Open access peer-reviewed chapter

Oxytocin as a Metabolic Modulator

Written By

Neeru Bhatt

Submitted: 04 January 2021 Reviewed: 08 April 2021 Published: 06 May 2021

DOI: 10.5772/intechopen.97630

From the Edited Volume

Oxytocin and Health

Edited by Wei Wu and Ifigenia Kostoglou-Athanassiou

Chapter metrics overview

332 Chapter Downloads

View Full Metrics


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.


  • Oxytocin
  • metabolism
  • endocrine system
  • obesity
  • energy balance

1. Introduction

Oxytocin, which was long thought to be a hormone exclusively involved in social bonding, parturition, and lactation; now is extensively researched for its other possible implications. Evidence indicates that oxytocin alters lipid, protein, and sugar metabolism through various ways including modulation of appetite and satiety, enzyme activity, cellular signals, secretion of metabolic hormones, and energy consumption [1, 2].

1.1 Oxytocin synthesis and secretion

Oxytocin (Oxt) a nonapeptide hormone is a member of the G-protein coupled receptor family. It regulates a range of physiologic actions in mammals other than reproductive deeds [3]. The word oxytocin was taken from the Greek words (ω k ν ξ, τ o k ox ξ) meaning “quick birth”. The uterine-contracting property of oxytocin was discovered by Dale [4], whereas the milk ejection property of oxytocin was revealed in the following years [5, 6].

Oxytocin is composed of nine amino acids (Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-GlyNH2) with a disulphide bridge between cysteine residues 1 and 6 [7, 8]. It is predominantly synthesized in magnocellular neurons of the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei of the brain. It is released into the blood circulation through the posterior pituitary gland where it is released to regulate parturition and lactation. In addition, oxytocin is produced and released outside the nervous system, such as the gastrointestinal tract [9] and bone marrow osteoblasts [10, 11] liver, placenta, amnion, heart [12], and subcutaneous adipose tissue. In adipose tissue, oxytocin has autocrine and paracrine effects via oxytocin receptors [9, 10, 13]. A variety of stimuli such as parturition, suckling, and certain stresses are responsible for the release of oxytocin in the circulation.

Endogenous oxytocin does not readily cross the blood–brain barrier, but circulating oxytocin may directly enter the hindbrain or act on the vagus nerve [14, 15, 16, 17]. Oxytocin can enter into the cerebrospinal fluid (CSF), as proved in an animal study [18]. A significant amount of oxytocin was found in cerebrospinal fluid when copious amounts of oxytocin were injected intravenously or intranasally in nonhuman primates [18]. Additionally, exogenous oxytocin administration may accelerate endogenous oxytocin secretion either directly through PVN oxytocin autoreceptors or indirectly through peripheral oxytocin receptors [19, 20]. Generally, oxytocin receptors are found throughout the central nervous system including the hypothalamus, basal ganglia, VTA, nucleus accumbens, frontal cortex, insula, NTS, and spinal cord. Oxytocin receptors are also present in peripheral regions (vagus nerve, anterior pituitary gland, adipocytes, gastrointestinal tract, and pancreas) that regulate food intake and metabolism [12, 21, 22, 23, 24, 25]. Infect, mRNA for oxytocin and its receptors throughout the entire human gastrointestinal (GI) tract was recently found. Such receptors are known as allosteric modulators [12] (Figure 1).

Figure 1.

Chemical structure of oxytocin [26].

1.2 The therapeutic potential of oxytocin

The therapeutic potential of oxytocin has been studied extensively for the last few years. Use of oxytocin in the treatment of autism spectrum disorder (ASD) [26, 27], schizophrenia [26, 28], and obesity [20, 28, 29, 30, 31] have been investigated and documented in leading journals. It has opened a new door for many more untouched aspects of oxytocin to be disclosed. Recently it was found that oxytocin could reverse the effects of beta-amyloid on mice hippocampal LTP in an in vitro study. ERK phosphorylation and Ca2+-permeable AMPA receptors are involved in this effect of oxytocin [32]. Beta-amyloid is the main culprit of Alzheimer’s disease, which gets deposited around the neurons of the brain and impaired cognitive functions.

1.3 Physiological role of oxytocin in feeding regulation

Oxytocin exerts a direct as well as an indirect effect on metabolism and energy balance. The direct effect is through anorexigenic activity with increased oxytocin secretion and/or signaling leading to decreased food intake via net effects on multiple different homeostatic and neurobehavioral pathways. Peripheral oxytocin induces anorexia was first demonstrated by Arletti et al. [33]. The indirect effect of oxytocin is explicitly on muscles potentiating the majority of the slow-twitch muscles.

Oxytocin not only affects food intake but also the choice of food that is consumed. Studies conducted with a variety of animal models, including rats, mice, and rhesus monkeys fed with standard chow with a substantial proportion of calories from carbohydrates. Such studies have shown that oxytocin reduced intake of sucrose [34, 35, 36], glucose, fructose-sweetened beverages), and HFDs sweetened with sucrose [19, 20, 30, 37, 38, 39], sucrose appears to activate a greater proportion of PVN oxytocin neurons relative to intake of fat (intralipid) [40]. Oxytocin has also been shown to suppress energy intake in animals fed HFDs without sucrose. Moreover, systemic administration of oxytocin antagonists (readily crosses the blood–brain barrier) [41] stimulates the intake of sucrose, but not chow or intralipid [42]. Conversely, impairments of oxytocin signaling is associated with increased consumption of carbohydrates, including sucrose [34, 43, 44], and glucose [44], as well as fat [38, 45], implicating a potential physiological role for oxytocin to limit consumption of both simple sugars and fat.

