a trending increase in adiponectin levels, stronger in patients with type 2 diabetes mellitus, metabolic syndrome, and prediabetes (SMD: 0.25, 95%CI= 0.04, 0.46) µg/mL; P-value=0.021; I² =16.8%; P heterogeneity= 0.30). Additionally, supplementation with probiotic/synbiotic was linked to a slight increase in desire to eat (SMD: 0.34, 95%CI= 0.03, 0.66) P-value = 0.030; I² =39.4%; P heterogeneity= 0.16).
Conclusion
Our meta-analysis indicates a favorable impact of probiotic/synbiotic supplementation on regulating leptin and adiponectin secretion.
... Oxytocin (OT) is a 9-amino acid neuropeptide synthesized by the paraventricular nucleus and supraoptic nucleus in hypothalamic regions, which is secreted from the posterior lobe of the pituitary gland [10]. Recent studies have revealed that OT plays an important role in controlling the metabolism, appetite, and body weight of humans and animals [11]. Previous studies also found that the intraperitoneal, subcutaneous, intracerebroventricular, or intranasal injection of OT not only reduces food intake and/or body weight, but also activates lipolysis in adipose tissue brought on by β-oxidation, and reduces the fat weight in some mammals, such as mice [12][13][14][15][16][17][18], rats [18][19][20][21][22][23][24][25], monkeys [26], and humans [27,28]. ...
... It is becoming increasingly obvious that OT, a neuropeptide synthesized in the hypothalamus, is involved in controlling metabolism, appetite, and body weight [11]. In our previous study, we found that the body weight and food intake were reduced by chronic peripheral OT administration in conventional PCOS model rats [32]. ...
Polycystic ovary syndrome (PCOS) is frequently seen in females of reproductive age and is associated with metabolic disorders that are exacerbated by obesity. Although body weight reduction programs via diet and lifestyle changes are recommended for modifying reproductive and metabolic phenotypes, the drop-out rate is high. Thus, an efficacious, safe, and continuable treatment method is needed. Recent studies have shown that oxytocin (OT) reduces body weight gain and food intake, and promotes lipolysis in some mammals, including humans (especially obese individuals), without any adverse effects. In the present study, we evaluated the changes in endogenous OT levels, and the effects of acute and chronic OT administration on body weight changes, food intake, and fat mass using novel dihydrotestosterone-induced PCOS model rats. We found that the serum OT level was lower in PCOS model rats than in control rats, whereas the hypothalamic OT mRNA expression level did not differ between them. Acute intraperitoneal administration of OT during the dark phase reduced the body weight gain and food intake in PCOS model rats, but these effects were not observed in control rats. In contrast, chronic administration of OT decreased the food intake in both the PCOS model rats and control rats. These findings indicate that OT may be a candidate medicine that is efficacious, safe, and continuable for treating obese PCOS patients.
... For example, intranasal oxytocin treatment showed a significant reduction in body weight loss, total cholesterol, and low-density lipoprotein in obese but nondiabetic adults [291]. The beneficial effect of exogenous oxytocin was also observed in persons with leptin-resistant obesity [292]. ...
The high prevalence of metabolic syndrome in persons with schizophrenia has spurred investigational efforts to study the mechanism beneath its pathophysiology. Early psychosis dysfunction is present across multiple organ systems. On this account, schizophrenia may be a multisystem disorder in which one organ system is predominantly affected and where other organ systems are also concurrently involved. Growing evidence of the overlapping neurobiological profiles of metabolic risk factors and psychiatric symptoms, such as an association with cognitive dysfunction, altered autonomic nervous system regulation, desynchrony in the resting-state default mode network, and shared genetic liability, suggest that metabolic syndrome and schizophrenia are connected via common pathways that are central to schizophrenia pathogenesis, which may be underpinned by oxytocin system dysfunction. Oxytocin, a hormone that involves in the mechanisms of food intake and metabolic homeostasis, may partly explain this piece of the puzzle in the mechanism underlying this association. Given its prosocial and anorexigenic properties, oxytocin has been administered intranasally to investigate its therapeutic potential in schizophrenia and obesity. Although the pathophysiology and mechanisms of oxytocinergic dysfunction in metabolic syndrome and schizophrenia are both complex and it is still too early to draw a conclusion upon, oxytocinergic dysfunction may yield a new mechanistic insight into schizophrenia pathogenesis and treatment.
... Leptin receptor is broadly expressed in the hypothalamus, and its regulation of puberty and gonadotropin levels is complex, mediated through indirect effects on GnRH neurons [36,37] The absence of effects of Lepr cKO on puberty, estrous cycles, and embryo numbers confirms that that the leptin receptors regulating these processes were not deleted. Leptin receptor is also expressed in hypothalamic oxytocin-producing neurons, particularly in the paraventricular nucleus (PVN), which are critical for leptin regulation of satiety [38]. Pgr, however, is barely expressed in the PVN [39]. ...
Leptin is required for fertility, including initiation of estrous cycles. It is therefore challenging to assess the role of leptin signaling during pregnancy. While neuron-specific transgene approaches suggest that leptin signaling in the central nervous system is most important, experiments with pharmacologic inhibition of leptin in the uterus or global replacement of leptin during pregnancy suggest leptin signaling in the reproductive tract may be required. Here, conditional leptin receptor knockout (Lepr cKO) with a progesterone receptor-driven Cre recombinase was used to examine the importance of leptin signaling in pregnancy. Lepr cKO mice have almost no leptin receptor in uterus or cervix, and slightly reduced leptin receptor levels in corpus luteum. Estrous cycles and progesterone concentrations were not affected by Lepr cKO. Numbers of viable embryos did not differ between primiparous control and Lepr cKO dams on days 6.5 and 17.5 of pregnancy, despite a slight reduction in the ratio of embryos to corpora lutea, showing that uterine leptin receptor signaling is not required for embryo implantation. Placentas of Lepr cKO dams had normal weight and structure. However, over four parities, Lepr cKO mice produced 22% fewer live pups than controls, and took more time from pairing to delivery by their fourth parity. Abnormal birth outcomes of either dystocia or dead pups occurred in 33% of Lepr cKO deliveries but zero control deliveries, and the average time to deliver each pup after crouching was significantly increased. Thus, leptin receptor signaling in the reproductive tract is required for normal labor and delivery.
Summary sentence.
Mice lacking leptin receptor in the reproductive tract produce fewer live pups and have more adverse labor outcomes than controls, but normal numbers of embryos near term, showing that leptin receptor signaling is required for normal parturition.
