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Low Sympathetic Tone and Obese Phenotype in Oxytocin-deficient Mice
Abstract
Oxytocin (Oxt) is secreted both peripherally and centrally and is involved in several functions including parturition, milk let-down reflex, social behavior, and food intake. Recently, it has been shown that mice deficient in Oxt receptor develop late-onset obesity. In this study, we characterized a murin model deficient in Oxt peptide (Oxt(-/-)) to evaluate food intake and body weight, glucose tolerance and insulin tolerance, leptin and adrenaline levels. We found that Oxt(-/-) mice develop late-onset obesity and hyperleptinemia without any alterations in food intake in addition to having a decreased insulin sensitivity and glucose intolerance. The lack of Oxt in our murin model also results in lower adrenalin levels which led us to hypothesize that the metabolic changes observed are associated with a decreased sympathetic nervous tone. It has been shown that Oxt neurons in the paraventricular nucleus (PVN) are a component of a leptin-sensitive signaling circuit between the hypothalamus and caudal brain stem for the regulation of food intake and energy homeostasis. Nevertheless, the lack of Oxt in these mice does not have a direct impact on feeding behavior whose regulation is probably dependent on the complex interplay of several factors. The lack of hyperphagia evident in the Oxt(-/-) mice may, in part, be attributed to the developmental compensation of other satiety factors such as cholecystokinin or bombesin-related peptides which merits further investigation. These findings identify Oxt as an important central regulator of energy homeostasis.
... Oxt regulates energy metabolism, the lean/fat composition of the body and thermoregulation. Mice homozygous for deletions of Oxt or its receptor (Oxtr) show late-onset obesity, albeit are normophagic [5,6]. Oxt/Oxtr −/− mice are not obese as newborns but become obese later in life because the obesity caused by the lack of Oxt takes time to reach full force [7]. ...
... The causes are still mysterious although certain features of PWS such as abnormalities in thermoregulation, sleep control and altered pain perception indicate an altered autonomic nervous system (ANS) [30]. Oxt and Oxtr −/− mice have lower adrenalin levels than control [5,6], but whether this altered ANS activity is associated with features of Oxt/Oxtr −/− mice needs to be further researched. Indeed, Oxt plays an essential role in glucose metabolism but the lack of research about Oxt and insulin resistance in PWS prevents further analysis. ...
... This suggests that there is probably a time-window during which Oxt system can be rewired and compensated due to neuroplasticity of the brain of infants [20]. Additionally, in infants the obesity is not established yet and muscles are not infiltrated with fat, as happen when the Oxt system is dysfunctional in adulthood, which makes it still possible to rescue the muscle phenotype of PWS individuals and consequently to normalize the Oxt-system [5,11]. In summary, the lack of consistency in the existing clinical trials shows that simply providing exogenous Oxt may not be sufficient to address the nature of the Oxt abnormality. ...
Prader–Willi Syndrome (PWS) is a genetic neurodevelopmental disorder that is caused by either the deletion of the paternal allele of 15q11-q13, maternal uniparental disomy of chromosome 15 or defects in the chromosome 15 imprinting centre and is characterized by cognitive impairment, hyperphagia and low metabolic rate with significant risk of obesity, as well as a variety of other maladaptive behaviours and autistic spectrum disorder (ASD). Many of the features seen in PWS are thought to be due to hypothalamic dysfunction resulting in hormonal abnormalities and impaired social functioning. The preponderance of evidence indicates that the Oxytocin system is dysregulated in PWS individuals and that this neuropeptide pathways may provide promising targets for therapeutic intervention although the process by which this dysregulation occurs in PWS awaits mechanistic investigation. PWS individuals present abnormalities in thermoregulation an impaired detection for temperature change and altered perception of pain indicating an altered autonomic nervous system. Recent studies indicate that Oxytocin is involved in thermoregulation and pain perception. This review will describe the update on PWS and the recent discoveries on Oxytocin regulation of thermogenesis together with the potential link between Oxytocin regulation of thermogenesis and PWS to create a new groundwork for the treatment of this condition.
... What sparked our interest at that time was that Oxt-and Oxtr-deficient mice developed their metabolic phenotype in the absence of hyperphagia. This is in contrast to the expectation that hypothalamic Oxt decreases food intake by increasing leptin concentration in plasma [35][36][37]. Moreover, the metabolic role of Oxt is different in young versus older animals or it takes time to reach full force. ...
... This concept was named in our laboratory "the oxytocin paradox". Several explanations have been given to this discrepancy, including that Oxt may only mark the identity of neurons projecting from PVN, but its action is mediated by classical neurotransmitters such as GABA; alternatively, Oxt may be anorexigenic in normal mice, but developmental mechanisms may compensate for its absence in Oxt −/− or Oxtr −/− mice [3,36,38]. The appetite of Oxt −/− reported as normal, in spite of the hyperleptinemia, was possibly excessive relative to the level of adiposity [39]. ...
... The appetite of Oxt −/− reported as normal, in spite of the hyperleptinemia, was possibly excessive relative to the level of adiposity [39]. This was not the case since the stomachs of Oxt-deficient mice were reported comparable to wildtype mice for size and weight, ruling out any excess in food consumption [36,40]. The tipping point of these observations was that Oxtr-deficient mice are thermogenically impaired, with a basal temperature lower than wildtype. ...
The research program on oxytocin started in 1895, when Oliver and Schafer reported that a substance extracted from the pituitary gland elevates blood pressure when injected intravenously into dogs. Dale later reported that a neurohypophysial substance triggers uterine contraction, lactation, and antidiuresis. Purification of this pituitary gland extracts revealed that the vasopressor and antidiuretic activity could be attributed to vasopressin, while uterotonic and lactation activity could be attributed to oxytocin. In 1950, the amino-acid sequences of vasopressin and oxytocin were determined and chemically synthesized. Vasopressin (CYFQNCPRG-NH2) and oxytocin (CYIQNCPLG-NH2) differ by two amino acids and have a disulfide bridge between the cysteine residues at position one and six conserved in all vasopressin/oxytocin-type peptides. This characterization of oxytocin led to the Nobel Prize awarded in 1955 to Vincent du Vigneaud. Nevertheless, it was only 50 years later when the evidence that mice depleted of oxytocin or its receptor develop late-onset obesity and metabolic syndrome established that oxytocin regulates energy and metabolism. Oxytocin is anorexigenic and regulates the lean/fat mass composition in skeletal muscle. Oxytocin’s effect on muscle is mediated by thermogenesis via a pathway initiated in the myocardium. Oxytocin involvement in thermogenesis and muscle contraction is linked to Prader-Willi syndrome in humans, opening exciting therapeutic avenues.
... Despite the importance of the Oxt-OxtR system in the food intake and homeostasis of body weight (Maejima et al., 2018), knockout (KO) and ablation studies still question such findings (Sutton et al., 2016;Worth and Luckman, 2021). For example, Oxt or Oxtr KO mice showed increased body weight at around 4 months of age (termed late-onset obesity), while their food intake was not different from that of wild-type mice (Camerino, 2009;Takayanagi et al., 2008). Diphtheria toxin-based genetic ablation of Oxt-expressing cells in adult mice increased the body weight of male mice with a high-fat diet, but not those with normal chow, and in both cases, food intake was unaffected (Wu et al., 2012b). ...
... We found that AAV-Cre-injected Oxt flox/mice were heavier than those in the other groups ( Figure 1E and F). Importantly, this increase in body weight was considered unlikely to be a reflection of late-onset obesity, as previously reported (Camerino, 2009;Takayanagi et al., 2008), because we did not find a significant difference between the wild-type and Oxt -/mice ( Figure 1F). Next, we analyzed the relationship between the number of remaining Oxt+ neurons and body weight. ...
... In turn, the plasma concentrations of triglyceride and leptin were higher in Oxt flox/mice that had received AAV-Cre injection than in those that had received vehicle injection ( Figure 3D). Of note, a prominent increase in plasma leptin was also reported in the late-onset obesity cases of 6-month-old Oxt KO mice (Camerino, 2009). Our data regarding Oxt cKO showed the plasma leptin phenotype in the earlier stage of 13-week-old mice. ...
Decades of studies have revealed molecular and neural circuit bases for body weight homeostasis. Neural hormone oxytocin (Oxt) has received attention in this context because it is produced by neurons in the paraventricular hypothalamic nucleus (PVH), a known output center of hypothalamic regulation of appetite. Oxt has an anorexigenic effect, as shown in human studies, and can mediate satiety signals in rodents. However, the function of Oxt signaling in the physiological regulation of appetite has remained in question, because whole-body knockout (KO) of Oxt or Oxt receptor ( Oxtr ) has little effect on food intake. We herein show that acute conditional KO (cKO) of Oxt selectively in the adult PVH, but not in the supraoptic nucleus, markedly increases body weight and food intake, with an elevated level of plasma triglyceride and leptin. Intraperitoneal administration of Oxt rescues the hyperphagic phenotype of the PVH Oxt cKO model. Furthermore, we show that cKO of Oxtr selectively in the posterior hypothalamic regions, especially the arcuate hypothalamic nucleus, a primary center for appetite regulations, phenocopies hyperphagic obesity. Collectively, these data reveal that Oxt signaling in the arcuate nucleus suppresses excessive food intake.
... Despite the importance of the OT-OTR system in the food intake and homeostasis of body weight (Maejima et al., 2018), knockout (KO) and ablation studies still question such findings (Sutton et al., 2016;Worth and Luckman, 2021). For example, OT or OTR KO mice showed increased body weight at around 4 months old (termed late-onset obesity), while their food intake was not different from that of wild-type mice (Camerino, 2009;Takayanagi et al., 2008). Diphtheria toxin-based genetic ablation of OT-expressing cells in adult mice increased the body weight of male mice with a high-fat diet, but not those with normal chow, and in both cases, food intake was unaffected (Wu et al., 2012b). ...
... We found that AAV-Creinjected OT flox/mice were heavier than mice in the other groups ( Figure 1E and 1F). Importantly, this increase in body weight was considered unlikely to be a reflection of lateonset obesity, as previously reported (Camerino, 2009;Takayanagi et al., 2008), because we did not find a significant difference between the wild-type and OT -/mice ( Figure 1F). Next, . ...
... In turn, the plasma concentrations of triglyceride and leptin were higher in OT flox/mice that had received AAV-Cre injection than in those that had received vehicle injection ( Figure 3D). Although a prominent increase in plasma leptin was also reported in the late-onset obesity cases of 6-month-old OT KO mice (Camerino, 2009), our data were obtained in the early stage of 13-week-old mice, in which OT KO mice showed no body weight phenotype. These results suggest that the cKO of OT affects the homeostasis of viscera and blood constituents. ...
Decades of studies have revealed molecular and neural circuit bases for body weight homeostasis. Neural hormone oxytocin (OT) has received attention in this context because it is produced by neurons in the paraventricular hypothalamic nucleus (PVH), a known output center of hypothalamic regulation of appetite. OT has an anorexigenic effect, as shown in human studies, and can mediate satiety signals in rodents. However, the function of OT signaling in the physiological regulation of appetite has remained in question, because whole-body knockout (KO) of OT or OT receptor (OTR) has little effect on food intake. We herein show that acute conditional KO (cKO) of OT selectively in the adult PVH, but not in the supraoptic nucleus, markedly increases body weight and food intake, with an elevated level of plasma triglyceride and leptin. Intraperitoneal administration of OT rescues the hyperphagic phenotype of the PVH OT cKO model. Furthermore, we show that cKO of OTR selectively in the posterior hypothalamic regions, which include the primary centers for appetite regulations, phenocopies hyperphagic obesity. Collectively, these data functionally reveal that OT signaling in the posterior hypothalamic regions suppresses excessive food intake.
... Oxytocin receptor or OT deficient mice are associated with adultonset obesity (Kasahara et al., 2007;Takayanagi et al., 2008;Camerino, 2009;Sun et al., 2019) that appears at 8 (Tamma et al., 2009), 10 (Kasahara et al., 2007 or 16 weeks (Camerino, 2009) in OT null mice and 12 weeks in OTR null mice . The adult-onset obesity in the OT and OTR null mice is characterized by increased body weight (Kasahara et al., 2007;Takayanagi et al., 2008;Camerino, 2009), fat mass (Sun et al., 2019) and/or fat pad weight Camerino, 2009). ...
... Oxytocin receptor or OT deficient mice are associated with adultonset obesity (Kasahara et al., 2007;Takayanagi et al., 2008;Camerino, 2009;Sun et al., 2019) that appears at 8 (Tamma et al., 2009), 10 (Kasahara et al., 2007 or 16 weeks (Camerino, 2009) in OT null mice and 12 weeks in OTR null mice . The adult-onset obesity in the OT and OTR null mice is characterized by increased body weight (Kasahara et al., 2007;Takayanagi et al., 2008;Camerino, 2009), fat mass (Sun et al., 2019) and/or fat pad weight Camerino, 2009). ...
... Oxytocin receptor or OT deficient mice are associated with adultonset obesity (Kasahara et al., 2007;Takayanagi et al., 2008;Camerino, 2009;Sun et al., 2019) that appears at 8 (Tamma et al., 2009), 10 (Kasahara et al., 2007 or 16 weeks (Camerino, 2009) in OT null mice and 12 weeks in OTR null mice . The adult-onset obesity in the OT and OTR null mice is characterized by increased body weight (Kasahara et al., 2007;Takayanagi et al., 2008;Camerino, 2009), fat mass (Sun et al., 2019) and/or fat pad weight Camerino, 2009). The finding that this occurs despite having no changes in overall daily food intake (Kasahara et al., 2007;Takayanagi et al., 2008;Camerino, 2009) suggests that other mechanisms (such as impairments in energy expenditure) may contribute to their obesity phenotype. ...
Obesity is a growing health concern, as it increases risk for heart disease, hypertension, type 2 diabetes, cancer, COVID-19 related hospitalizations and mortality. However, current weight loss therapies are often associated with psychiatric or cardiovascular side effects or poor tolerability that limit their long-term use. The hypothalamic neuropeptide, oxytocin (OT), mediates a wide range of physiologic actions, which include reproductive behavior, formation of prosocial behaviors and control of body weight. We and others have shown that OT circumvents leptin resistance and elicits weight loss in diet-induced obese rodents and non-human primates by reducing both food intake and increasing energy expenditure (EE). Chronic intranasal OT also elicits promising effects on weight loss in obese humans. This review evaluates the potential use of OT as a therapeutic strategy to treat obesity in rodents, non-human primates, and humans, and identifies potential mechanisms that mediate this effect.
... Indeed, mice that are homozygous for deletions of either Oxt or its receptor develop late onset obesity and metabolic syndrome. Interestingly, Oxt-and Oxtr-deficient mice develop a metabolic phenotype in the absence of hyperphagia [15,16]. The metabolic role of Oxt diverges in young versus older animals or, alternatively, it takes time to reach full force. ...