Oxytocin has a profound effect in termination of the food intake. The food intake is physiologically regulated by oxytocin neurons, responding to fasting and satiety conditions. It has been observed that food consumption activates oxytocin neurons [40, 46], whereas fasting is known to depress oxytocin neurons and recovery is possible with refeeding [29] or the leptin administration [47], conversely suppression of exocytosis of oxytocin, or genetic reduction of oxytocin expression increases food intake [29], and ablation of oxytocin neurons increase body weight gain by decreasing energy expenditure in male mice fed a high-fat diet (HFD) [48]. The ablation of the neurons that express oxytocin receptors, in the nucleus of the solitary tract (NTS) and arcuate nucleus induces hyperphagia [49, 50] and satiety [51]. Additionally, oxytocin also displays a circadian rhythmic pattern with a rise of circulating oxytocin level during the day and vice versa [52, 53].

1.4 The metabolic functions of oxytocin

Oxytocin is a potent regulator of caloric intake and metabolism. Metabolism is an exclusive attribute of living cells. Disturbance in metabolism can have a toll on both body and mind. Although, the epidemics of metabolic diseases have largely been attributed to genetic makeup, changes in diet, exercise and aging. However, other environmental factors may contribute to the rapid increase in the incidences.

Oxytocin has a direct effect on adipose tissue. It induces adipose tissue lipolysis [16, 20] and fat oxidation [20, 30, 54], subsequently leading to reduced body fat and weight gain [20] as well as glucose intolerance and insulin resistance. Moreover, oxytocin is believed to reduce visceral and liver fat deposition [30]. Such deposits are metabolically important and are known to increase the prognosis of metabolic syndrome and cardiovascular disease [55]. Sub chronic treatment of oxytocin extended improved adipocyte differentiation and increased gene expression of factors involved in adipogenesis in rats. This effect is related to an increased fatty acid-binding protein, peroxisome proliferator-activated receptor gamma, insulin-sensitive glucose transporter 4, leptin, and CD31 mRNA levels [56].

1.5 Energy balance

Energy balance is a complex physiological process that is regulated by multiple interactions between the gastrointestinal tract (GIT), adipose tissue, and the central nervous system (CNS). It requires both afferent signals from the periphery about the state of the energy stores as well as different signals that influence energy intake and expenditure [57] and is also influenced by behavioral, sensorial, autonomic, nutritional, and endocrine mechanisms [58]. Energy balance is quite essential in daily life to be in shape physically as well as metabolically. Nevertheless, at times energy balance (intake and expenditure) may alter partially or completely, leading to consequent pathological changes in body weight. Adaptations to body weight changes include modifications at the level of circulating appetite-related hormones that, in turn, may profoundly interact with the homeostatic and hedonistic neural centers. The homeostatic control system makes it possible to maintain energy reserves through signals of hunger stimulation that are usually downregulated when the body receives an adequate caloric intake. However, this homeostatic system is asymmetrical, showing greater effectiveness in defending against energy deficit in the light of reduced efficiency in the defense against the energy excess. Furthermore, the homeostatic system is strongly influenced by hedonic signals, based on reward mechanisms, frequently causing food intake even in the absence of biological needs. This review will summarize the role of the main central and peripheral hormones involved in controlling energy balance.


2. Mechanisms underlying the effects of oxytocin on energy balance

The proposed mechanisms underlying the effects of oxytocin on calorie balance are discussed under the following topics.

2.1 Oxytocin may regulate appetite

Oxytocin may induce satiety by slowing gastric emptying [59, 60, 61]. Gastric emptying is a principal trait of postprandial glycemia. A lower rate of gastric emptying and a high-fat diet rationally enhances the glycemic index of carbohydrates. Moreover, slowing of gastric emptying by fat depends on the small intestine exposed to lipolytic products. Oxytocin is released in response to a fatty meal [62], which regulates gastric emptying [63, 64].

Conversely, systemic administration of oxytocin led to enhanced gastric emptying [63, 64] also oxytocin receptor antagonist atosiban delayed gastric emptying significantly [9]. Though the results from human studies are conflicting and only one human study on diabetic gastroparesis has reported prolonged gastric emptying time (40–80 mIU/min) [65]. The prokinetic effect of oxytocin on the gut has been assumed to be similar to the one in uterine myometrium and mammary myoepithelial cells; i.e., the intracellular release of Ca2+ which leads to muscle contraction via myosin light kinase activity [12]. In normal subjects, oxytocin has been found in the gut where it is secreted after a meal [62] and stimulates colonic activity [66].

Oxytocin can influence other appetite-regulating hormones. Intravenous administration of oxytocin modulated levels of ghrelin (which is orexigenic) in human subjects [67], whereas 24 IU intranasal administration of oxytocin did not show any significant changes in fasting or postprandial levels of ghrelin [68, 69]. Ghrelin is a gastric hormone, which regulates hunger and food intake. Likewise, oxytocin administration can influence cholecystokinin concentration in circulation [60] but this change was not related to differences in caloric consumption between oxytocin and placebo conditions [35]. Oxytocin facilitates cholecystokinin elicited excitation of neurons within the nucleus of the solitary tract and reduces food intake [49].

2.2 Oxytocin and glucose homeostasis

Oxytocin influences glucose and insulin homeostasis, along with bodyweight balance. Numerous studies have shown that oxytocin encourages glucose uptake [70, 71] and stimulates insulin secretion [72, 73, 74, 75, 76] as well as pancreatic glucagon secretion [75], which extends a hint about the involvement of oxytocin in the prognosis of diabetes. Intracerebroventricular oxytocin can improve insulin levels by activation of vagal cholinergic neurons innervating pancreatic beta-cells [76]. Conversely, insulin can modulate oxytocin levels in the hypothalamus by activating the insulin-regulated aminopeptidase as well [77, 78].

Studies have suggested that oxytocin has the capacity to reduce obesity-related diabetic changes, such as glucose intolerance, insulin resistance, and pancreatic islet hypertrophy [19, 20, 30, 38, 79, 80]. Two weeks of treatment with oxytocin decreased adiposity and food intake in obese mice lacking leptin, although, it worsens glucose metabolism, most likely due to an increase in corticosterone levels and enhanced hepatic glucose production. It could be suggested that the effect of oxytocin in decreasing fat mass is independent of leptin, while the beneficial impact on glucose metabolism requires the presence of leptin [81]. Whereas, oxytocin treatment for a longer period, notably reduced body fat accumulation, fasting blood glucose levels, and improved insulin sensitivity and glucose tolerance in leptin receptor-deficient mice [82]. The hypoglycemic stimulatory effect on insulin secretion and sensitivity, and improvement of pancreatic islet cells after oxytocin administration strongly suggested that oxytocin might be a therapeutic target for treating diabetes.

Oxytocin influences glucose metabolism in various ways. It may have a direct effect on glucose metabolism through the promotion of muscle cell differentiation. It has been found that a higher oxytocin concentration is linked with the anabolic effects of steroids in bovine and ovine skeletal muscle [83, 84]. A rapid increase in muscle regeneration was observed in old mice with a cardiotoxin muscle injury, when oxytocin was administered subcutaneously [79], though, the regenerative capacity of skeletal muscle and the levels of oxytocin receptor in muscle stem cells decrease with the age [79].

Further oxytocin-induced augmentation of muscle mass directly affects glucose uptake and insulin sensitivity. Oxytocin receptors are widely distributed in adipocytes of both humans and animals, especially in rats [12, 85, 86]. Oxytocin augments the transient increase in intracellular Ca2+ and stimulates PKC activity [87, 88], which in turn increases glucose uptake in mice adipocytes [88, 89, 90]. It has been noted that oxytocin stimulates glucose oxidation via enhancement of pyruvate dehydrogenase activity in mice adipocytes [90]. Oxytocin treatment induced a higher mRNA expression for gluconeogenesis and lowered glycaemia in lean control mice, probably because of the decreased liver glycogen content [82]. So, oxytocin treatment enhances net hepatic glucose oxidation, reduced glycogen synthase activity, and increased glycogen phosphorylase activity [91].

Oxytocin modulates pancreatic function centrally via vagal cholinergic neurons innervating β-cells [76] and peripherally by stimulating phosphoinositide turnover and activating PKC in pancreatic β-cells [92]. Insulin secretion (independent of glucose concentration) was found to be stimulated in isolated mouse pancreatic islets with oxytocin infusion [91]. Additionally, oxytocin increases insulin and glucagon secretion in both in vivo and in situ conditions and appears to have a greater effect on glucagon secretion than on insulin secretion (and to a much greater extent in insulin-deficient diabetic rats) [93, 94, 95]. Peripherally oxytocin regulates whole-body 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]. In contrast, increases in plasma glucose and hepatic glycogenolytic activity concurrent with an absence of effects on peripheral insulin sensitivity have also been reported [95].

2.3 The lipolytic effect of oxytocin

The lipolytic effect of oxytocin is well studied in animal models [16, 20] and human trials [100]. The intravenous administration of oxytocin (10 mIU/kg) increased plasma levels of non-esterified free fatty acids and reduced plasma levels of triglycerides in women with obese history [100]. Even the intranasal administration of oxytocin (24 IU before meals and at bedtime) in overweight or obese men and women for eight weeks resulted in improved lipid profile (lower levels of total cholesterol and LDL cholesterol), reduced waist circumference, and weight loss [80]. Oxytocin also acts as a homeostatic inhibitor of consumption, capable of mitigating multiple aspects of consumption behavior and energy metabolism [34]. Markedly, oxytocin reduces metabolically important fat for instance visceral and liver fat [30]. Such fat deposits are mostly responsible for the increased risk of metabolic syndrome and cardiovascular disease [55].

2.4 Energy expenditure

Despite the weight loss, it is believed that oxytocin contributed to the preservation of lean body mass, a key determinant of energy expenditure [54], activation of brown fat [97, 101, 102] and conversion of white adipose tissue to beige fat that is capable of thermogenesis [68, 82]. In young female athletes and non-athletes aged 14–21 years, fasting levels of oxytocin were positively associated with resting energy expenditure [68].


3. Conclusions

Metabolic disorders have reached to an explosive level and data projected by different government or non-government bodies are scary. Some alternative treatments should be adopted other than the conventional mode of treatment to coping such situations. Hormones are very powerful chemical substances and work precisely in the target organ. They mostly secrete far away from the site of action. Oxytocin is one such hormone that was long known for its reproductive involvement and is now being investigated for its multifunctional attributes. The therapeutic implications of oxytocin are gaining momentum. Studies have revealed that oxytocin alters metabolism in various ways including modulation of appetite and satiety, enzyme activity, cellular signals, secretion of hormones, and energy consumption. Despite the wealth of basic research showing broad anorexigenic effects of oxytocin, clinical studies on oxytocin’s therapeutic potential in obesity, and associated disorders are still in their infancy and exhaustive research is needed. Future replicated and validated studies will help to characterize and better understand the underlying mechanisms for the regulation/dysregulation of metabolism and would be a good approach for treating the obese population, which is the need of the hour.



All the researchers and authors referred and cited here are duly acknowledged.


Conflict of interest

The author declares no conflict of interest, financial or otherwise.


Other declarations

I am grateful to IOOS Programme of Intech Open for waiving publication fees completely.