... Another hypothesis was that the appetite of Oxt −/− reported as normal, in spite of the hyperleptinemia, was excessive relative to the degree of adiposity [20]. This hypothesis was ruled out by the evidence that the stomachs of Oxt −/− mice were comparable to wild-type mice for size and weight excluding any excess in food consumption [16]. A very important point is that Oxtr-deficient mice have a basal temperature lower than wild-type, which shed a light on the role of Oxt on temperature regulation and lean/fat mass composition in this model [15]. ...
... Oxt signaling is important for whole-body glucose metabolism and Oxt administration in humans reducing fasting respiratory quotient meaning that Oxt can induce a shift from carbohydrate to fat oxidation [21,22]. Recently, and about 10 years after these first discoveries, three different studies have been published by Yuan et al. [23], Sun et al. [24], Conte et al. [19], each of them presenting a different theory on the role of Oxt in the regulation of energy metabolism and the paradox of normophagic obesity that we first described for Oxt −/− and Oxtr −/− mice [15,16]. Specifically, in Yuan et al. [23], the author analyzed the role of Oxt in energy homeostasis after a cold stress (CS) challenge and found that Oxt dissipates stored energy in brown adipose tissue (BAT) and white adipose tissue (WAT) improving metabolic dysfunctions in obese mice. ...
The origin of the Oxytocin/Vasopressin system dates back about 600 million years. Oxytocin (Oxt) together with Vasopressin (VP) regulate a diversity of physiological functions that are important for osmoregulation, reproduction, metabolism, and social behavior. Oxt/VP-like peptides have been identified in several invertebrate species and they are functionally related across the entire animal kingdom. Functional conservation enables future exploitation of invertebrate models to study Oxt’s functions not related to pregnancy and the basic mechanisms of central Oxt/VP signaling. Specifically, Oxt is well known for its effects on uteri contractility and milk ejection as well as on metabolism and energy homeostasis. Moreover, the striking evidence that Oxt is linked to energy regulation is that Oxt- and Oxytocin receptor (Oxtr)-deficient mice show late onset obesity. Interestingly Oxt−/− or Oxtr−/− mice develop weight gain without increasing food intake, suggesting that a lack of Oxt reduce metabolic rate. Oxt is expressed in a diversity of skeletal muscle phenotypes and regulates thermogenesis and bone mass. Oxt may increases skeletal muscle tonicity and/or increases body temperature. In this review, the author compared the three most recent theories on the effects of Oxt on body composition.
... Oxt and Oxt receptor (Oxtr) are implicated in the regulation of energy homeostasis, but the detailed mechanism is still unclear. Murine models deficient in Oxt or Oxtr develops late-onset obesity (Takayanagi et al. 2008, Camerino 2009a. Interestingly, the metabolic syndrome profile observed in the lack of Oxt or Oxtr occurred in the absence of hyperphagia since Oxt−/− or Oxtr−/− mice showed no significant change in food intake, suggesting that a lack of Oxt may reduce metabolic rate and energy expenditure (Takayanagi et al. 2008, Camerino 2009a) Moreover people at a high risk of metabolic diseases show ectopic fat deposits within the muscle and intramyocellular lipids (Dumitru et al. 2018). ...
... Murine models deficient in Oxt or Oxtr develops late-onset obesity (Takayanagi et al. 2008, Camerino 2009a. Interestingly, the metabolic syndrome profile observed in the lack of Oxt or Oxtr occurred in the absence of hyperphagia since Oxt−/− or Oxtr−/− mice showed no significant change in food intake, suggesting that a lack of Oxt may reduce metabolic rate and energy expenditure (Takayanagi et al. 2008, Camerino 2009a) Moreover people at a high risk of metabolic diseases show ectopic fat deposits within the muscle and intramyocellular lipids (Dumitru et al. 2018). ...
... These data are consistent with our hypothesis that Oxt has an analgesic effect through the activation of TRPV1 in SOL muscle after CS. The lack of Oxt/Oxtr signaling in mice other than chronic heart failure leads to late-onset obesity, and impaired thermogenesis without a change in food consumption (Breton et al. 2002, Mantella et al. 2003, Kublaoui et al. 2008, Takayanagi et al. 2008, Camerino 2009a, Trayhurn 2017, Dumitru et al. 2018. Considering also that Oxtr gene expression increases in SOL together with the Mhc1/Mhc2b gene expression ratio in SOL but not in TA muscle (Camerino et al. 2019). ...
We explored the involvement of Oxytocin receptor (Oxtr)/ Transient-receptor-potential-vanilloid-1 (TRPV1) genes and Oxytocin (Oxt) on the adaptation of skeletal muscle to cold stress challenge in mice. Oxtr expression in hypothalamic paraventricular (PVN), supraoptic nuclei (SON), and hippocampus (HIPP) were evaluated by immunohistochemistry in parallel with the measurement of circulating Oxt. The Oxtr and TRPV1 gene expression in Soleus (SOL) and Tibialis Anterior (TA) muscles were investigated by RT-PCR. Histological studies of the cardiac muscle after cold stress were also performed. Male mice (n=15) were divided into controls maintained at room temperature (RT=24°C), exposed to cold stress (CS) at T=4°C for 6 hours (6h), and 5 days (5d). Immunohistochemical studies showed that Oxtr protein expression increased by 2-fold (p=0.01) in PVN and by 1.5-fold (p=0.0001) in HIPP after 6h and 5d CS, but decreased by 2-fold (p=0.026) in SON at 5d. Both Oxtr and TRPV1 gene expression increased after 6h and 5d CS in SOL and TA muscles. Oxtr vs TRPV1 gene expression in SOL and TA muscles evaluated by regression analysis was linearly correlated following CS at 6h and 5d but not at control temperature of 24+1°C, supporting the hypothesis of coupling between these genes. The circulating levels of Oxt are unaffected after 6h CS but decreased by 0.2-fold (p=0.0141) after 5d CS. This is the first report that Oxtr and TRPV1 expression are upregulated in response to cold acclimation in skeletal muscle. The up-regulation of Oxtr in PVN and HIPP balances the decrease of circulating Oxt.
... The glimpse of something missing in the Oxt-and Oxtr-deficient mice was the fact that their metabolic phenotype matured in the absence of hyperphagia. This is in contrast to the expectation that hypothalamic Oxt decreases food intake by increasing leptin concentration in plasma [23,24]. Moreover, the metabolic role of Oxt diverges in young versus older animals or alternatively it takes time to reach full force. ...
... Another hypothesis was that the appetite of Oxt−/− reported as normal, in spite of the hyperleptinemia, was excessive relative to the degree of adiposity [27]. This hypothesis was ruled out by the evidence that the stomachs of Oxt-deficient mice were reported comparable to wild-type mice for size and weight, which exclude any excess in food consumption [24]. Oxtr-deficient mice are thermogenically impaired, with a basal temperature lower than wild-type, which shed a light on the role of Oxt on temperature regulation and lean/fat mass composition in this model [23]. ...
... Nevertheless, the role of Oxt-expressing neurons in energy regulation is not clear yet [36,37]. Although initial work on Oxt KO reported no metabolic phenotype, recent work showed late onset obesity in Oxtr and Oxt KO mice [23,24]. This obesity was initially explained as the result of altered energy expenditure rather than altered food intake [23,38]. ...
Oxytocin (Oxt) is a nine amino acid peptide important in energy regulation and is essential to stress-related disorders. Specifically, low Oxt levels are associated with obesity in human subjects and diet-induced or genetically modified animal models. The striking evidence that Oxt is linked to energy regulation is that Oxt- and oxytocin receptor (Oxtr)-deficient mice show a phenotype characterized by late onset obesity. Oxt−/− or Oxtr−/− develop weight gain without increasing food intake, suggesting that a lack of Oxt reduce metabolic rate. Oxt is differentially expressed in skeletal muscle exerting a protective effect toward the slow-twitch muscle after cold stress challenge in mice. We hypothesized that Oxt potentiates the slow-twitch muscle as it does with the uterus, triggering “the oxytonic contractions”. Physiologically, this is important to augment muscle strength in fight/flight response and is consistent with the augmented energetic need at time of labor and for the protection of the offspring when Oxt secretion spikes. The normophagic obesity of Oxt−/− or Oxtr−/− mice could have been caused by decreased skeletal muscle tonicity which drove the metabolic phenotype. In this review, we summarized our findings together with the recent literature on this fascinating subjects in a “new oxytonic perspective” over the physicology of Oxt.
... For instance, the involvement of OT in parturition has been demonstrated not only in a vast number of mammalian species (e.g., non-human primates 8 , rabbits 9 , and many others 10 (including vasotocin), 11,12 ), but possibly also in non-vertebrates such as annelids in the form of what has been considered distant homologs 13 . OT has also been implicated in the regulation of energy balance and metabolism in mammals [14][15][16] . There is thus a growing consensus that OT and structurally similar peptides are highly conserved, possibly reflecting conservation in their function 4,17-19 . ...
... For instance, the involvement of OT in parturition has been demonstrated not only in a vast number of mammalian species (e.g., non-human primates 8 , rabbits 9 , and many others 10 (including vasotocin), 11,12 ), but possibly also in non-vertebrates such as annelids in the form of what has been considered distant homologs 13 . OT has also been implicated in the regulation of energy balance and metabolism in mammals [14][15][16] . There is thus a growing consensus that OT and structurally similar peptides are highly conserved, possibly reflecting conservation in their function 4,[17][18][19] . ...
Oxytocin is a neuropeptide associated with both psychological and somatic processes like parturition and social bonding. Although oxytocin homologs have been identified in many species, the evolutionary timeline of the entire oxytocin signaling gene pathway has yet to be described. Using protein sequence similarity searches, microsynteny, and phylostratigraphy, we assigned the genes supporting the oxytocin pathway to different phylostrata based on when we found they likely arose in evolution. We show that the majority (64%) of genes in the pathway are ‘modern’. Most of the modern genes evolved around the emergence of vertebrates or jawed vertebrates (540 - 530 million years ago, ‘mya’), including OXTR, OXT and CD38. Of those, 45% were under positive selection at some point during vertebrate evolution. We also found that 18% of the genes in the oxytocin pathway are ‘ancient’, meaning their emergence dates back to cellular organisms and opisthokonta (3500–1100 mya). The remaining genes (18%) that evolved after ancient and before modern genes were classified as ‘medium-aged’. Functional analyses revealed that, in humans, medium-aged oxytocin pathway genes are highly expressed in contractile organs, while modern genes in the oxytocin pathway are primarily expressed in the brain and muscle tissue.
... Oxt regulates energy metabolism [7]. About 15 years ago, based on our lab results, we suggested that mice homozygous for deletions of Oxt or its receptor (Oxtr) show late-onset obesity with no changes in food consumption [8,9]. Oxt/Oxtr −/− mice showed normal body weight at birth and late-onset obesity around reproductive age [3]. ...
... Oxt is related to the regulation of energy and metabolism [8,9], as Oxt concentration increases in pregnancy and lactation in females, and Oxt triggers aggressive behavior and augments muscle strength. Evolutionarily, this is of paramount importance given that labor is needed for the protection of offspring when the offspring is most vulnerable to predators and Oxt concentration in plasma is at its peak [64,65]. ...
Oxytocin (Oxt) regulates thermogenesis, and altered thermoregulation results in Prader-Willi syndrome (PWS), Schaaf-Yang syndrome (SYS), and Autism spectrum disorder (ASD). PWS is a genetic disorder caused by the deletion of the paternal allele of 15q11-q13, the maternal uniparental disomy of chromosome 15, or defects in the imprinting center of chromosome 15. PWS is characterized by hyperphagia, obesity, low skeletal muscle tone, and autism spectrum disorder (ASD). Oxt also increases muscle tonicity and decreases proteolysis while PWS infants are hypotonic and require assisted feeding in early infancy. This evidence inspired us to merge the results of almost 20 years of studies and formulate a new hypothesis according to which the disruption of Oxt’s mechanism of thermoregulation manifests in PWS, SYS, and ASD through thermosensory abnormalities and skeletal muscle tone. This review will integrate the current literature with new updates on PWS, SYS, and ASD and the recent discoveries on Oxt’s regulation of thermogenesis to advance the knowledge on these diseases.
... The studies, in vitro, in and ex vivo, for all the degenerative diseases discussed in this manuscript (autism, cardiovascular diseases, obesity/diabetes and COVID-19) are listed in Table 1. [116] myocytes, [117] rat newborn cardiomyocytes [118] apoE−/− mice [119] Sprague-Dawley rats [120][121][122][123] Japanese white rabbits [124] WHHL rabbits [125] Porcine model [126] rat heart [127][128][129][130] dog heart [131] combined with obesity and/or diabetes H9c2 cells [132] obesity/diabetes neonatal rat cardiomyocytes [133] mouse bone marrow cells [134] mice obese diabetic ob/ob: [135] obese diabetic db/db: [136][137][138] OXT KO: [139,140], OXTRs KO: [141] diet induced obesity: [142][143][144][145][146][147] rats zucker rats: [148][149][150] high-fat diet-rats: [151][152][153][154][155] DHT-induced PCOS model rats: [156] OLETF rats: [157][158][159] other species NHPs, [160] prairie voles, [161] intranasal OXT, overweight and obese men: [162] intranasal OXT, ingestion and metabolic function in healthy men: [163] intranasal OXT in patients: [164] intravenous infusion of synthetic OXT analog to healthy men: [165] insulin sensitivity following intranasal OXT in healthy men: [166] intranasal OXT in fasted healthy men: [167,168] intranasal OXT in normal weight volunteers: [169] COVID-19 mice [170] OXTRs in human endothelial cells [171] effects of viral infection on OXTR [172] * All the references from Table 1 are presented in Table 2, with the related result of oxytocin intervention and/or treatment of degenerative diseases. ...
... In leptin-resistant db/db mice, peripheral OXT injection suppresses food intake by activating vagal afferent neurons and, thereby, ameliorates obesity [136], while in the same animals, chronic OXT treatment also led to a reduction in visceral adipose tissue inflammation and plasma markers of systemic inflammation, which is believed to play a role in disease progression [137]. Studies in OXT KO mice have indicated that the genetic absence of OXT is associated with enhanced initial and sustained intake of sucrose solutions [138], and a strong link between OXT deficiency, late-onset obesity and decreased sympathetic tone [139]. In another study, OXTR−/− mice demonstrated that the oxytocin receptor plays essential roles in the regulation of energy homeostasis [140]. ...
Oxytocin is a hormone secreted from definite neuroendocrine neurons located in specific nuclei in the hypothalamus (mainly from paraventricular and supraoptic nuclei), and its main known function is the contraction of uterine and/or mammary gland cells responsible for parturition and breastfeeding. Among the actions of the peripherally secreted oxytocin is the prevention of different degenerative disorders. These actions have been proven in cell culture and in animal models or have been tested in humans based on hypotheses from previous studies. This review presents the knowledge gained from the previous studies, displays the results from oxytocin intervention and/or treatment and proposes that the well described actions of oxytocin might be connected to other numerous, diverse actions of the biomolecule.
... In parallel with the line of research employing oxytocin administration in animals, oxytocin and OXTR gene knockout studies have been instrumental in further elucidating the different roles oxytocin plays in the coordination of energy balance. Initial studies have shown that mice homozygous for deletions of either oxytocin [125] or the OXTR [126] developed late-onset obesity which was not associated with hyperphagia. In addition to having excess weight, these mice displayed increased proportion of fat mass, hyper-lipidemia, decreased insulin sensitivity, impaired thermogenesis [97,[125][126][127], premature sarcopenia [73], as well as osteoporosis due to impaired bone formation [76,77]. ...
... Initial studies have shown that mice homozygous for deletions of either oxytocin [125] or the OXTR [126] developed late-onset obesity which was not associated with hyperphagia. In addition to having excess weight, these mice displayed increased proportion of fat mass, hyper-lipidemia, decreased insulin sensitivity, impaired thermogenesis [97,[125][126][127], premature sarcopenia [73], as well as osteoporosis due to impaired bone formation [76,77]. Metabolic perturbations, including decreased energy expenditure and/or decreased muscle tonicity, are thought to drive obesity in normophagic oxytocin/OXTR-deficient mice. ...
The hypothalamic peptide oxytocin and its receptor are involved in a range of physiological processes, including parturition, lactation, cell growth, wound healing, and social behavior. More recently, increasing evidence has established the effects of oxytocin on food intake, energy expenditure, and peripheral metabolism. In this review, we provide a comprehensive description of the central oxytocinergic system in which oxytocin acts to shape eating behavior and metabolism. Next, we discuss the peripheral beneficial effects oxytocin exerts on key metabolic organs, including suppression of visceral adipose tissue inflammation, skeletal muscle regeneration, and bone tissue mineralization. A brief summary of oxytocin actions learned from animal models is presented, showing that weight loss induced by chronic oxytocin treatment is related not only to its anorexigenic effects, but also to the resulting increase in energy expenditure and lipolysis. Following an in-depth discussion on the technical challenges related to endogenous oxytocin measurements in humans, we synthesize data related to the association between endogenous oxytocin levels, weight status, metabolic syndrome, and bone health. We then review clinical trials showing that in humans, acute oxytocin administration reduces food intake, attenuates fMRI activation of food motivation brain areas, and increases activation of self-control brain regions. Further strengthening the role of oxytocin in appetite regulation, we review conditions of hypothalamic insult and certain genetic pathologies associated with oxytocin depletion that present with hyperphagia, extreme weight gain, and poor metabolic profile. Intranasal oxytocin is currently being evaluated in human clinical trials to learn whether oxytocin-based therapeutics can be used to treat obesity and its associated sequela. At the end of this review, we address the fundamental challenges that remain in translating this line of research to clinical care.
... Oxytocin and OXTR mediated signaling also has strong anti-obesity effects. Both OXTR-and oxytocin-deficient mice developed obesity, without changes in food intake and locomotor activity (16,17), suggesting that the physiological role of oxytocin is to increase energy expenditure (18). On the other hand, oxytocin treatment has been shown to decrease food intake, body weight (BW), abdominal and subcutaneous fat mass, and improve insulin secretion in obese mice (19). ...
The high prevalence of obesity has become a pressing global public health problem and there exists a strong association between increased BMI and mortality at a BMI of 25 kg/m² or higher. The prevalence of obesity is higher among middle-aged adults than among younger groups and the combination of aging and obesity exacerbate systemic inflammation. Increased inflammatory cytokines such as interleukin 6 and tumor necrosis factor alpha (TNFα) are hallmarks of obesity, and promote the secretion of hepatic C-reactive protein (CRP) which further induces systematic inflammation. The neuropeptide oxytocin has been shown to have anti-obesity and anti-inflammation effects, and also suppress sweet-tasting carbohydrate consumption in mammals. Previously, we have shown that the Japanese herbal medicine Kamikihito (KKT), which is used to treat neuropsychological stress disorders in Japan, functions as an oxytocin receptors agonist. In the present study, we further investigated the effect of KKT on body weight (BW), food intake, inflammation, and sweet preferences in middle-aged obese mice. KKT oral administration for 12 days decreased the expression of pro-inflammatory cytokines in the liver, and the plasma CRP and TNFα levels in obese mice. The effect of KKT administration was found to be different between male and female mice. In the absence of sucrose, KKT administration decreased food intake only in male mice. However, while having access to a 30% sucrose solution, both BW and food intake was decreased by KKT administration in male and female mice; but sucrose intake was decreased in female mice alone. In addition, KKT administration decreased sucrose intake in oxytocin deficient lean mice, but not in the WT lean mice. The present study demonstrates that KKT ameliorates chronic inflammation, which is strongly associated with aging and obesity, and decreases food intake in male mice as well as sucrose intake in female mice; in an oxytocin receptor dependent manner.
... OT is a nonapeptide hormone produced by OT neurons in the paraventricular hypothalamus (PVH) that regulates energy metabolism 38 , alongside reproductive and social functions 39 . Mice lacking OT or the Otr gene exhibit obesity linked to reduced energy expenditure 40,41 . PVH OT neurons are activated during hypoglycemia, send axonal projections to the SC, and influence glucose tolerance 42 . ...
The sympathetic nervous system is vital in maintaining homeostasis and responding to environmental changes 1–3 . This regulation is coordinated by the spinal sympathetic preganglionic neurons (SPNs), which influence various organs both through neuronal pathways via postganglionic neurons and through endocrine processes by innervating the adrenal gland. Despite decades of research supporting the concept of selective control within this system 1,4–9 , the neural circuit organization responsible for the specificity of sympathetic outflow remains poorly understood. Notably, classical anatomical studies in rats have not revealed a definitive molecular code governing SPNs, nor have they confirmed the existence of SPNs strictly corresponding to specific output targets 1,6,10,11 . To reconcile this discrepancy, we aim to integrate recent transcriptome data of SPNs 12,13 in mice with viral-genetic toolkits ¹⁴ to map axonal projections and manipulate the functions of SPNs governing the gastrointestinal tract and adrenal gland. Here, we have identified two subtypes of SPNs in the lower thoracic spinal cord, defined at the molecular level, exhibiting non-overlapping patterns of innervation. Chemogenetic manipulations on these distinct SPN subtypes revealed selective impacts on the digestive functions in the gastrointestinal tracts or glucose metabolism mediated by the adrenal gland, respectively. This molecularly delineated parallel labeled-line organization in sympathetic outflows presents a potential avenue for selectively manipulating organ functions.
... Moreover, due to its role in maintaining energy homeostasis, oxytocin, a centrally acting neurotransmitter and hormone, is receiving more attention as a potential anti-obesity target [73]. Obesity was shown to be a characteristic of mice lacking either oxytocin or oxytocin receptors [74]. Also, in diet-induced obesity and genetically obese mouse models, long-term peripheral or central administration of oxytocin causes an inhibition of food intake, an increase in energy expenditure, and weight loss as seen in Table 2 [75]. ...
Many hormones act on the hypothalamus to control hunger and satiety through various pathways closely associated with several factors. When food is present in the gastro intestinal (GI) tract, enteroendocrine cells (EECs) emit satiety signals such as cholecystokinin (CCK), glucagon like peptide-1 (GLP-1) and peptide YY (PYY), which can then communicate with the vagus nerve to control food intake. More specifically, satiety has been shown to be particularly affected by the GLP-1 hormone and its receptor agonists that have lately been acknowledged as a promising way to reduce weight. In addition, there is increasing evidence that normal flora is also involved in the peripheral, central, and reward system that impact satiety. Moreover, neurologic pathways control satiety through neurotransmitters. In this review, we discuss the different roles of each of the GLP-1 hormone and its agonist, gut microbiomes, as well as neurotransmitters and their interconnected relation in the regulation of body's satiety homeostasis.
... Oxt receptor expression is observed in key metabolic organs such as adipose tissue [51] and endocrine pancreas [39], indicating its role in regulating adiposity and pancreatic function. Oxt-knockout mice develop obesity and glucose intolerance, highlighting the importance of Oxt in these processes [12]. Recent research suggests that PVN Oxt neurons respond to glucoprivation, and are necessary for the pancreatic beta cells response to glucose fluctuations [40]. ...
Evidence from animal experiments has shown that the hypothalamic paraventricular nucleus (PVN) plays a key role in regulating body weight and blood glucose levels. However, it is unclear whether neuron populations in the human PVN are involved in the development of type 2 diabetes mellitus (T2DM). To address this, we investigated the neuronal and glial populations in the PVN of 26 T2DM patients and 20 matched controls. Our findings revealed a significant reduction in oxytocin (Oxt) neuron density in the PVN of T2DM patients compared to controls, while other neuronal populations remained unchanged. This suggests that Oxt neurons may play a specific role in the pathophysiology of T2DM. Interestingly, the reduction in Oxt neurons was accompanied by a decreased melanocortinergic input in to the PVN as reflected by a reduction in alpha-MSH immunoreactivity. We also analysed two glial cell populations, as they are important for maintaining a healthy neural microenvironment. We found that microglial density, phagocytic capacity, and their proximity to neurons were not altered in T2DM patients, indicating that the loss of Oxt neurons is independent of changes in microglial immunity. However, we did observe a reduction in the number of astrocytes, which are crucial for providing trophic support to local neurons. Moreover, a specific subpopulation of astrocytes characterized by aquaporin 4 expression was overrepresented in T2DM patients. Since this subset of astrocytes is linked to the glymphatic system, their overrepresentation might point to alterations in the hypothalamic waste clearance system in T2DM. Our study shows selective loss of Oxt neurons in the PVN of T2DM individuals in association with astrocytic reduction and gliovascular remodelling. Therefore, hypothalamic Oxt neurons may represent a potential target for T2DM treatment modalities.
... However, recent research has discovered that adipocytes express RANKL/OPG which also play an important role in influencing OC development and regulating bone remodeling (Matsuo et al., 2020). Indeed, intraperitoneal injection with OT negatively modulates adipogenesis while promoting osteogenesis (Camerino, 2009). The differentiation of BMSCs into adipocytes is the key to bone marrow obesity and OP in postmenopausal women (Rajapakse et al., 2021). ...
Oxytocin (OT) is a neuropeptide known to affect social behavior and cognition. The epigenetic modification of the oxytocin receptor (OTR) via DNA methylation stimulates parturition and breast milk secretion and inhibits craniopharyngioma, breast cancer, and ovarian cancer growth significantly as well as directly regulates bone metabolism in their peripheral form rather than the central form. OT and OTR can be expressed on bone marrow mesenchymal stem cells (BMSCs), osteoblasts (OB), osteoclasts (OC), osteocytes, chondrocytes, and adipocytes. OB can synthesize OT under the stimulation of estrogen as a paracrine-autocrine regulator for bone formation. OT/OTR, estrogen, and OB form a feed-forward loop through estrogen mediation. The osteoclastogenesis inhibitory factor (OPG)/receptor activator of the nuclear factor kappa-B ligand (RANKL) signaling pathway is crucially required for OT and OTR to exert anti-osteoporosis effect. Downregulating the expression of bone resorption markers and upregulating the expression of the bone morphogenetic protein, OT could increase BMSC activity and promote OB differentiation instead of adipocytes. It could also stimulate the mineralization of OB by motivating OTR translocation into the OB nucleus. Moreover, by inducing intracytoplasmic Ca2+ release and nitric oxide synthesis, OT could regulate the OPG/RANKL ratio in OB and exert a bidirectional regulatory effect on OC. Furthermore, OT could increase the activity of osteocytes and chondrocytes, which helps increase bone mass and improve bone microstructure. This paper reviews recent studies on the role of OT and OTR in regulating cells in bone metabolism as a reference for their clinical use and research based on their reliable anti-osteoporosis effects.
... Investigaciones recientes en humanos y animales han asociado a la Oxt con la inhibición del consumo de alimentos palatables y ha surgido el interés por conocer el papel funcional que tiene la Oxt sobre el control de la conducta alimentaria y su posible uso terapéutico para el tratamiento de la hiperfagia y la obesidad (Burmester, Gibson, Butler, Bailey, & Terry, 2019;Iwasaki et al., 2019). El funcionamiento anómalo del sistema de Oxt está ligado a la obesidad en animales y en humanos, en modelos animales, se demostró que los ratones Oxtr -/-(con deficiencia funcional del receptor de Oxt) desarrollaron obesidad de inicio tardío (Camerino, 2009;Takayanagi et al., 2008). De forma semejante, los pacientes humanos con síndrome de Prader-Willi (quienes tienen un número reducido de neuronas de Oxt en el PVN), presentan hiperfagia y obesidad (Miller et al., 2017). ...
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.
... Among autonomic functions, the OXT neural system has been implicated in regulation of body temperature and metabolism by studies showing an impaired ability of cold defense and development of obesity in mice with deficiency in OXT signaling (Kasahara et al., 2007;Takayanagi et al., 2008;Camerino, 2009;Wu et al., 2012;Xi et al., 2017). In humans, it has been suggested that obesity and impaired thermoregulation in Prader-Willi syndrome may result from decreased OXT neurons in the PVH (PVH OXT neurons) (Swaab et al., 1995;Swaab, 1997). ...
Oxytocin alters autonomic functions besides social behaviors. However, the central neuronal links between hypothalamic oxytocinergic neurons and the autonomic nervous system remain unclear. Here we show that oxytocinergic neurons in the rat paraventricular hypothalamic nucleus (PVH), a pivotal site for energy homeostasis, innervate sympathetic premotor neurons in the rostral medullary raphe region (rMR) to stimulate brown adipose tissue (BAT) thermogenesis and cardiovascular functions. Oxytocin receptor stimulation in the rMR evokes BAT thermogenesis and tachycardia. In vivo optogenetic stimulation of the PVH→rMR long-range oxytocinergic pathway, using a virus-mediated system for amplified gene expression in oxytocinergic neurons, not only elicits BAT thermogenic and cardiac responses but also potentiates sympathetic responses evoked by glutamatergic transmission in the rMR. The PVH→rMR oxytocinergic pathway connects the hypothalamic circuit for energy homeostasis to thermogenic and cardiac sympathetic outflow, and, therefore, its defects may cause obesity and impaired thermoregulation, as seen in Prader-Willi syndrome.
... For example, lesion of OTR expressing neurones in the nucleus tractus solitarius (NTS) where OTRs are expressed (Loup et al., 1989) reduced the ability of satiety peptide cholecystokinin (CCK) to reduce food intake and prevented OTR antagonism action to stimulate food intake (Baskin et al., 2010). Similarly, suppressed food intake was observed upon optogenetic activation of PVN OT neurones (Atasoy et al., 2012) and OT -/-and OTR -/-mice are known to develop late-onset obesity (Camerino, 2009, Takayanagi et al., 2008. OT also plays an inhibitory role in drug addiction and dependence via action in the NAc: ...