Acronyms and abbreviations


Adenosine monophosphate




The cell adhesion molecule


Cerebrospinal fluid


Cardio vascular diseases


Extracellular signal-regulated kinase


High fructose syrup


Low density lipoprotein


Long term potentiation(hippocampus)


Messenger RNA


Nucleus tractus solitarius


Protein kinase




Ventral tegmental area


  1. 1. Ding C, Leow MKS, Magkos F. Oxytocin in metabolic homeostasis: implications for obesity and diabetes management. Obes Rev. 2019;20(1):22-40. doi: 10.1111/obr.12757
  2. 2. Sabatier N, Leng G, Menzies J. Oxytocin, feeding, and satiety, Fronti Endocrl. 2013; 4: 35
  3. 3. Meyer-Lindenberg A, Domes G, Kirsch P, Heinrichs M. Oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine. Nat Rev Neurosci. 2011; 12: 524-538
  4. 4. Dale HH. On some physiological actions of ergot. J Physio. 1906; 34:163-206
  5. 5. Ott I, Scott JC. The Action of Infundibulum upon Mammary Secretion. Proc Soc Exp Biol. 1910; 8: 48-49
  6. 6. Schafer EA, Mackenzie K. The action of animal extracts on milk secretion. Proceedings of the Royal Society of London Series B-Containing Papers of a Biological Character. 1911; 84:16-22
  7. 7. du Vigneaud V, Ressler C, Trippett S. The sequence of amino acids in oxytocin, with a proposal for the structure of oxytocin. J Biol Chem. 1953b; 205:949-957
  8. 8. Tuppy H. The amino-acid sequence in oxytocin. Biochim Biophys Acta. 1953; 11: 449-450
  9. 9. Ohlsson B, Björgell O, Ekberg O, Darwiche G. The oxytocin/vasopressin receptor antagonist atosiban delays the gastric emptying of a semisolid meal compared to saline in human. Bio Med cent Gastroenterol. 2006; 6:11. doi:10.1186/1471-230X-6-11
  10. 10. Qin J, Feng M, Wang C, Ye Y, Wang PS, Liu C. Oxytocin receptor expressed on the smooth muscle mediates the excitatory effect of oxytocin on gastric motility in rats. Neurogastroenterl Motil. 2009; 21:430-438. doi: 10.1111/j. 1365-2982.2009. 01282.x
  11. 11. Elabd C, Basillais A, Beaupied, H, Breuil V, Wagner N, Scheideler M, Zaragosi LE, Massiéra F, Lemichez E, Trajanoski Z, Carle G, Euller-Ziegler L, Ailhaud G, Benhamou CL, Dani C, Amri EZ. Oxytocin controls differentiation of human mesenchymal stem cells and reverses osteoporosis. Stem Cell. 2008; 26: 2399-2407
  12. 12. Gimpl G, Fahrenholz F. The oxytocin receptor system: structure, function, and regulation. Physiol Rev. 2001; 81:629-683
  13. 13. Feng M, Qin J, Wang C, Ye Y, Wang S, Xie D, Wang P S, Liu C. Estradiol upregulates the expression of oxytocin receptor in colon in rats. Am J Physiol Endocrinl Metabol. 2009; 296: E1059–E1066. doi: 10.1152/ ajpendo.90609.2008
  14. 14. Welch MG, Tamir H, Gershon MD. Expression and developmental regulation of oxytocin (OT) and oxytocin receptors (OTR) in the enteric nervous system (ENS) and intestinal epithelium. J Compar Neur. 2009; 512:256-270. doi: 10.1002/cne.21872
  15. 15. Ho JM, Anekonda VT, Thompson BW, Zhu M, Curry RW, Hwang B H, Morton GJ, Schwartz MW, Baskin DG, Appleyard SM, Blevins JE. Hindbrain oxytocin receptors contribute to the effects of circulating oxytocin on food intake in male rats. Endocrinl. 2014; 155:2845-2857. doi: 10.1210/en.2014-1148
  16. 16. Blevins JE, Graham JL, Morton GJ, Bales KL, Schwartz MW, Baskin DG, Havel PJ. Chronic oxytocin administration inhibits food intake, increases energy expenditure, and produces weight loss in fructose-fed obese rhesus monkeys. Am J Physiol Regul Integ Comparat Physiol. 2015; 308(5): R431-R438. doi: 10.1152/ajpregu.00441.2014
  17. 17. Iwasaki Y, Maejima Y, Suyama S, Yoshida M, Arai T, Katsurada K, Kumari P, Nakabayashi H, Kakei M, Yada T. Peripheral oxytocin activates vagal afferent neurons to suppress feeding in normal and leptin-resistant mice: a route for ameliorating hyperphagia and obesity. Am J Physiol Regul Integ Comparat Physiol. 2015;308: R360–R369. doi: 10.1152/ajpregu.00344.2014
  18. 18. Lee MR, Scheidweiler KB, Diao XX, Akhlaghi F, Cummins A, Huestis MA, Leggio L, Averbeck BB. Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid in rhesus macaques: determination using a novel oxytocin assay. Mol Psychiat. 2017; 23(1):115-122
  19. 19. Zhang G, Cai D. Circadian intervention of obesity development via resting stage feeding manipulation or oxytocin treatment. Am J Physiol Endocrinl Metab. 2011; 301: E1004–E1012. doi:10.1152/ajpendo.00196.2011
  20. 20. Deblon N, Veyrat-Durebex C, Bourgoin L, Caillon A, Bussier AL, Petrosino S, Piscitelli F, Legros JJ, Geenen V, Foti M. Wahli W, Di Marzo V, Rohner-Jeanrenaud F. Mechanisms of the anti-obesity effects of oxytocin in diet-induced obese rats. Pub Lib Sci One. 2011; 6(9): e25565. doi: 10.1371/journal.pone.0025565
  21. 21. Blevins JE, Baskin DG. Translational and therapeutic potential of oxytocin as an anti-obesity strategy: Insights from rodents, nonhuman primates and humans. Physiol Behav. 2015; 152(Pt B):438-449. doi: 10.1016/j.physbeh.2015.05.023
  22. 22. Qian W, Zhu T, Tang B Yu S, Hu H, Sun W, Pan R, Wang J, Wang D, Yang L, Mao C, Zhou L, Yuan G. Decreased circulating levels of oxytocin in obesity and newly diagnosed type 2 diabetic patients. J Clin Endocrinl Metab. 2014; 99: 4683– 4689
  23. 23. Feng Y, Kapormai K, Barr CL. Association of the GABRD gene and childhood - onset mood disorders. Genes Brain Behav. 2010; 9(6):668-672
  24. 24. Gould BR, Zingg HH. Mapping oxytocin receptor gene expression in the mouse brain and mammary gland using an oxytocin receptor-LacZ reporter mouse. Neurosci. 2003; 122:155-167
  25. 25. Antoni FA. Oxytocin receptors in rat adenohypophysis: evidence from radioligand binding studies. Endocrinl. 1986; 119:2393-2395. doi: 10.1210/endo-119-5-2393
  26. 26. Striepens N, Kendrick KM, Maier W, Hurlemann R. Prosocial effects of oxytocin and clinical evidence for its therapeutic potential. [Research Support, Non-U.S. Gov’t Review]. Front Neuroendocrinl. 2011; 32(4): 426-450. doi: 10.1016/j.yfrne.2011.07.001
  27. 27. Yamasue H, Yee JR, Hurlemann R, Rilling JK, Chen FS, MeyerLindenberg A, et al. Integrative approaches utilizing oxytocin to enhance prosocial behavior: from animal and human social behavior to autistic social dysfunction. J Neurosci. 2012; 32(41):14109-14117. doi:10.1523/JNEUROSCI.3327-12.2012
  28. 28. Montag C, Brockmann EM, Bayerl M, Rujescu D, Muller DJ, Gallinat J. Oxytocin and oxytocin receptor gene polymorphisms and risk for schizophrenia: A case–control study. World J Biol Psychi. 2012; 14(7): 500-508. doi:10.3109/15622975.2012.677547
  29. 29. Kublaoui BM, Gemelli T, Tolson KP, Wang Y, Zinn AR. Oxytocin deficiency mediates hyperphagic obesity of Sim1 haplo insufficient mice. Mol Endocrinl 2008; 22: 1723-1734
  30. 30. Maejima Y, Iwasaki Y, Yamahara Y, Kodaira M, Sedbazar U, Yada T. Peripheral oxytocin treatment ameliorates obesity by reducing food intake and visceral fat mass. Aging (Albany NY). 2011; 3(12):1169-1177
  31. 31. Maejima Y, Sedbazar U, Suyama S, Kohno D, Onaka T, Takano E, Yoshida N, Koike M, Uchiyama Y, Fujiwara K, Yashiro T, Horvath TL, Dietrich MO, Tanaka S, Dezaki K, Oh S, Hashimoto K, Shimizu H, Nakata M, Mori M, Yada T. Nesfatin-1-regulated oxytocinergic signaling in the paraventricular nucleus causes anorexia through a leptin independent melanocortin pathway. [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t]. Cell Metab. 2009; 10(5): 355-365. doi: 10.1016/j.cmet.2009.09.002
  32. 32. Takahashi J, Yamada D, Ueta Y, Iwai T, Koga E, Tanabe M, Oka JI, Saitoh A. Oxytocin reverses Aβ-induced impairment of hippocampal synaptic plasticity in mice. Bioche Biophy Res Commun. 2020; 528 (1): 174-178. doi: 10.1016/j.bbrc.2020.04.046
  33. 33. Arletti R, Benelli A, Bertolini A. Influence of oxytocin on feeding behavior in the rat. Peptides. 1989; 10: 89– 93
  34. 34. Olszewski PK, Klockars A, Schioth HB, Levine AS. Oxytocin as feeding inhibitor: maintaining homeostasis in consummatory behavior. Pharmacol Biochem Behav. 2010; 97: 47-54
  35. 35. Amico JA, Vollmer RR, Cai HM, Miedlar JA, Rinaman L. Enhanced initial and sustained intake of sucrose solution in mice with an oxytocin gene deletion. [Research Support, N.I.H., Extramural]. Am J Physiol Regul Integr Comp Physiol. 2005; 289(6): R1798–R1806. doi:10.1152/ajpregu.00558.2005
  36. 36. Sclafani A, Rinaman L, Vollmer RR, Amico JA. Oxytocin knockout mice demonstrate enhanced intake of sweet and nonsweet carbohydrate solutions. Am J Physiol Regul Integr Comp Physiol. 2007; 292(5): R1828–R1833. doi:10.1152/ajpregu.00826.2006
  37. 37. Mullis K, Kay K, Williams DL. Oxytocin action in the ventral tegmental area affects sucrose intake. Brain Res. 2013; 1513: 1585-1591
  38. 38. Zhang G, Bai H, Zhang H, Dean C, Wu Q, Li J, Guariglia S, Meng Q, Cai D. Neuropeptide exocytosis involving synaptotagmin-4 and oxytocin in hypothalamic programming of body weight and energy balance. Neuron. 2011; 69:523-535. doi:10.1016/j. neuron.2010.12.036 29
  39. 39. Morton GJ, Thatcher BS, Reidelberger RD, Ogimoto K, Wolden Hanson T, Baskin DG, Schwartz MW, Blevins JE. Peripheral oxytocin suppresses food intake and causes weight loss in diet-induced obese rats. Am J Physiol Endocrinl Metab. 2012; 302: E134 –E144
  40. 40. Johnstone LE, Fong TM, Leng G. Neuronal activation in the hypothalamus and brainstem during feeding in rats. Cell Metab. 2006; 4: 313-321