Oxytocin (OT), an endogenous hormone and neuropeptide has been highlighted for its therapeutic potential to modulate socio-behavioural deficits. However, OT’s high molecular weight and hydrophilicity limits the extent of central nervous system (CNS) brain penetration, highlighting a need to improve OT brain delivery. An alternative popular route of drug delivery is intranasal administration, which allows small peptides to bypass the blood brain barrier (BBB) and access the brain more directly. Yet, the degree of OT brain penetration remains controversial and requires further improvement. As such, this thesis examined the modulation of CNS OT penetration by use of intranasal OT alone and when conjugated to a novel cell penetrating peptide: glycosaminoglycan (GAG)-binding enhanced transduction (GET; P21-LK15- 8R), producing OT-GET, and its ability to affect locomotor activity and social behaviour in rats. In vitro assays were established to determine OT-GET’s bioactivity, ability to improve OT transduction across a nasal epithelial cell monolayer and potential cytotoxicity. Using a calcium fluorimetry assay, OT-GET induced robust [Ca2+]i transients in OTR expressing Hs 578t breast cancer cells. Subsequent examination of OT-GET in a cell permeability assay using immortalised nasal epithelial cells RPMI 2650 saw an increased rate of OT delivery across the monolayer compared to OT alone. Only the highest GET concentration produced cytotoxicity (on cell viability) effects, which emphasised the need to identify an ideal peptide conjugation ratio in order to achieve desired effects without concomitant toxicity. In rats, subcutaneous OT (0.1mg/kg) reversed phencyclidine (PCP)-induced hyperactivity. Intranasal OT (100μg) showed slight effect, where cumulative ambulatory counts in the 30 minutes post-PCP was not significantly different to rats pre-treated with subcutaneous OT, although counts remained higher than saline treated animals. The same dose of intranasal OT increased the time spent by weight-matched rat pairs in prosocial body sniffing. Interestingly, a separate quantification of OT levels in the olfactory bulb revealed that OT-GET treated animals had a significant increase in OT compared to OT treated animals. Overall, OT-GET improved OT permeation across a nasal cell monolayer in vitro and improved brain penetration (olfactory bulb) in vivo compared to OT alone. Intranasal OT-GET did not produce changes in rats’ social behaviour, which may be due to OT receptor (OTR) desensitisation.
... Oxytocin-knockout and oxytocin receptor-knockout mice demonstrated decreased insulin sensitivity, increased glucose excursions, increased abdominal fat pads, and increased triglycerides [254,255]. The mechanism of oxytocin in decreasing appetite and food intake is conveyed through a modulating effect on reward-driven eating by the expression of oxytocin receptors in the ventral tegmental area, as well as in nucleus accumbens [256] and from projections from oxytocin-producing neurons in the paraventricular nuclei and supraoptic nuclei in the hedonic pathways, in addition to affecting the positive-valence mechanism at the central amygdala [257]. ...
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.
... Vagotomy elevated plasma levels of ghrelin and inhibited the effects of ghrelin on reducing insulin secretion in rodents [78,138]. Oxtr −/− male mice had lower adrenalin levels than controls, but whether this altered ANS activity is associated with features of Oxtr −/− male mice needs further research [139]. ...
Background
In recent years, more studies have observed that patients with Prader–Willi syndrome have lower insulin levels and lower insulin resistance than body mass index-matched controls, which may suggest protected glucose metabolism.
Method
The PubMed and Web of Science online databases were searched to identify relevant studies published in the English language using the terms “Prader–Willi syndrome” with “glucose”, “insulin”, “diabetes mellitus”, “fat”, “adipo*”, “ghrelin”, “oxytocin”, “irisin” or “autonomic nervous system”.
Results
The prevalence of impaired glucose intolerance, type 2 diabetes mellitus and some other obesity-associated complications in patients with Prader–Willi syndrome tends to be lower when compared to that in general obesity, which is consistent with the hypothetically protected glucose metabolism. Factors including adipose tissue, adiponectin, ghrelin, oxytocin, irisin, growth hormone and the autonomic nervous system possibly modulate insulin sensitivity in patients with Prader–Willi syndrome.
Conclusion
Although lower insulin levels, lower IR and protected glucose metabolism are widely reported in PWS patients, the causes are still mysterious. Based on existing knowledge, we cannot determine which factor is of utmost importance and what are the underlying mechanisms, and further research is in urgent need.
... Participants in the SRC condition were better able to maintain parasympathetic arousal compared to participants in the SRD and AMB condition. We were surprised that no reliable results emerged in the sympathetic system, especially in light of prior findings that sympathetic arousal is lowest when oxytocin is released (Petersson et al., 1996; Camerino, 2009;Moberg et al., 2019). While we can conclude that shared reality buffers against the negative physiological effects of stress by increasing calmness via parasympathetic arousal, we are uncertain whether it also decreases fight-and flightiness. ...
When a person faces a stressor alongside someone else, do they get more or less stressed when the other person agrees that the situation is stressful? While an equally stressed partner could plausibly amplify stress by making the situation seem more real and worthy of distress, we find that social validation during co-experienced stressors reduces reactivity. Specifically, the psychological experience of shared reality calms some people down. In Study 1, 70 undergraduate females who jointly faced a stressful event with someone else reported feeling less anxious when the other person felt the same way about the stressor, relative to when the other person appraised the situation in the opposite way or provided no indication of their appraisal. These findings were reflected in participants’ physiological reactivity, especially in the parasympathetic nervous system. In Study 2, we generalize these findings to co-experienced stressors in the daily lives of 102 heteronormative romantic couples in the New York City area. In line with tend-and-befriend theory, we found that shared reality during co-experienced stressors reduced anxiety for almost all females (99% of the sample) and for a minority of males (42% of the sample). Together, these findings unify major theories in health and social psychology by implying that shared reality reduces stressor reactivity, and that this effect is partially moderated by sex.
... 15 These data are mechanistically supported by the development of obesity in mice deficient in either Oxt or the OxtR. 16,17 Taken together with the anorexigenic role of Oxt during maintenance of metabolic homeostasis, [18][19][20][21][22] there is a distinct biological plausibility that defective Oxt-ergic signalling during development could have metabolic consequences for the offspring. ...
Background
Despite the importance of oxytocinergic signalling for satiety regulation and energy balance, the impact of exposure to synthetic oxytocin during childbirth on obesity during childhood remains unknown.
Objectives
To examine the association between oxytocin exposure during labour and the risk of being overweight or obese during childhood.
Methods
Synthetic oxytocin exposure data of mothers from the Danish Medical Birth Registry were linked with self-reported anthropometric data of their children from the Danish National Birth Cohort (5 months–11 years of age). Multinomial logistic regression and latent class growth analyses were performed to determine the association between oxytocin exposure and obesity during childhood.
Results
With the exception of the normal weight-to-overweight group between ages 5 and 12 months, none of the other analyses revealed a significant association between synthetic oxytocin use and the risk of being overweight until the age of 11 years. Furthermore, latent class growth analysis did not reveal an association between oxytocin exposure at birth and the risk of being overweight or obese during childhood.
Conclusions
Our analysis of a large cohort of children who varied in their synthetic oxytocin exposure status at childbirth did not reveal an association between oxytocin exposure and the risk of childhood overweight/obesity.
... Along with this, haploinsufficiency of single minded 1 (SIM1) gene necessary for the formation of PVN, results downregulation in the OTRs in hypothalamus and associated with hyperphagic obesity and significant increase in susceptibility to diet induced obesity in mice [13][14][15][16] and human [17,18], but exogenous OT reverses weight gain as well as excessive food intake [14]. These studies suggest that the OT signaling plays an important role in energy metabolism regulation, and supported by a study on mice deficient with either OT [19] or OTRs [20] results in the development of obesity in later stage. ...
Growing evidence suggests that oxytocin (OT) plays an important factor for the control of food intake, body weight, and energy metabolism in human and non-human animals. It has reported previously, the downregulation in oxytocin receptors (OTRs) expression is linked with the development of obesity, but exogenous OT reverse body weight and food intake in obese animal model. It is important to know that, whether intraperitoneal administration crosses blood brain barrier. Therefore, in the present experiment, we study the impact of intraperitoneal administration of synthetic OT 0.0116 mg/kg and antagonist OTA 1mg/kg on food intake, and body weight of female mice, Mus musculus for different duration i.e. 30, 60, and 90 days. In this study, it was observed that there was significant decrease (p<0.001, one way analysis of variance [ANOVA]) in the body weight, food intake, and gonadosomatic indices after the intraperitoneal exposure of OT at dose 0.0116mg/kg upto 90 days and inhibits via antagonist atosiban. These results indicates that intraperitoneal administration of OT can be used for treatment for longer duration without any side effects and maintains homeostasis in physiologic system regulates body weight and gonadal weight in female mice, which represent an important therapeutic tool for the obesity and metabolic disorder in female.
... Recently, the oxytocin (OXT) signaling pathway has emerged as an attractive target for treating obesity . Mutations in OXT or its receptor (OXTR) are directly associated with obesity in animals (Kasahara et al., 2007;Takayanagi et al., 2008;Camerino, 2009;Zhang et al., 2011;Sun et al., 2019) and humans (Wheeler et al., 2013;Qian et al., 2014;Yuan et al., 2016). OXT is a hypothalamic neuropeptide that participates in the network of appetite regulation (Maejima et al., 2014), as well as many other neurologic processes (Shen, 2015). ...
Background: Oxytocin is a hypothalamic neuropeptide that participates in the network of
appetite regulation. Recently the oxytocin signaling pathway has emerged as an attractive target for treating obesity. However, the short half-life limits its development as a clinical therapeutic. Here we provide results from testing a long-lasting, potent and selective oxytocin analogue ASK1476 on its efficacy to reduce food intake and body weight in comparison to the native oxytocin peptide.
Methods: ASK1476 features two specific amino acid substitutions in positions 7 and 8 combined with a short polyethylene glycol spacer. Short time dose escalation experiments testing increasing doses of 3 days each were performed in diet-induced overweight (DIO) male rats assessing effects on body weight as well as changes in food intake. Furthermore, DIO rats were tested for changes in body weight, food intake, temperature, and locomotor activity over 28 days of treatment (oxytocin, ASK1476, or vehicle).
Results: In dose escalation experiments, significant reductions in food intake relative to
baseline were detected beginning with doses of 15 nmol/kg ASK1476 (-15.2±2.3 kcal/d,
p=0.0017) and 20 nmol/kg oxytocin (-11.2.9±2.4 kcal/d, p=0.0106) with corresponding
significant changes in body weight (ASK1476: -5.2±0.8 g, p=0.0016; oxytocin: -2.6±0.7 g,
p=0.0326). In long-term experiments, there was no difference on body weight change between 120 nmol/kg/d ASK1476 (-71.4±34.2 g, p=0.039) and 600 nmol/kg/d oxytocin (-91.8±32.2 g, p=0.035) relative to vehicle (706.9±28.3 g), indicating a stronger dose response for ASK1476. Likewise, both ASK1476 and oxytocin at these doses resulted in similar reductions in 28-day cumulative food intake (ASK1476: -562.7±115.0 kcal, p=0.0001; oxytocin: -557.1±101.3 kcal, p=0.0001) relative to vehicle treatment (2716±75.4 kcal), while no effects were detected on locomotor activity or body temperature.
Conclusion: This study provides proof-of-concept data demonstrating an oxytocin analogue with extended in vivo stability and improved potency to reduce food intake and body weight in DIO animals which could mark a new avenue in anti-obesity drug interventions.
... Not only does oxytocin influence feeding behavior, but it further affects body composition and energy expenditure. In multiple animal models, loss of central oxytocin signaling via oxytocin neuron ablation or oxytocin receptor deletion increases fat mass and decreases energy expenditure [162][163][164][165]. Furthermore, recent work suggests that exogenous oxytocin treatment is associated with increased brown adipose tissue thermogenesis and "browning" of white adipose tissue, which is consistent with the increased energy expenditure induced by oxytocin treatment [166][167][168]. ...
The central nervous system is critical in metabolic regulation, and accumulating evidence points to a distributed network of brain regions involved in energy homeostasis. This is accomplished, in part, by integrating peripheral and central metabolic information and subsequently modulating neuroendocrine outputs through the paraventricular and supraoptic nucleus of the hypothalamus. However, these hypothalamic nuclei are generally protected by a blood-brain-barrier limiting their ability to directly sense circulating metabolic signals—pointing to possible involvement of upstream brain nuclei. In this regard, sensory circumventricular organs (CVOs), brain sites traditionally recognized in thirst/fluid and cardiovascular regulation, are emerging as potential sites through which circulating metabolic substances influence neuroendocrine control. The sensory CVOs, including the subfornical organ, organum vasculosum of the lamina terminalis, and area postrema, are located outside the blood-brain-barrier, possess cellular machinery to sense the metabolic interior milieu, and establish complex neural networks to hypothalamic neuroendocrine nuclei. Here, evidence for a potential role of sensory CVO-hypothalamic neuroendocrine networks in energy homeostasis is presented.
... Body weight modulation by oxytocin is not restricted to regulation of food intake, however. Oxt null (Camerino, 2009) and Oxtr null mice (Takayanagi et al., 2008) display late onset obesity in the absence of increased food ingestion. A number of in vivo studies have demonstrated that oxytocin promotes lipolysis of adipocytes via increased sympathetic nervous system tone (Deblon et al., 2011;Zhang and Chai, 2011;Plante et al., 2015;Blevins et al., 2016). ...
A model of oxytocin in the regulation of metabolic status has described one of oxytocin synthesis and release from the neurohypophysis in response to leptin, to suppress further leptin release. In addition, a lipogenic role for oxytocin has been suggested, consistent with an insulinergic action. This model, however, may be incorrect. Oxytocin reduces fat mass in the absence of either leptin or leptin receptor signalling, thereby challenging the interdependence between leptin and oxytocin. An oxytocin induced production of the anti-lipolytic prostaglandin E2 (PGE2) might account for this. Media from 3T3-L1 differentiated adipocytes treated with oxytocin (0-50 nmol.L-1) for 24 hrs were assayed for PGE2, leptin, adiponectin, and glycerol. Harvested cells were analysed for lipid droplet triglyceride and cytosolic free fatty acid (FFA) by flow cytometry, and for altered expression of lipolytic and lipogenic associated gene ontology transcripts by cDNA array. Both PGE2 and leptin secretion were significantly increased by oxytocin treatment whilst adiponectin secretion was not. A significant increase in cytosolic FFA was detected following oxytocin treatment, similar to that determined following treatment with isoproterenol (positive control). A significant increase in glycerol release to the culture media confirmed a lipolytic effect. No enrichment of lipolytic and lipogenic associated gene ontology transcripts was determined, but significant overrepresentation of chemosensory olfactory transcripts was. In conclusion, oxytocin stimulates lipolysis in 3T3-L1 adipocytes, mediated by autocrine/paracrine actions of PGE2 and leptin. To confirm that this response is mediated solely by the oxytocin receptor, further experiments would require those effects being blocked by a specific oxytocin antagonist.
... These in vivo OT effects in muscle protein metabolism could be mediated by the stimulation of the sympathetic autonomic nervous system, since there is evidence that OT stimulates secretion of adrenaline [67][68][69] and sympathetic preganglionic neurons [70]. In fact, OT knockout animals have less adrenaline release [71] and develop premature sarcopenia [11]. From this perspective, it is known that the sympathetic nervous system directly innervates skeletal muscle fiber, [72] inducing an anabolic effect in the skeletal muscle protein metabolism [18,28]. ...