  41. 41. Boccia ML, Goursaud AP, Bachevalier J, Anderson KD, Pedersen CA. Peripherally administered non-peptide oxytocin antagonist, L368,899, accumulates in limbic brain areas: a new pharmacological tool for the study of social motivation in non-human primates. Horm Behav. 2007; 52(3): 344-351. doi: 10.1016/j.yhbeh.2007. 05.009
  42. 42. Olszewski PK, Klockars A, Olszewska AM, Fredriksson R, Schioth HB, Levine AS. Molecular, immunohistochemical, and pharmacological evidence of oxytocin’s role as inhibitor of carbohydrate but not fat intake. Endocrinl. 2010; 151(10): 4736-4744. doi: 10.1210/en.2010-0151
  43. 43. Amico JA, Vollmer RR, Cai HM, Miedlar JA, Rinaman L. Enhanced initial and sustained intake of sucrose solution in mice with an oxytocin gene deletion. Am J Physiol Regul Integr Comp Physiol. 2005; 289: R1798 –R1806
  44. 44. Herisson FM, Brooks LL, Waas JR, Levine AS, Olszewski PK. Functional relationship between oxytocin and appetite for carbohydrates versus saccharin. Neuroreport. 2014; 25: 909 –914
  45. 45. Zhang G, Bai H, Cai D. Neuropeptide exocytosis involving synaptotagmin-4 and oxytocin in hypothalamic programming of body weight and energy balance. Neuron. 2011; 69: 523– 535
  46. 46. Hume C, Sabatier N, Menzies J. High-sugar, but not high-fat, food activates supraoptic nucleus neurons in the male rat. Endocrinl. 2017; 158: 2200-2211
  47. 47. Tung YCL, Ma M, Piper S, Coll A, O’Rahilly S, Yeo GS. Novel leptin-regulated genes revealed by transcriptional profiling of the hypothalamic paraventricular nucleus. J Neurosci. 2008; 28:12419-12426
  48. 48. Wu Z, Xu Y, Zhu Y, Sutton AK, Zhao R, Lowell BB, Olson DP, Tong Q. An obligate role of oxytocin neurons in diet induced energy expenditure. Pub Lib Sci One. 2012; 7: e45167. doi: 10.1371 /journal. pone. 0045167
  49. 49. Baskin DG, Kim F, Gelling RW, Russell BJ, Schwartz MW, Morton GJ, Simhan HN, Moralejo DH, Blevins JE. A new oxytocin-saporin cytotoxin for lesioning oxytocin-receptive neurons in the rat hindbrain. Endocrinl. 2010; 151: 4207-4213
  50. 50. Ong ZY, Bongiorno DM, Hernando MA, Grill HJ. Effects of endogenous oxytocin receptor signaling in nucleus tractus solitarius on satiation-mediated feeding and thermogenic control in male rats. Endocrinl. 2017; 158: 2826-2836
  51. 51. Fenselau H, Campbell JN, Verstegen AM, Madara JC, Xu J, Shah BP, Resch JM, Yang Z, Mandelblat-Cerf Y, Livneh Y, Lowell BB. A rapidly acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by αMSH. Nat Neurosci. 2017; 20: 42-51
  52. 52. Zhang G, Bai H, Zhang H, Dean C, Wu Q, Li J, Guairglia S, Meng Q, Cai D. Neuropeptide exocytosis involving synaptotagmin-4 and oxytocin in hypothalamic programming of body weight and energy balance. Neuron. 2011; 69: 523– 535
  53. 53. Maejima Y, Takahashi S, Takasu K, Takenoshita S, Ueta Y, Shimomura K. Orexin action on oxytocin neurons in the paraventricular nucleus of the hypothalamus. Neuroreport. 2017; 28: 360-366
  54. 54. Blevins JE, Thompson BW, Anekonda VT, Ho JM, Graham JL, Roberts ZS, Hwang BH, Ogimoto K, Wolden-Hanson T, Nelson J, Kaiyala KJ, Havel PJ, Bales KL, Morton GJ, Schwartz MW, Baskin DG. Chronic CNS oxytocin signaling preferentially induces fat loss in high-fat diet-fed rats by enhancing satiety responses and increasing lipid utilization. Am J Physiol Regul Integrat Comparat Physiol. 2016; 310: R640–R658. doi: 10.1152/ajpregu.00220.2015
  55. 55. Pischon T, Boeing H, Hoffmann K, Bergmann M, Schulze MB, Overvad K, van der Schouw YT, Spencer E, Moons KGM, Tjønneland A, Halkjaer J, Jensen MK, Stegger J, Clavel-Chapelon F, Boutron-Ruault MC, Chajes V, Linseisen J, Kaaks R, Trichopoulou A, Trichopoulos D, Bamia C, Sieri S, Palli D, Tumino R, Vineis P, Panico S, Peeters PHM, May AM, Bueno-de-Mesquita HB, van Duijnhoven FJB, Hallmans G, Weinehall L, Manjer J, Hedblad B, Lund E, Agudo A, Arriola L, Barricarte A, Navarro C, Martinez C, Quirós JR, Key T, Bingham S, Khaw KT, Boffetta P, Jenab M, Ferrari P, Riboli E. General and abdominal adiposity and risk of death in Europe. New Eng J Med. 2008; 359:2105-2120. doi: 10.1056/NEJMoa0801891
  56. 56. Hoyda D, Fry M, Ahima RS, Ferguson AV. Adiponectin selectively inhibits oxytocin neurons of the paraventricular nucleus of the hypothalamus. J Physiol. 2007; 585 (3): 805-816
  57. 57. Sandoval D, Cota D, Seeley RJ. The integrative role of CNS fuel-sensing mechanisms in energy balance and glucose regulation. Annu Rev Physiol. 2008; 70: 513-535
  58. 58. Boguszewski CL, Paz-Filho G, Velloso LA. Neuroendocrine body weight regulation: integration between fat tissue, gastrointestinal tract, and the brain. Endokrynol Pol. 2010; 61, 194-206