Aims
Although it is well established that skeletal muscle contains oxytocin (OT) receptors and OT-knockout mice show premature development of sarcopenia, the role of OT in controlling skeletal muscle mass is still unknown. Therefore, the present work aimed to determine OT's effects on skeletal muscle protein metabolism.
Main methods
Total proteolysis, proteolytic system activities and protein synthesis were assessed in isolated soleus muscle from prepubertal female rats. Through in vivo experiments, rats received 3-day OT treatment (3UI.kg⁻¹.day⁻¹, i.p.) or saline, and muscles were harvested for mass-gain assessment.
Key findings
In vitro OT receptor stimulation reduced total proteolysis, specifically through attenuation of the lysosomal and proteasomal proteolytic systems, and in parallel activated the Akt/FoxO1 signaling and suppressed atrogenes (e.g., MuRF-1 and atrogin-1) expression induced by motor denervation. On the other hand, the protein synthesis was not altered by in vitro treatment with the OT receptor-selective agonist. Although short-term OT treatment did not change the atrogene mRNA levels, the protein synthesis was stimulated, resulting in soleus mass gain, probably through an indirect effect.
Significance
Taken together, these data show for the first time that OT directly inhibits the proteolytic activities of the lysosomal and proteasomal systems in rat oxidative skeletal muscle by suppressing atrogene expression via stimulation of Akt/FoxO signaling. Moreover, the data obtained from in vivo experiments suggest OT's ability to control rat oxidative skeletal muscle mass.
... Peripherally oxytocin regulates wholebody glucose metabolism. Studies have shown that oxytocin-deficient (Oxt −/− ) and high-fat diet-fed OTR-deficient (Oxtr −/− ) mice had decreased insulin sensitivity and impaired glucose tolerance [96,97], and both insulin sensitivity, as well as glucose tolerance, were restored after oxytocin administration in obese diabetic (db/db) mice fed with standard and high-fat diets [20,30,82,98]. Improvements in glucose tolerance, lowering of postprandial plasma glucose and insulin concentrations have been reported in subjects with normal weight and obesity who were given oxytocin [33,68,69,80,99]. ...
Oxytocin (9-amino acid peptide) hormone is a member of the G-protein coupled receptor family. It regulates a range of physiologic actions in mammals other than assisting parturition and lactation functions. Evidence indicates that oxytocin alters lipids, protein, and sugar metabolism through various ways including modulation of appetite and satiety, enzyme activity, cellular signals, secretion of metabolic hormones, and energy consumption. Alterations in these processes have the potential to shift developmental trajectories and influence disease processes. Oxytocin can be a potential avenue for the treatment of endocrine disorders such as obesity, diabetes mellitus, and associated disorders. The chapter will include a comprehensive study about oxytocin and its physiological and pathological functions, which makes it a potential target for drug therapy.
... This might be of relevance as several functions have been identified for OXT in the last decade. Indeed, recent studies have suggested a role for this hormone in social behaviors such as trust [9][10][11][12][13] or couple formation [14,15] as well as in metabolism [16][17][18][19]. Another fact of particular importance is that OXT has been reported to play a role in sodium balance [20,21]. ...
Purpose The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a well-known complication of trans-sphenoidal pituitary surgery, related to inappropriate secretion of arginine vasopressin (AVP). Its diagnosis is based on hyponatremia, with a peak of occurrence around day 7 after surgery and, to date, no early marker has been reported. In particular, copeptin levels are not predictive of hyponatremia in this case. Oxytocin (OXT) is secreted into the peripheral blood by axon terminals adjacent to those of AVP neurons in the posterior pituitary. Besides its role in childbirth and lacta-tion, recent evidences suggested a role for OXT in sodium balance. The contribution of this hormone in the dysnatremias observed after pituitary surgery has however never been investigated. Methods We analyzed the urinary output of OXT in patients subjected to transsphenoidal pituitary surgery. Results While OXT excretion remained stable in patients who presented a normonatremic postoperative course, patients who were later diagnosed with SIADH-related hyponatremia presented with a significantly increased urinary secretion of OXT 4 days after surgery. Conclusion Taken together, these results show for the first time that urinary OXT output remains normally stable after trans-sphenoidal pituitary surgery. OXT excretion however becomes abnormally high on or around 4 days after surgery in patients later developing hyponatremia, suggesting that this abnormal dynamics of OXT secretion might serve as an early marker for transsphenoidal surgery-related hyponatremia attributed to SIADH.
... This might be of relevance as several functions have been identified for OXT in the last decade. Indeed, recent studies have suggested a role for this hormone in social behaviors such as trust [9][10][11][12][13] or couple formation [14,15] as well as in metabolism [16][17][18][19]. Another fact of particular importance is that OXT has been reported to play a role in sodium balance [20,21]. ...
Purpose
The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a well-known complication of transsphenoidal pituitary surgery, related to inappropriate secretion of arginine vasopressin (AVP). Its diagnosis is based on hyponatremia, with a peak of occurrence around day 7 after surgery and, to date, no early marker has been reported. In particular, copeptin levels are not predictive of hyponatremia in this case. Oxytocin (OXT) is secreted into the peripheral blood by axon terminals adjacent to those of AVP neurons in the posterior pituitary. Besides its role in childbirth and lactation, recent evidences suggested a role for OXT in sodium balance. The contribution of this hormone in the dysnatremias observed after pituitary surgery has however never been investigated.
Methods
We analyzed the urinary output of OXT in patients subjected to transsphenoidal pituitary surgery.
Results
While OXT excretion remained stable in patients who presented a normonatremic postoperative course, patients who were later diagnosed with SIADH-related hyponatremia presented with a significantly increased urinary secretion of OXT 4 days after surgery.
Conclusion
Taken together, these results show for the first time that urinary OXT output remains normally stable after transsphenoidal pituitary surgery. OXT excretion however becomes abnormally high on or around 4 days after surgery in patients later developing hyponatremia, suggesting that this abnormal dynamics of OXT secretion might serve as an early marker for transsphenoidal surgery-related hyponatremia attributed to SIADH.
... In addition, Yuan et al. (28) recently reported that peripheral administration of OT promotes BAT differentiation in vitro and the expression of genes involved in thermogenesis in interscapular BAT (IBAT) in high-fat diet (HFD)-fed mice. Furthermore, reduced OT signaling is associated with obesity (24,(29)(30)(31), reductions of EE (23,24,31,32), and deficits in BAT thermogenesis (32)(33)(34)(35) in mice. Collectively, these findings support a role for increased BAT thermogenesis in OT-elicited weight loss in mice. ...
Previous studies indicate that oxytocin (OT) administration reduces body weight in high fat diet (HFD)-induced obese (DIO) rodents through both reductions in food intake and increases in energy expenditure. We recently demonstrated that chronic hindbrain [fourth ventricular (4V)] infusions of OT evoke weight loss in DIO rats. Based on these findings, we hypothesized that chronic 4V OT would elicit weight loss in DIO mice. We assessed the effects of 4V infusions of OT (16 nmol/day) or vehicle over 28 days on body weight, food intake and body composition. OT reduced body weight by approximately 4.5±1.4% in DIO mice relative to OT pre-treatment body weight (P<0.05). These effects were associated with reduced adiposity and adipocyte size (inguinal white adipose tissue (IWAT)] (P<0.05) and attributed, in part, to reduced energy intake (P<0.05) at a dose that did not increase kaolin intake (P=NS). OT tended to increase uncoupling protein-1 expression in IWAT (0.05<P<0.1) suggesting that OT stimulates browning of WAT. To assess OT-elicited changes in brown adipose tissue (BAT) thermogenesis, we examined the effects of 4V OT on interscapular BAT temperature (T IBAT ). 4V OT (1 μg) elevated T IBAT at 0.75 (P=0.08), 1, and 1.25 h (P<0.05) post-injection; a higher dose (5 μg) elevated T IBAT at 0.75, 1, 1.25, 1.5, 1.75 (P<0.05), and 2-h (0.05<P<0.1) post-injection. Together, these findings support the hypothesis that chronic hindbrain OT treatment evokes sustained weight loss in DIO mice by reducing energy intake and increasing BAT thermogenesis at a dose that is not associated with evidence of visceral illness.
... There is a growing literature that suggests OXT and its receptor may play an important role in regulating body weight and metabolism. For example, OXTR and OXT deficient mice exhibit late onset obesity and insulin resistance [14,15]. In rodent models of obesity, chronic central or peripheral infusions of OXT have been shown to decrease weight gain [16][17][18][19][20] and improve insulin resistance [18,20,21]. ...
Background:
Obesity and adipose tissue expansion is characterized by a chronic state of systemic inflammation that contributes to disease. The neuropeptide, oxytocin, working through its receptor has been shown to attenuate inflammation in sepsis, wound healing, and cardiovascular disease. The current study examined the effects of chronic oxytocin infusions on adipose tissue inflammation in a murine model of obesity, the leptin receptor-deficient (db/db) mouse.
Methods:
The effect of obesity on oxytocin receptor protein and mRNA expression in adipose tissue was evaluated by Western blotting and real-time polymerase chain reaction. Mice were implanted with osmotic minipumps filled with oxytocin or vehicle for 8 weeks. At study endpoint adipose tissue inflammation was assessed by measurement of cytokine and adipokine mRNA tissue levels, adipocyte size and macrophage infiltration via histopathology, and plasma levels of adiponectin and serum amyloid A as markers of systemic inflammation.
Results:
The expression of adipose tissue oxytocin receptor was increased in obese db/db mice compared to lean controls. In adipose tissue oxytocin infusion reduced adipocyte size, macrophage infiltration, IL-6 and TNFα mRNA expression, and increased the expression of the anti-inflammatory adipokine, adiponectin. In plasma, oxytocin infusion reduced the level of serum amyloid A, a marker of systemic inflammation, and increased circulating adiponectin.
Conclusions:
In an animal model of obesity and diabetes chronic oxytocin treatment led to a reduction in visceral adipose tissue inflammation and plasma markers of systemic inflammation, which may play a role in disease progression.
... administration (34) and this may be related to the septal OXTRs (35). In addition, because OXT KO mice and OXTR KO mice show significantly increased body weight (16,36), the OXT/OXTR system appears to be strongly involved in obesity and/or control of food intake (37,38). As OXT appears to have a dual function in body weight control and recognition, we speculated that OXT is more effective for ameliorating the recognition impairment caused by a HFD. ...
Excessive intake of fat is a major risk factor for lifestyle-related diseases such as heart disease and also affects brain function such as object recognition memory, social recognition, anxiety behavior, and depression-like behavior. Although oxytocin (OXT) has been reported to improve object recognition, social recognition, anxiety behavior, and depression-like behavior in specific conditions, previous studies did not explore the impact of OXT in high-fat diet (HFD)-fed mice. Furthermore, it remains unclear whether intake of HFD affects OXT/oxytocin receptor (OXTR) in the brain. Here, we demonstrated that peripheral OXT administration improves not only social recognition but also object recognition and depressive-like behavior in HFD-fed mice. In contrast, peripheral OXT administration to HFD-fed male mice increased fear and anxiety-related behavior. In addition, we observed that intake of HFD decreased OXTR and c-fos mRNA expression in the hippocampus, specifically. Furthermore, peripheral OXT administration increased OXT mRNA expression in the hypothalamus. Altogether, these findings suggest that OXT has the potential to improve various recognition memory processes via peripheral administration but also has side effects that increase fear-related behavior in males.
Introduction: GLP-1 receptor agonists are the number one drug prescribed for the treatment of obesity and type 2 diabetes. These drugs are not, however, without side-effects and in an effort to maximize therapeutic effect while minimizing adverse effects, gut hormone co-agonists received considerable attention as new drug targets in the fight against obesity. Numerous previous reports identified the neuropeptide oxytocin (OXT) as a promising anti-obesity drug. The aim of this study is to evaluate OXT as a possible co-agonist for GLP-1 and examine the effects of its co-administration on food intake (FI) and body weight (BW) in mice. Methods: FI and c-Fos levels were measured in the feeding-centers of the brain in response to an intraperitoneal injection of saline, OXT, GLP-1 or OXT/GLP-1. The action potential frequency and cytosolic Ca2+ ([Ca2+]i) in response to OXT, GLP-1 or OXT/GLP-1were measured in ex-vivo PVN neuronal cultures. Finally, FI and BW changes were compared in diet induced obese mice treated with saline, OXT, GLP-1 or OXT/GLP-1 for 13 days. Results: Single injection of OXT/GLP-1 additively decreased FI, and increased c-Fos expression specifically in the paraventricular (PVN) and supraoptic nucleus (SON). 70% of GLP-1 receptor positive neurons in the PVN also expressed OXT receptors, and OXT/GLP-1 co-administration dramatically increased firing and [Ca2+]i in the PVN OXT neurons. The chronic OXT/GLP-1 co-administration decreased BW without changing FI. Conclusion: Chronic OXT/GLP-1 co-administration decreases BW, possibly via the activation of PVN OXT neurons. OXT might be a promising candidate as an incretin co-agonist in obesity treatment.
Since hypothalamic obesity (HyOb) was first described over 120 years ago by Joseph Babinski and Alfred Fröhlich, advances in molecular genetic laboratory techniques have allowed us to elucidate various components of the intricate neurocircuitry governing appetite and weight regulation connecting the hypothalamus, pituitary gland, brainstem, adipose tissue, pancreas, and gastrointestinal tract. On a background of an increasing prevalence of population-level common obesity, the number of survivors of congenital (eg, septo-optic dysplasia, Prader–Willi syndrome) and acquired (eg, central nervous system tumors) hypothalamic disorders is increasing, thanks to earlier diagnosis and management as well as better oncological therapies. Although to date the discovery of several appetite-regulating peptides has led to the development of a range of targeted molecular therapies for monogenic obesity syndromes, outside of these disorders these discoveries have not translated into the development of efficacious treatments for other forms of HyOb. This review aims to summarize our current understanding of the neuroendocrine physiology of appetite and weight regulation, and explore our current understanding of the pathophysiology of HyOb.
Background
Dysregulation of feeding behavior leads to a variety of pathological manifestations ranging from obesity to anorexia. The foraging behavior of animals affected by food deficiency is not fully understood.
Methods
Home-Cage system was used to monitor the behaviors. Immunohistochemical staining was used to monitor the trend of neuronal activity. Chemogenetic approach was used to modify neuronal activity.
Results
We described here a unique mouse model of foraging behavior and unveiled that food deprivation significantly increases the general activities of mice with a daily rhythmic pattern, particularly foraging behavior. The increased foraging behavior is potentiated by food cues (mouthfeel, odor, size, and shape) and energy deficit, rather than macronutrient protein, carbohydrate, and fat. Notably, energy deficiency increases nocturnal neuronal activity in paraventricular hypothalamic nucleus (PVH), accompanying a similar change in rhythmic foraging behavior. Activating neuronal activity in PVH enhances the amplitude of foraging behavior in mice. Conversely, inactivating neuronal activity in PVH decreases the amplitude of foraging behavior and impairs the rhythm of foraging behavior.