  59. 59. Wu CL, Hung CR, Chang FY, Pau KYF, Wang JL, Wang PS. Involvement of cholecystokinin receptor in the inhibition of gastric emptying by oxytocin in male rats. Pflugers Arch. 2002; 445:187-193. doi: 10.1007/s00424-002-0925-7
  60. 60. Wu CL, Hung CR, Chang FY, Pau KYF, Wang PS. Pharmacological effects of oxytocin on gastric emptying and intestinal transit of a non-nutritive liquid meal in female rats, Naunyn-Schmiedeberg's Arc Pharmacol. 2003; 367 (4): 406-413
  61. 61. Rogers RC, Hermann GE. Oxytocin, oxytocin antagonist, TRH, and hypothalamic paraventricular nucleus stimulation effects on gastric motility. Peptides. 1987; 8:505-513.
  62. 62. Ohlsson B, Forsling ML, Rehfeld JF, Sjölund K: Cholecystokinin leads to increased oxytocin secretion in healthy women. Eur J Surg. 2002; 168:114-118
  63. 63. Hashmonai M, Torem S, Argov S, Barzilai A, Schramek A: Prolonged post-vagotomy gastric atony treated by oxytocin. Br J Surg. 1979; 66:550-551
  64. 64. Petring OU. The effect of oxytocin on basal and pethidine-induced delayed gastric emptying. Br J Clin Pharmacol. 1989; 28:329-332
  65. 65. Borg J, Ohlsson B. Oxytocin prolongs the gastric emptying time in patients with diabetes mellitus and gastroparesis, but does not affect satiety or volume intake in patients with functional dyspepsia. Bio Med Centr Res Notes. 2012; 5:148. doi: 10.1186/1756-0500-5-148
  66. 66. Ohlsson B, Ringström G, Abrahamsson H, Simrén M, Björnsson ES. Oxytocin stimulates colonic motor activity in healthy women. Neurogastroenterol Mot. 2004; 16:233-240
  67. 67. Schorr M, Marengi DA, Pulumo RL, Yu E, Eddy KT, Klibanski A, Miller KK, Lawson EA. Oxytocin and its relationship to bone mineral density and hip geometry across the weight spectrum. J Clin Endocrinol Metabol. 2017; 102:2814-2824
  68. 68. Lawson EA, Marengi DA, DeSanti RL, Holmes TM, Schoenfeld DA, Tolley CJ. Oxytocin reduces caloric intake in men. Obesity. 2015; 23: 950-956
  69. 69. Ott V, Finlayson G, Lehnert H et al. Oxytocin reduces reward-driven food intake in humans. Diabetes. 2013; 62: 3418-3425
  70. 70. Florian M, Jankowski M, Gutkowska J. Oxytocin increases glucose uptake in neonatal rat cardiomyocytes. Endocrinl. 2010; 151(2):482-491. doi:10.1210/ en.2009-0624
  71. 71. Lee ES, Uhm KO, Lee YM, Kwon J, Park SH, Soo KH. Oxytocin stimulates glucose uptake in skeletal muscle cells through the calcium-CaMKK-AMPK pathway. Regul Pept. 2008; 151(1-3):71-74. doi: 10.1016/j.regpep.2008.05.001
  72. 72. Knudtzon J. Acute effects of oxytocin and vasopressin on plasma levels of glucagon, insulin and glucose in rabbits. Horm Metab Res. 1983; 15:103-104. doi:10.1055/s-2007-
  73. 73. Chiodera P, Coiro V, Camellini L, Rossi G, Pignatti D, Volpi R, Roti E. Effect of pharmacological doses of oxytocin on insulin response to glucose in normal man. Horm Res. 1984; 20(2):150-154. doi:10.1159/000179988
  74. 74. Paolisso G, Sgambato S, Giugliano D, Pizza G, Tesauro P, Varricchio M, D'Onofrio F. Effects of oxytocin delivery on counter-regulatory hormone response in insulin dependent (type 1) diabetic subjects. Horm Res. 1989; 31:250-255. doi:10.1159/ 000181126
  75. 75. Altszuler N, Winkler B, Rosenberg CR, Pi-Sunyer FX, Fuchs AR. Role of insulin and glucagon in oxytocin effects on glucose metabolism. Proc Soc Exp Biol Med. 1992; 199(2):236-242. doi:10.3181/00379727-199-43353
  76. 76. Björkstrand E, Eriksson M, Uvnäs-Moberg K. Evidence of a peripheral and a central effect of oxytocin on pancreatic hormone release in rats. Neuroendocrinl. 1996; 63(4):377-383. doi:10.1159/000126978
  77. 77. Fernando RN, Larm J, Albiston AL, Chai SY. Distribution and cellular localization of insulin-regulated aminopeptidase in the rat central nervous system. J Comparative Neurol. 2005; 487 (4): 372-390
  78. 78. Zambotti-Villela L, Yamasaki SC, Villarroel JS, Alponti RF, Silveira PF. Aspartyl, arginyl and alanyl aminopeptidase activities in the hippocampus and hypothalamus of streptozotocin-induced diabetic rats. Brain Res. 2007; 1170:112-118
  79. 79. Elabd C, Cousin W, Upadhyay P, Chen RY, Chooljian MS, Li J, Kung S, Jiang KP, Conboy IM. Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Nat Commun. 2014; 5: 4082
  80. 80. Zhang H, Wu C, Chen Q, Chen X, Xu Z, Wu J, et al. Treatment of obesity and diabetes using oxytocin or analogs in patients and mouse models. Pub Lib Sci One. 2013; 8(5): e61477. doi: 10.1371/journal.pone.0061477
  81. 81. Altirriba J, Poher AL, Caillon A, Arsenijevic D, Veyrat-Durebex C, Lyautey J, Dulloo A, Rohner-Jeanrenaud F. Divergent effects of oxytocin treatment of obese diabetic mice on adiposity and diabetes. Endocrinl. 2014; 155(11):4189-4201. doi:10.1210/ en.2014-1466
  82. 82. Plante E, Menaouar A, Danalache BA, Yip D, Broderick TL, Chiasson JL, Jankowski M, Gutkowska J. Oxytocin treatment prevents the cardiomyopathy observed in obese diabetic male db/db mice. Endocrinl. 2015; 156(4):1416-1428. doi:10.1210/en.2014- 1718
  83. 83. Jager ND, Hudson NJ, Reverter A, Wang YH, Nagaraj SH, Café L M, Greenwood PL, Barnard RT, Kongsuwan KP, Dalrymple BP. Chronic exposure to anabolic steroids induces the muscle expression of oxytocin and a more than fiftyfold increase in circulating oxytocin in cattle. Physiol Genom. 2011; 43: 467-478
  84. 84. Kongsuwan K, Knox MR, Allingham PG, Pearson R, Dalrymple BP. The effect of combination treatment with trenbolone acetate and estradiol-17β on skeletal muscle expression and plasma concentrations of oxytocin in sheep. Domest Anim Endocrinl. 2012; 43: 67-73
  85. 85. Tsuda T, Ueno Y, Yoshikawa T, Kojo H, Osawa T. Microarray profiling of gene expression in human adipocytes in response to anthocyanins. Biochem Pharmacol. 2006; 71: 1184-1197
  86. 86. Gajdosechova L, Krskova K, Segarra AB, Spolcova A, Suski M, Olszanecki R, Zorad S. Hypooxytocinaemia in obese Zucker rats relates to oxytocin degradation in liver and adipose tissue. J Endocrinl. 2014; 220: 333-343
  87. 87. Schwartz Y, Goodman HM, Yamaguchi H. Refractoriness to growth hormone is associated with increased intracellular calcium in rat adipocytes. Proc Natl Acad Sci U S A. 1991; 88: 6790– 6794
  88. 88. Egan JJ, Saltis J, Wek SA, Simpson IA, Londos C. Insulin, oxytocin, and vasopressin stimulate protein kinase C activity in adipocyte plasma membranes. Proc Natl Acad Sci U S A. 1990; 87: 1052– 1056
  89. 89. Mühlbacher C, Karnieli E, Schaff P, Obermaier B, Mushack J, Rattenhuber E, Häring HU. Phorbol esters imitate in rat fat-cells the full effect of insulin on glucose-carrier translocation, but not on 3-O-methylglucose-transport activity. Biochem J. 1988; 249: 865– 870
  90. 90. Mukherjee SP, Mukherjee C. Stimulation of pyruvate dehydrogenase activity in adipocytes by oxytocin: evidence for mediation of the insulin-like effect by endogenous hydrogen peroxide independent of glucose transport. Arch Biochem Biophys. 1982; 214: 211– 222
  91. 91. Arino J, Bosch F, Gomez-Foix AM, Guinovart JJ. Oxytocin inactivates and phosphorylates rat hepatocyte glycogen synthase. Biochem J. 1989; 261: 827– 830
  92. 92. Gao ZY, Drews G, Henquin JC. Mechanisms of the stimulation of insulin release by oxytocin in normal mouse islets. Biochem J. 1991; 276: 169-174
  93. 93. Dunning BE, Moltz JH, Fawcett CP. Modulation of insulin and glucagon secretion from the perfused rat pancreas by the neurohypophysial hormones and by desamino-D-arginine vasopressin (DDAVP). Peptides. 1984; 5: 871– 875
  94. 94. Widmaier EP, Shah PR, Lee G. Interactions between oxytocin, glucagon and glucose in normal and streptozotocin-induced diabetic rats. Regul Pept. 1991; 34: 235– 249
  95. 95. Paolisso G, Pizza G, De Riu S, Marrazzo G, Sgambato S, Giugliano D, Varricchio M, D’Onofrio F. Effects of oxytocin upon the endocrine pancreas secretion and glucose turnover in normal man. Eur J Endocrinl. 1990; 123: 504– 510
  96. 96. Camerino C. Low sympathetic tone and obese phenotype in oxytocin deficient mice. Obesity. 2009; 17: 980 –984
  97. 97. Watanabe S, Wei FY, Matsunaga T, Matsunaga N, Kaitsuka T, Tomizawa K. Oxytocin protects against stress-induced cell death in murine pancreatic β-cells. Sci Rep. 2016; 6: 25185
  98. 98. Mohan S, Khan D, Moffett RC, Irwin N, Flatt PR. Oxytocin is present in islets and plays a role in beta-cell function and survival. Peptides. 2018; 100: 260– 268
  99. 99. Klement J, Ott V, Rapp K, Brede S, Piccinini F, Cobelli C, Lehnert H, Hallschmid M. Oxytocin improves beta-cell responsivity and glucose tolerance in healthy men. Diabetes. 2016; 66(2): 264-271.
  100. 100. Burt RL, Leake NH, Dannenburg WN. Effect of synthetic oxytocin on plasma non esterified fatty acids, triglycerides, and blood glucose. Obstet Gyneco.1963; 21:708-712
  101. 101. Kasahara Y, Takayanagi Y, Kawada T, Itoi K, Nishimori K. Impaired thermoregulatory ability of oxytocin-deficient mice during cold-exposure. Biosci Biotechnol Biochem. 2007; 71: 3122-3126
  102. 102. Takayanagi Y, Kasahara Y, Onaka T, Takahashi N, Kawada T, Nishimori K. Oxytocin receptor-deficient mice developed late-onset obesity. Neuroreport. 2008; 19: 951-955

Written By

Neeru Bhatt

Submitted: 04 January 2021 Reviewed: 08 April 2021 Published: 06 May 2021