Discussion
These results illustrate that energy status and food cues regulate the rhythmic foraging behavior via PVH neuronal activity. Understanding foraging behavior provides insights into the underlying mechanism of eating-related disorders.
Neuregulin 4 (Nrg4) is an adipose tissue-enriched secreted factor that modulates glucose and lipid metabolism. Nrg4 is closely associated with obesity and preserves diet-induced metabolic disorders. However, the specific mechanisms via which Nrg4 regulates metabolic homeostasis remain incompletely understood. Here, this work finds that the Nrg4 receptor, ErbB4, is highly expressed in the hypothalamus, and the phosphorylation of hypothalamic ErbB4 is reduced in diet-induced obesity (DIO) mice. Peripheral Nrg4 can act on ErbB4 via blood circulation and excite neurons in the paraventricular nucleus of hypothalamus (PVN). Central administration of recombinant Nrg4 protein (rNrg4) reduces obesity and related metabolic disorders by influencing energy expenditure and intake. Overexpression of ErbB4 in the PVN protects against obesity, whereas its knock down in oxytocin (Oxt) neuron accelerates obesity. Furthermore, Nrg4-ErbB4 signaling excites Oxt release, and ablation of Oxt neuron considerably attenuates the effect of Nrg4 on energy balance. These data suggest that the hypothalamus is a key target of Nrg4, which partially explains the multifaceted roles of Nrg4 in metabolism.
Oxytocin (OT) is a neurohormone involved early in neurodevelopment and is implicated in multiple functions, including sensory modulation. Evidence of such modulation has been observed for different sensory modalities in both healthy and pathological conditions. This review summarizes the pleiotropic modulation that OT can exercise on an often overlooked sensory system: thermosensation. This system allows us to sense temperature variations and compensate for the variation to maintain a stable core body temperature. Oxytocin modulates autonomic and behavioral mechanisms underlying thermoregulation at both central and peripheral levels. Hyposensitivity or hypersensitivity for different sensory modalities, including thermosensitivity, is a common feature in autism spectrum disorder (ASD), recapitulated in several ASD mouse models. These sensory dysregulations occur early in post-natal development and are correlated with dysregulation of the oxytocinergic system. In this study, we discussed the potential link between thermosensory atypia and the dysregulation of the oxytocinergic system in ASD.
New findings:
What is the central question of this study? In this study, we assessed the effects of an obesogenic diet on the control of hydromineral balance in rats. What is the main finding and its importance? The results showed that, when dehydrated, rats fed a high-fat diet drink less water than their control-diet-fed counterparts. Thus, we sought the neurohumoral and biomolecular alterations that might support these changes in fluid intake. Further results indicated that changes in AQP7 and PPAR-α expression in the white adipose tissue might be involved in these results.
Abstract:
High-fat diet (HFD) increases fat accumulation, glycaemia, and blood triglycerides and it is used as a model to study obesity. Besides the metabolic changes, obesity likely affects water intake. We assessed the effects of HFD on behavioral and hormonal responses to water deprivation. Additionally, we measured if the adipose tissue is differentially affected by water deprivation in control and HFD-fed rats. HFD rats showed a decreased basal water intake when compared to control-fed rats. When subjected to 48 hours of water deprivation, as expected, both control and HFD rats drank more water than the hydrated rats. However, the increase in water intake was lessened in HFD dehydrated rats. Similarly, the increase in hematocrit in dehydrated rats was less pronounced in HFD dehydrated rats. These results suggest that HFD diminishes drinking behavior. White adipose tissue weight, glycaemia, and plasma glycerol concentration were increased in HFD rats, however, after 48 hours of water deprivation, these parameters were significantly decreased in dehydrated HFD rats, when compared to controls. The increase in adipose tissue caused by HFD may mitigate the effects of dehydration, possibly through the increased production of metabolic water caused by lipolysis in the adipocytes. Oxytocin possibly mediates the lipolytic response, since both its secretion and receptor expression are affected by dehydration in both control and HFD rats, which suggests that oxytocin signaling is maintained in these conditions. Changes in mediators of the lipolysis, such as AQP7 and PPAR-α, might contribute to the different effects observed in control and HFD rats. This article is protected by copyright. All rights reserved.
Background
Oxytocin is a nonapeptide synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. Historically, this molecule has been involved as a key factor in the formation of infant attachment, maternal behavior and pair bonding and, more generally, in linking social signals with cognition, behaviors and reward. In the last decades, the whole oxytocin system has gained a growing interest as it was proposed to be implicated in etiopathogenesis of several neurodevelopmental and neuropsychiatric disorders.
Methods
With the main goal of an in-depth understanding of the oxytocin role in the regulation of different functions and complex behaviors as well as its intriguing implications in different neuropsychiatric disorders, we performed a critical review of the current state of art. We carried out this work through PubMed database up to June 2021 with the search terms: 1) “oxytocin and neuropsychiatric disorders”; 2) “oxytocin and neurodevelopmental disorders”; 3) “oxytocin and anorexia”; 4) “oxytocin and eating disorders”; 5) “oxytocin and obsessive-compulsive disorder”; 6) “oxytocin and schizophrenia”; 7) “oxytocin and depression”; 8) “oxytocin and bipolar disorder”; 9) “oxytocin and psychosis”; 10) “oxytocin and anxiety”; 11) “oxytocin and personality disorder”; 12) “oxytocin and PTSD”.
Results
Biological, genetic, and epigenetic studies highlighted quality and quantity modifications in the expression of oxytocin peptide or in oxytocin receptor isoforms. These alterations would seem to be correlated with a higher risk of presenting several neuropsychiatric disorders belonging to different psychopathological spectra. Collaterally, the exogenous oxytocin administration has shown to ameliorate many neuropsychiatric clinical conditions.
Conclusion
Finally, we briefly analyzed the potential pharmacological use of oxytocin in patient with severe symptomatic SARS-CoV-2 infection due to its anti-inflammatory, anti-oxidative and immunoregulatory properties.
Maintaining homeostasis while navigating one's environment involves accurately assessing and interacting with external stimuli while remaining consciously in tune with internal signals such as hunger and thirst. Both atypical social interactions and unhealthy eating patterns emerge as a result of dysregulation in factors that mediate the prioritization and attention to salient stimuli. Oxytocin is an evolutionarily conserved peptide that regulates attention to exteroceptive and interoceptive stimuli in a social environment by functioning in the brain as a modulatory neuropeptide to control social behavior, but also in the periphery as a hormone acting at oxytocin receptors (Oxtr) expressed in the heart, gut, and peripheral ganglia. Specialized sensory afferent nerve endings of Oxtr-expressing nodose ganglia cells transmit cardiometabolic signals via the Vagus nerve to integrative regions in the brain that also express Oxtr(s). These brain regions are influenced by vagal sensory pathways and coordinate with external events such as those demanding attention to social stimuli, thus the sensations related to cardiometabolic function and social interactions are influenced by oxytocin signaling. This review investigates the literature supporting the idea that oxytocin mediates the interoception of cardiovascular and gastrointestinal systems, and that the modulation of this awareness likewise influences social cognition. These concepts are then considered in relation to Autism Spectrum Disorder, exploring how atypical social behavior is comorbid with cardiometabolic dysfunction.
Glucose homeostasis is maintained by the glucoregulatory hormones, glucagon, insulin and somatostatin, secreted from the islets of Langerhans. Glucagon is the body’s most important anti-hypoglycemic hormone, mobilizing glucose from glycogen stores in the liver in response to fasting, thus maintaining plasma glucose levels within healthy limits. Glucagon secretion is regulated by both circulating nutrients, hormones and neuronal inputs. Hormones that may regulate glucagon secretion include locally produced insulin and somatostatin, but also urocortin-3, amylin and pancreatic polypeptide, and from outside the pancreas glucagon-like peptide-1 and 2, peptide tyrosine tyrosine and oxyntomodulin, glucose-dependent insulinotropic polypeptide, neurotensin and ghrelin, as well as the hypothalamic hormones arginine-vasopressin and oxytocin, and calcitonin from the thyroid. Each of these hormones have distinct effects, ranging from regulating blood glucose, to regulating appetite, stomach emptying rate and intestinal motility, which makes them interesting targets for treating metabolic diseases. Awareness regarding the potential effects of the hormones on glucagon secretion is important since secretory abnormalities could manifest as hyperglycemia or even lethal hypoglycemia. Here, we review the effects of each individual hormone on glucagon secretion, their interplay, and how treatments aimed at modulating the plasma levels of these hormones may also influence glucagon secretion and glycemic control.
Oxytocin and oxytocin receptors are synthesized in the periphery where paracrine/autocrine actions have been described alongside endocrine actions effected by central release of oxytocin from the posterior pituitary. In the female reproductive system, classical actions of uterine contraction and milk ejection from mammary glands are accompanied by actions in the ovaries where roles in steroidogenesis, follicle recruitment and ovulation have been described. Steroidogenesis, contractile activity, and gamete health are similarly affected by oxytocin in the male reproductive tract. In the cardiovascular system, a local oxytocinergic system appears to play an important cardio-protective role. This role is likely associated with emerging evidence that peripheral oxytocin is an important hormone in the endocrinology of glucose homeostasis due to its actions in adipose, the pancreas, and the largely ignored oxytocinergic systems of the adrenal glands and liver. Gene polymorphisms are shown to be associated with a number of reported traits, not least factors associated with metabolic syndrome.
There has been a long history of research on the effects of oxytocin on feeding behaviour. The classic-held view is that the neurohormone is anorexigenic at least in rodents, though the data for humans is not so clear cut. Likewise, a physiological role for oxytocin is disputed. Thus, while pharmacological, anatomical and pharmacological data suggest oxytocin may have a function in satiety signalling, this view is not supported by the latest research using the genetic recording and manipulation of oxytocin neurones. Here, we avoid a discussion of the pharmacological effects of oxytocin and examine evidence, from both sides of the argument, as to whether the endogenous oxytocin system has a role in the regulation of normal feeding.
The hypothalamic peptide oxytocin has been increasingly recognized as a hormone and neurotransmitter with important effects on energy intake, metabolism, and body weight and is under investigation as a potential novel therapeutic agent for obesity. The main neurons producing oxytocin and expressing the oxytocin receptor are strategically located in brain areas known to be critically involved in homeostatic energy balance as well as hedonic and motivational aspects of eating behavior. In this chapter, we will review the central and peripheral physiology of oxytocin and the interaction of oxytocin with key hormones and neural circuitries that affect food intake and metabolism. Next, we will synthesize the available data on endogenous oxytocin levels related to caloric intake, body weight, and metabolic status. We will then review the effects of exogenous oxytocin administration on eating behavior, body weight, and metabolism in humans, including in healthy individuals as well as specific populations with suspected perturbations involving oxytocin pathways. Finally, we will address the promise and fundamental challenges of translating this line of research to clinical care.
Rates of delivery by caesarean section (CS) are increasing around the globe and, although several epidemiological associations have already been observed between CS and health outcomes in later life, more are sure to be discovered as this practice continues to gain popularity. The components of vaginal delivery that protect offspring from the negative consequences of CS delivery in later life are currently unknown, although much attention to date has focused on differences in microbial colonisation. Here, we present the case that differing hormonal experiences at birth may also contribute to the neurodevelopmental consequences of CS delivery. Levels of each of the 'birth signalling hormones' (oxytocin, arginine vasopressin, epinephrine, norepinephrine and the glucocorticoids) are lower following CS compared to vaginal delivery, and there is substantial evidence for each that manipulations in early life results in long-term neurodevelopmental consequences. We draw from the research traditions of neuroendocrinology and developmental psychobiology to suggest that the perinatal period is a sensitive period, during which hormones achieve organisational effects. Furthermore, there is much to be learned from research on developmental programming by early-life stress that may inform research on CS, as a result of shared neuroendocrine mechanisms at work. We compare and contrast the effects of early-life stress with those of CS delivery and propose new avenues of research based on the links between the two bodies of literature. The research conducted to date suggests that the differences in hormone signalling seen in CS neonates may produce long-term neurodevelopmental consequences.
Oxytocin, a protein hormone mainly produced by hypothalamus, has been shown to repress body weight gain in obese animals, in part, by reducing food intake and increasing energy expenditure. Till now, activation of brown fat tissue (BAT) thermogenesis and white adipose tissue (WAT) browning are considered as two main factors for oxytocin-induced energy expenditure. However, the underlying molecular mechanisms are still not understood well. Here, we observed that oxytocin expression in the hypothalamus and its receptor in adipose tissues were induced by cold exposure in mice. In differentiated adipocytes, oxytocin stimulated brown adipocyte specific gene expression by inducing PRDM16. In high fat diet induced obese mice, oxytocin delivery by osmotic minipumps increased body core temperature and decreased body weight gain. Glucose and insulin tolerance were improved by oxytocin. Hyperinsulinemia and fatty liver were ameliorated in oxytocin-treated animals. Moreover, oxytocin treatment induced thermogenic gene expressions in BAT, inguinal WAT (iWAT), and skeletal muscle. Taken together, our findings revealed a new aspect of oxytocin, i.e. oxytocin induces iWAT browning and stimulates thermogenesis in BAT, iWAT and skeletal muscle, through which oxytocin promotes thermogenesis and thus combats obesity and metabolic dysfunctions.
Oxytocin, a neurohypophyseal hormone, has been traditionally considered essential for mammalian reproduction. In addition to uterine contractions during labor and milk ejection during nursing, oxytocin has been implicated in anterior pituitary function, paracrine effects in the testis and ovary and the neural control of maternal and sexual behaviors. To determine the essential role(s) of oxytocin in mammalian reproductive function, mice deficient in oxytocin have been generated using embryonic stem cell technology. A deletion of exon 1 encoding the oxytocin peptide was generated in embryonic stem cells at a high frequency and was successfully transmitted in the germ line. Southern blot analysis of genomic DNA from homozygote offspring and in situ hybridization with an exonic probe 3' of the deletion failed to detect any oxytocin or neurophysin sequences, respectively, confirming that the mutation was a null mutation. Mice lacking oxytocin are both viable and fertile. Males do not have any reproductive behavioral or functional defects in the absence of oxytocin. Similarly, females lacking oxytocin have no obvious deficits in fertility or reproduction, including gestation and parturition. However, although oxytocin-deficient females demonstrate normal maternal behavior, all offspring die shortly after birth because of the dam's inability to nurse. Postpartum injections of oxytocin to the oxytocin deficient mothers restore milk ejection and rescue the offspring. Thus, despite the multiple reproductive activities that have been attributed to oxytocin, oxytocin plays an essential role only in milk ejection in the mouse.
Agouti-related protein (AgRP), a neuropeptide abundantly expressed in the arcuate nucleus of the hypothalamus, potently stimulates
feeding and body weight gain in rodents. AgRP is believed to exert its effects through the blockade of signaling by α-melanocyte-stimulating
hormone at central nervous system (CNS) melanocortin-3 receptor (Mc3r) and Mc4r. We generated AgRP-deficient (Agrp−/−) mice to examine the physiological role of AgRP. Agrp−/− mice are viable and exhibit normal locomotor activity, growth rates, body composition, and food intake. Additionally, Agrp−/− mice display normal responses to starvation, diet-induced obesity, and the administration of exogenous leptin or neuropeptide
Y (NPY). In situ hybridization failed to detect altered CNS expression levels for proopiomelanocortin, Mc3r, Mc4r, or NPY
mRNAs in Agrp−/− mice. As AgRP and the orexigenic peptide NPY are coexpressed in neurons of the arcuate nucleus, we generated AgRP and NPY
double-knockout (Agrp−/−;Npy−/−) mice to determine whether NPY or AgRP plays a compensatory role in Agrp−/− or NPY-deficient (Npy−/−) mice, respectively. Similarly to mice deficient in either AgRP or NPY, Agrp−/−;Npy−/− mice suffer no obvious feeding or body weight deficits and maintain a normal response to starvation. Our results demonstrate
that neither AgRP nor NPY is a critically required orexigenic factor, suggesting that other pathways capable of regulating
energy homeostasis can compensate for the loss of both AgRP and NPY.
To assess the role of the α1b-adrenergic receptor (AR) in glucose homeostasis, we investigated glucose metabolism in knockout mice deficient of this receptor
subtype (α1b-AR-/-). Mutant mice had normal blood glucose and insulin levels, but elevated leptin concentrations in the fed state. During the
transition to fasting, glucose and insulin blood concentrations remained markedly elevated for at least 6 h and returned to
control levels after 24 h whereas leptin levels remained high at all times. Hyperinsulinemia in the post-absorptive phase
was normalized by atropine or methylatropine indicating an elevated parasympathetic activity on the pancreatic β cells, which
was associated with increased levels of hypothalamic NPY mRNA. Euglycemic clamps at both low and high insulin infusion rates
revealed whole body insulin resistance with reduced muscle glycogen synthesis and impaired suppression of endogenous glucose
production at the low insulin infusion rate. The liver glycogen stores were 2-fold higher in the fed state in the α1b-AR-/- compared with control mice, but were mobilized at the same rate during the fed to fast transition or following glucagon injections.
Finally, high fat feeding for one month increased glucose intolerance and body weight in the α1b-AR-/-, but not in control mice. Altogether, our results indicate that in the absence of the α1b-AR the expression of hypotalamic NPY and the parasympathetic nervous activity are both increased resulting in hyperinsulinemia
and insulin resistance as well as favoring obesity and glucose intolerance development during high fat feeding.
Sexual activity and mating are accompanied by a high level of arousal, whereas anecdotal and experimental evidence demonstrate that sedation and calmness are common phenomena in the postcoital period in humans. These remarkable behavioral consequences of sexual activity contribute to a general feeling of well being, but underlying neurobiological mechanisms are largely unknown. Here, we demonstrate that sexual activity and mating with a receptive female reduce the level of anxiety and increase risk-taking behavior in male rats for several hours. The neuropeptide oxytocin has been shown to exert multiple functions in male and female reproduction, and to play a key role in the regulation of emotionality after its peripheral and central release, respectively. In the present study, we reveal that oxytocin is released within the brain, specifically within the hypothalamic paraventricular nucleus, of male rats during mating with a receptive female. Furthermore, blockade of the activated brain oxytocin system by central administration of an oxytocin receptor antagonist immediately after mating prevents the anxiolytic effect of mating, while having no effect in nonmated males. These findings provide direct evidence for an essential role of an activated brain oxytocin system mediating the anxiolytic effect of mating in males.
• black–white box
• elevated plus maze
• paraventricular nucleus
• risk-taking behavior
• anxiety
Single-minded 1 (Sim1) encodes a transcription factor essential for formation of the hypothalamic paraventricular nucleus (PVN). Sim1 haploinsufficiency is associated with hyperphagic obesity and increased linear growth in humans and mice, similar to the phenotype of melanocortin 4 receptor (Mc4r) mutations. PVN neurons in Sim1(+/-) mice are hyporesponsive to the melanocortin agonist melanotan II. PVN neuropeptides oxytocin (Oxt), TRH and CRH inhibit feeding when administered centrally. Consequently, we hypothesized that altered PVN neuropeptide expression mediates the hyperphagia of Sim1(+/-) mice. To test this hypothesis, we measured hypothalamic expression of PVN neuropeptides in Sim1(+/-) and wild-type mice. Oxt mRNA and peptide were decreased by 80% in Sim1(+/-) mice, whereas TRH, CRH, arginine vasopressin (Avp), and somatostatin mRNAs were decreased by 20-40%. Sim1(+/-) mice also showed abnormal regulation of Oxt but not CRH mRNA in response to feeding state. A selective Mc4r agonist activated PVN Oxt neurons in wild-type mice, supporting involvement of these neurons in melanocortin feeding circuits. To test whether Oxt itself regulates feeding, we measured the effects of central administration of an Oxt receptor antagonist or repeated doses of Oxt on food intake of Sim1(+/-) and wild-type mice. Sim1(+/-) mice were hypersensitive to the orexigenic effect of the Oxt receptor antagonist. Oxt decreased the food intake and weight gain of Sim1(+/-) mice at a dose that did not affect wild-type mice. Our results support the importance of Oxt neurons in feeding regulation and suggest that reduced Oxt neuropeptide is one mechanism mediating the hyperphagic obesity of Sim1(+/-) mice.
Gonadal failure induces bone loss while obesity prevents it. This raises the possibility that bone mass, body weight, and gonadal function are regulated by common pathways. To test this hypothesis, we studied leptin-deficient and leptin receptor–deficient mice that are obese and hypogonadic. Both mutant mice have an increased bone formation leading to high bone mass despite hypogonadism and hypercortisolism. This phenotype is dominant, independent of the presence of fat, and specific for the absence of leptin signaling. There is no leptin signaling in osteoblasts but intracerebroventricular infusion of leptin causes bone loss in leptin-deficient and wild-type mice. This study identifies leptin as a potent inhibitor of bone formation acting through the central nervous system and therefore describes the central nature of bone mass control and its disorders.
The oxytocin receptor has been suggested to be involved in energy metabolism, such as food intake and energy consumption. Here, we demonstrate that oxytocin receptor-deficient (Oxtr-/-) male mice exhibited late-onset obesity with increases in abdominal fat pads and fasting plasma triglycerides. Daily food intake and spontaneous motor activity of Oxtr-/- mice were not significantly different as compared with wild-type mice. In contrast, brown adipose tissue in Oxtr-/- mice contained large lipid droplets and cold-induced thermogenesis was impaired. This study demonstrates that oxytocin receptor plays essential roles in the regulation of energy homeostasis.
The inhibition of food intake in rats that results from various anorexigenic treatments is frequently associated with pituitary secretion of oxytocin (OT), but is not caused by circulating OT. We, therefore, evaluated the potential role of brain OT in mediating anorexia induced in rats by systemic administration of cholecystokinin (CCK), hypertonic saline (HS), or lithium chloride (LiCl), treatments that are known to stimulate pituitary OT secretion as well as to inhibit food intake. Food intake was analyzed in 22-h food-deprived rats pretreated with icv injections of either artificial cerebrospinal fluid (aCSF) or 9 nmol of an OT receptor antagonist, [d(CH2)5, Tyr(OMe)2,Orn8]vasotocin (OVT), which was the dose found to be most effective to antagonize the anorexia induced by CCK and HS. Pretreatment with the OT receptor antagonist icv significantly blunted the anorexigenic effect of each agent. After CCK (10 micrograms/kg, ip), food intake increased from 28 +/- 5% of basal intake after a CSF icv to 48 +/- 8% after OVT icv (P less than 0.01); after HS (2 ml 2 M NaCl, ip), food intake increased from 9 +/- 4% of basal intake after aCSF icv to 43 +/- 7% after OVT icv (P less than 0.01); and after LiCl (1.125 mmol/kg, ip), food intake increased from 55 +/- 4% of basal intake after a CSF icv to 80 +/- 9% after OVT icv (P less than 0.01). These data support the hypothesis that pituitary secretion of OT after anorexigenic treatments in rats is associated with coactivation of centrally projecting brain OT pathways, some of which are causally related to the induced inhibition of food intake.
Increasing evidence indirectly suggests a role for oxytocinergic neurons in the control of ingestive behaviors. The present study was aimed at directly investigating a possible effect of oxytocin on food and water intake in rats. Oxytocin, whether administered intracerebroventricularly (ICV) (1-10 micrograms/rat) or intraperitoneally (IP) (375-3,000 micrograms/kg) dose dependently inhibited food intake in freely feeding animals; in schedule-fed animals fasting for 21 h, oxytocin not only reduced food intake but also reduced the time spent eating and increased the latency to first meal. On the other hand, oxytocin antagonist d(CH2)5Tyr(Me)-[Orn8]-vasotocin, ICV injected at the dose of 10 micrograms/rat, increased food intake and time spent eating and reduced the latency to first meal; moreover, it completely prevented the effect of oxytocin. Water intake was studied both in freely drinking animals and in three different models of thirst (water deprivation, hypertonic saline administration, angiotensin II injection). In all cases, oxytocin dose dependently inhibited water intake, in a dose range of 0.1-10 micrograms/rat (ICV) or 93-750 micrograms/kg (IP). In the water deprivation model, ICV pretreatment with d(CH2)5Tyr(Me)-[Orn8]-vasotocin completely prevented the antidipsogenic effect of oxytocin. In conclusion, these data show that oxytocin directly inhibits food and water intake in rats, the effect being specifically mediated by brain oxytocin receptors. This may support the idea that the brain oxytocinergic system plays an important role in the regulation of ingestive behaviors.
We evaluated the effects of lateral intracerebroventricular administration of oxytocin (OT) and/or a selective oxytocin-receptor antagonist (OTX), 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-OT, on ingestion of intraorally delivered 12.5% glucose in rats that were either nondeprived or deprived of food for 20 h. In deprived rats, OT delivered 30 min before an initial intake test yielded a dose-related reduction of intraoral glucose intake. The highest dose tested, 20 nmol, reduced intraoral glucose intake by 45%. The effect was short-lived, however. Intraoral intake for a second test, initiated 60 min after the termination of the first, increased as a function of OT dose so that total session intake was unaffected by OT treatment. The suppression of intraoral intake by 20 nmol OT was reversed by pretreatment (45 min before testing) with OTX. In nondeprived rats, by contrast, OT yielded no effect on first-test, second-test, or total session intakes. Significant increases in first-test and total session intakes were obtained when OTX (20 nmol) was administered alone both in deprived (32% increase in first-test intake) and nondeprived (31% increase) rats. In general, the results obtained are consistent with the suggestion that OT contributes to the control of meal size and, in particular, to the process of satiation, which is the aspect of ingestive control highlighted by the specialized intake test used in the present study.
The development of type 2 diabetes is linked to insulin resistance coupled with a failure of pancreatic beta-cells to compensate by adequate insulin secretion.
Here, we review studies obtained from genetically engineered mice that provide novel insights into the pathophysiology of insulin resistance.
Knockout models with monogenic impairment in insulin action have highlighted the potential role for insulin signalling molecules in insulin resistance at a tissue-specific level. Polygenic models have strengthened the idea that minor defects in insulin secretion and insulin action, when combined, can lead to diabetes, emphasizing the importance of interactions of different genetic loci in the production of diabetes. Knockout models with tissue-specific alterations in glucose or lipid metabolism have dissected the individual contributions of insulin-responsive organs to glucose homeostasis. They have demonstrated the central role of fat as an endocrine tissue in the maintenance of insulin sensitivity and the development of insulin resistance. Finally, these models have shown the potential role of impaired insulin action in pancreatic beta-cells and brain in the development of insulin deficiency and obesity.
We previously showed that leptin inhibits bone formation by an undefined mechanism. Here, we show that hypothalamic leptin-dependent antiosteogenic and anorexigenic networks differ, and that the peripheral mediators of leptin antiosteogenic function appear to be neuronal. Neuropeptides mediating leptin anorexigenic function do not affect bone formation. Leptin deficiency results in low sympathetic tone, and genetic or pharmacological ablation of adrenergic signaling leads to a leptin-resistant high bone mass. beta-adrenergic receptors on osteoblasts regulate their proliferation, and a beta-adrenergic agonist decreases bone mass in leptin-deficient and wild-type mice while a beta-adrenergic antagonist increases bone mass in wild-type and ovariectomized mice. None of these manipulations affects body weight. This study demonstrates a leptin-dependent neuronal regulation of bone formation with potential therapeutic implications for osteoporosis.
Results from previous studies indicate that oxytocin (OT)-containing neural pathways are activated in laboratory rats after systemic administration of CCK or d-fenfluramine and that centrally released OT may participate in the anorexigenic effects of these treatments. To explore the relationship between feeding behavior and OT function, the effects of CCK and d-fenfluramine on feeding and central c-Fos expression were compared in wild-type (OT+/+) and OT-deficient mice (OT-/-) of C57BL/6 background. Male OT+/+ and OT-/- mice were administered saline or CCK (1, 3, or 10 microg/kg ip) after overnight food deprivation. Saline-treated OT+/+ and OT-/- mice consumed equivalent amounts of food after an overnight fast. CCK inhibited deprivation-induced food intake in a dose-dependent manner to a similar extent in both genotypes. CCK treatment also induced similar hindbrain and forebrain patterns of increased c-Fos expression in mice of both genotypes. After treatment with d-fenfluramine (10 mg/kg ip), both OT+/+ and OT-/- mice consumed significantly less food than untreated controls, with no difference between genotypes. We conclude that OT signaling pathways are unnecessary for the anorexigenic effects of systemically administered CCK and d-fenfluramine in C57BL/6 mice.
Oxytocin is released not only from the axon terminals in the neurothypophysis but also from the dendrites in the hypothalamus. In the present study, we examined the role of dendritic oxytocin release in regulating presynaptic noradrenaline release within the hypothalamus. In vivo microdialysis experiments showed that local application of oxytocin augmented high-K+-induced noradrenaline release in the hypothalamic supraoptic nucleus. Oxytocin application to the hypothalamic synaptosomal preparation in vitro also potentiated high-K+-induced noradrenaline release. The effect of oxytocin was dose-dependent and was blocked by an oxytocin receptor antagonist. We then examined roles of oxytocin released from the dendrites using in vivo microdialysis. Local application of an oxytocin receptor antagonist impaired noradrenaline release in the supraoptic nucleus in response to high-K+ solution or noxious stimuli. An i.c.v. injection of an oxytocin receptor antagonist also impaired oxytocin release from the pituitary after noxious stimuli. These data suggest that dendritic oxytocin facilitates activation of oxytocin neurons, at least in part by augmentation of noradrenaline release via a presynaptic action.
Hindbrain projections of oxytocin neurons in the parvocellular paraventricular nucleus (pPVN) are hypothesized to transmit leptin signaling from the hypothalamus to the nucleus of the solitary tract (NTS), where satiety signals from the gastrointestinal tract are received. Using immunocytochemistry, we found that an anorectic dose of leptin administered into the third ventricle (3V) increased twofold the number of pPVN oxytocin neurons that expressed Fos. Injections of fluorescent cholera toxin B into the NTS labeled a subset of pPVN oxytocin neurons that expressed Fos in response to 3V leptin. Moreover, 3V administration of an oxytocin receptor antagonist, [d-(CH2)5,Tyr(Me)2,Orn8]-vasotocin (OVT), attenuated the effect of leptin on food intake over a 0.5- to 4-h period (P < 0.05). Furthermore, to determine whether oxytocin contributes to leptin's potentiation of Fos activation within NTS neurons in response to CCK, we counted the number of Fos-positive neurons in the medial NTS (mNTS) after 3V administration of OVT before 3V leptin and intraperitoneal CCK-8 administration. OVT resulted in a significant 37% decrease (P < 0.05) in the potentiating effect of leptin on CCK activation of mNTS neuronal Fos expression. Furthermore, 4V OVT stimulated 2-h food intake by 43% (P < 0.01), whereas 3V OVT at the same dose was ineffective. These findings suggest that release of oxytocin from a descending pPVN-to-NTS pathway contributes to leptin's attenuation of food intake by a mechanism that involves the activation of pPVN oxytocin neurons by leptin, resulting in increased sensitivity of NTS neurons to satiety signals.
A number of changes occur in the oxytocin (OT) system during gestation, such as increases in hypothalamic OT mRNA, increased neural lobe and systemic OT, and morphological and electrophysiological changes in OT-containing magnocellular neurons, suggestive of altered neuronal sensitivity, which may be mediated by ovarian steroids. Because central norepinephrine (NE) and histamine (HA) are potent stimulators of OT release during parturition and lactation, the present study investigated the effects of central noradrenergic and histaminergic receptor activation on systemic (NE, HA) and intranuclear (NE) OT release in pregnant rats and in ovariectomized rats treated with ovarian steroids. Plasma OT levels in late gestation were significantly higher compared with all other groups, and neither adrenergic nor histaminergic receptor blockade decreased these elevated levels. Furthermore, the alpha-adrenergic agonist phenylephrine, but not histamine, stimulated systemic OT release to a significantly greater extent in late gestation than in midpregnant, ovariectomized, or steroid-treated females. Although basal extracellular OT levels in the paraventricular nucleus, as measured with microdialysis, were unchanged during pregnancy or steroid treatment, noradrenergic receptor stimulation of intranuclear OT release was significantly elevated in midgestation females compared with all other groups. These studies indicate that sensitivity of intranuclear and systemic OT release to noradrenergic receptor activation differentially varies during the course of gestation.
Experiments were conducted to determine if the chronic absence of the neurotransmitter oxytocin (OT) in null mice resulted in alterations in the responsiveness and abundance of central OT receptors. Self-grooming elicited by intracerebroventricularly administered OT was studied as an indicator of the activation of central OT receptors and autoradiography was used to map the distribution and density of OT receptors in OT null and wild type mice. The intracerebroventricular administration of OT, but not vehicle, artificial cerebrospinal fluid (aCSF), produced a robust increase in grooming behavior in both OT null and wild type animals, P<.001. However, OT-induced grooming was significantly greater in OT null than wild type mice, P<.005. The enhanced grooming was selective to OT as indicated by the finding that grooming to intracerebroventricular arginine vasopressin (AVP) was of the same magnitude in both OT null and wild type mice. OT-induced grooming appears to be mediated through the activation of OT receptors because pretreatment of animals with an OT antagonist, Atosiban, abolished OT-induced grooming, but not AVP-induced grooming. OT receptor distribution and binding in brains of OT null and wild type mice were examined by autoradiography and were not significantly different. The results indicate that the chronic absence of OT in null mice leads to an increase in OT receptor responsiveness that contributes to the augmented grooming activity elicited by centrally administered OT.
In the proestrous female rat, norepinephrine, oxytocin and nitric oxide (NO) all participate in the regulation of the preovulatory gonadotropin-releasing hormone (GnRH) surge. Recent studies from our laboratory have demonstrated that oxytocin induces dose-dependent release of GnRH from proestrous basal hypothalamus explants. The present studies were undertaken to determine whether norepinephrine could also stimulate GnRH release from similar explants, to identify the receptors responsible for this effect and to investigate interactions between norepinephrine, oxytocin and NO. Norepinephrine significantly stimulated GnRH release from proestrous basal hypothalamus explants, and coadministration of the alpha(1)-adrenergic antagonist prazosin blocked this effect. Combined administration of oxytocin and norepinephrine stimulated significantly more GnRH release than either drug alone, and this stimulation was blocked by inhibition of NO synthase, or by an oxytocin receptor antagonist. NO production was measured from the same samples using a modified Griess reaction. Oxytocin, but not norepinephrine, significantly increased NO production, as did norepinephrine and oxytocin in combination. Oxytocin receptor antagonist administration attenuated the stimulation of NO production by norepinephrine/oxytocin. These results demonstrate for the first time that oxytocin and norepinephrine dramatically stimulate GnRH release from basal hypothalamus explants harvested on the afternoon of proestrus, and indicate that this involves oxytocin receptor and NO-dependent mechanisms.
Oxytocin secretion from the posterior pituitary gland is increased during parturition, stimulated by the uterine contractions that forcefully expel the fetuses. Since oxytocin stimulates further contractions of the uterus, which is exquisitely sensitive to oxytocin at the end of pregnancy, a positive feedback loop is activated. The neural pathway that drives oxytocin neurons via a brainstem relay has been partially characterised, and involves A2 noradrenergic cells in the brainstem. Until close to term the responsiveness of oxytocin neurons is restrained by neuroactive steroid metabolites of progesterone that potentiate GABA inhibitory mechanisms. As parturition approaches, and this inhibition fades as progesterone secretion collapses, a central opioid inhibitory mechanism is activated that restrains the excitation of oxytocin cells by brainstem inputs. This opioid restraint is the predominant damper of oxytocin cells before and during parturition, limiting stimulation by extraneous stimuli, and perhaps facilitating optimal spacing of births and economical use of the store of oxytocin accumulated during pregnancy. During parturition, oxytocin cells increase their basal activity, and hence oxytocin secretion increases. In addition, the oxytocin cells discharge a burst of action potentials as each fetus passes through the birth canal. Each burst causes the secretion of a pulse of oxytocin, which sharply increases uterine tone; these bursts depend upon auto-stimulation by oxytocin released from the dendrites of the magnocellular neurons in the supraoptic and paraventricular nuclei. With the exception of the opioid mechanism that emerges to restrain oxytocin cell responsiveness, the behavior of oxytocin cells and their inputs in pregnancy and parturition is explicable from the effects of hormones of pregnancy (relaxin, estrogen, progesterone) on pre-existing mechanisms, leading through relative quiescence at term inter alia to net increase in oxytocin storage, and reduced auto-inhibition by nitric oxide generation. Cyto-architectonic changes in parturition, involving evident retraction of glial processes between oxytocin cells so they get closer together, are probably a response to oxytocin neuron activation rather than being essential for their patterns of firing in parturition.
Evidence in rats suggests that central oxytocin (OT) signaling pathways contribute to suppression of food intake during dehydration (i.e., dehydration anorexia). The present study examined water deprivation-induced dehydration anorexia in wild-type and OT -/- mice. Mice were deprived of food alone (fasted, euhydrated) or were deprived of both food and water (fasted, dehydrated) for 18 h overnight. Fasted wild-type mice consumed significantly less chow during a 60-min refeeding period when dehydrated compared with their intake when euhydrated. Conversely, fasting-induced food intake was slightly but not significantly suppressed by dehydration in OT -/- mice, evidence for attenuated dehydration anorexia. In a separate experiment, mice were deprived of water (but not food) overnight for 18 h; then they were anesthetized and perfused with fixative for immunocytochemical analysis of central Fos expression. Fos was elevated similarly in osmo- and volume-sensitive regions of the basal forebrain and hypothalamus in wild-type and OT -/- mice after water deprivation. OT-positive neurons expressed Fos in dehydrated wild-type mice, and vasopressin-positive neurons were activated to a similar extent in wild-type and OT -/- mice. Conversely, significantly fewer neurons within the hindbrain dorsal vagal complex were activated in OT -/- mice after water deprivation compared with activation in wild-type mice. These findings support the view that OT-containing projections from the hypothalamus to the hindbrain are necessary for the full expression of compensatory behavioral and physiological responses to dehydration.
Oxytocin mediates social affiliation behaviors and social memory in rodents. It has been suggested that disruptions in oxytocin contribute to the deficits in reciprocal social interactions that characterize autism. The present experiments employed a new social approach task for mice which is designed to detect low levels of sociability, representing the first diagnostic criterion for autism. Two lines of oxytocin knockout mice were tested, the National Institute of Mental Health line in Bethesda, and the Baylor/Emory line at the University of North Carolina in Chapel Hill. Similar methods were used for each line to evaluate tendencies to spend time with a stranger mouse versus with an inanimate novel object with no social valence. Adult C57BL/6J males were tested identically, as controls to confirm the robustness of the methods used in the social task. Comprehensive phenotyping of general health, neurological reflexes, olfactory and other sensory abilities, and motor functions was employed to assess both lines. No genotype differences were detected in any of the control measures for either line. Normal sociability, measured as time spent with a novel stranger mouse as compared to time spent with a novel object, was seen in both the NIMH and the Baylor/Emory lines of oxytocin null mutants, heterozygotes, and wild-type littermate controls. Normal preference for social novelty, measured as time spent with a second novel stranger as compared to time spent with a more familiar mouse, was seen in both the NIMH and the Baylor/Emory lines of oxytocin null mutants, heterozygotes, and wild-type littermate controls, with minor exceptions. Similar behavioral results from two independent targeted gene mutations, generated with different targeting vectors, bred on different genetic backgrounds, and tested in different laboratory environments, corroborates the negative findings on sociability in oxytocin mutant mice. Intact tendencies to spend time with another mouse versus with a novel object, in both lines of oxytocin knockouts, supports an interpretation that oxytocin plays a highly specific role in social memory, but is not essential for general spontaneous social approach in mice.
During pregnancy body weight, and particularly adiposity, increase, due to hyperphagia rather than decreased energy metabolism. These physiological adaptations provide the growing fetus(es) with nutrition and prepare the mother for the metabolically-demanding lactation period following birth. Mechanisms underlying the hyperphagia are still poorly understood. Although the peripheral signals that drive appetite and satiety centers of the brain are increased in pregnancy, the brain may become insensitive to their effects. For example, leptin secretion increases but hypothalamic resistance to leptin actions develops. However, several adaptations in hypothalamic neuroendocrine systems may converge to increase ingestive behavior. Oxytocin is one of the anorectic hypothalamic neuropeptides. Oxytocin neurons, both centrally-projecting parvocellular oxytocin neurons and central dendritic release of oxytocin from magnocellular neurons, may play a key role in regulating energy intake. During feeding in non-pregnant rats, magnocellular oxytocin neurons, especially those in the supraoptic nucleus, become strongly activated indicating their imminent role in meal termination. However, in mid-pregnancy the excitability of these neurons is reduced, central dendritic oxytocin release is inhibited and patterns of oxytocin receptor binding in the brain alter. Our recent data suggest that lack of central oxytocin action may partly contribute to maternal hyperphagia. However, although opioid inhibition is a major factor in oxytocin neuron restraint during pregnancy and opioids enhance food intake, an increase in opioid orexigenic actions were not observed. While changes in several central input pathways to oxytocin neurons are likely to be involved, the high level of progesterone secretion during pregnancy is probably the ultimate trigger for the adaptations.
We previously reported that oxytocin knockout (OT KO) mice display markedly enhanced intake of sweet and nonsweet carbohydrate solutions compared with intake by wild-type (WT) mice of the same background strain. The present study was conducted to determine whether OT KO mice demonstrate enhanced intake of Intralipid, a palatable lipid emulsion. Male or female mice of both genotypes that were naive to the test solution were given continuous two-bottle access to Intralipid and water with food available ad libitum for 3 days. Throughout the experiment, mice of both genotypes showed a marked preference for Intralipid over water. On the 1st day, OT KO mice displayed twofold greater preference and consumed nearly twice as much Intralipid compared with WT cohorts. However, on subsequent days of exposure, Intralipid preference and intake did not differ between genotypes over a range of lipid concentrations presented in descending or ascending order. Daily and hourly measures of lipid vs. sucrose intake confirmed that OT KO mice consumed more sucrose solution, but not lipid emulsion, than WT mice. During ad libitum access to Intralipid, both genotypes consumed significantly more calories from the emulsion as concentration increased. Both genotypes maintained consistent total daily caloric intake (lipid plus chow) and compensated by decreasing chow intake over the course of the study. These findings, coupled with prior reports from our laboratory, support the view that OT signaling pathways participate in limiting intake of palatable carbohydrate-containing solutions, but do not appear to play a role in limiting intake of Intralipid.
The role of the neuropeptide oxytocin (OT) ranges from the modulation of neuroendocrine physiological effects to the establishment of complex social and bonding behaviours. Experimental studies in animals, as well as case reports in humans, suggest that OT affects different aspects of sexual behaviour and has predominantly facilitating properties for sexual appetence and performance. Using a previously established experimental paradigm of sexual arousal and masturbation-induced orgasm, this study investigated the acute effects of intranasal OT application (24I.U.) on endocrine parameters and measures of sexual appetence and function in healthy men (n=10). In a double-blind, placebo-controlled, balanced cross-over design, sexual arousal, and orgasm were induced by an erotic film and masturbation. In addition to the continuous recording of endocrine (OT, cortisol, prolactin, epinephrine, norepinephrine) and cardiovascular data (heart rate), parameters of appetitive, consummatory, and refractory sexual behaviour were assessed using the acute sexual experience scale (ASES). OT plasma levels were significantly elevated after intranasal OT throughout the whole experiment (>60 min). In addition, OT treatment induced significantly higher increases in epinephrine plasma levels during sexual activity without affecting cortisol levels, prolactin levels or heart rate. OT treatment did not alter appetitive, consummatory, and refractory sexual behaviour according to the ASES. However, when subjects were asked about their subjective perception of whether OT or placebo had been applied, eight out of 10 subjects in the OT group answered correctly, thus pointing to an altered perception of arousal. In conclusion, intranasally administered OT leads to a marked increase in OT plasma levels together with increased secretion of catecholamines when subjects are engaged in sexual activity in a laboratory setting. As the effects of OT on sexual behaviour were equivocal, future studies should examine possible facilitating effects further by including males, females, and couples in a field setting, taking into account that OT exerts the most prominent behavioural effects in pair bond formations.
Social approach in oxytocin knockout mice: comparison of two independent lines tested in different laboratory environments
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Oxytocin innervation of caudal brainstem nuclei activated by cholecystokinin Oxytocin deficiency mediates hyperphagic obesity of Sim1 haploinsufficient mice
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The magnocellular oxytocin system, the fount of maternity: adaptations in pregnancy
- Ludwig
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