[en] Apart from its role during labor and lactation, oxytocin is involved in several other functions. Interestingly, oxytocin- and oxytocin receptor-deficient mice develop late-onset obesity with normal food intake, suggesting that the hormone might exert a series of beneficial metabolic effects. This was recently confirmed by data showing that central oxytocin infusion causes weight loss in diet-induced obese mice. The aim of the present study was to unravel the mechanisms underlying such beneficial effects of oxytocin. Chronic central oxytocin infusion was carried out in high fat diet-induced obese rats. Its impact on body weight, lipid metabolism and insulin sensitivity was determined. We observed a dose-dependent decrease in body weight gain, increased adipose tissue lipolysis and fatty acid β-oxidation, as well as reduced glucose intolerance and insulin resistance. The additional observation that plasma oxytocin levels increased upon central infusion suggested that the hormone might affect adipose tissue metabolism by direct action. This was demonstrated using in vitro, ex vivo, as well as in vivo experiments. With regard to its mechanism of action in adipose tissue, oxytocin increased the expression of stearoyl-coenzyme A desaturase 1, as well as the tissue content of the phospholipid precursor, N-oleoyl-phosphatidylethanolamine , the biosynthetic precursor of the oleic acid-derived PPAR-alpha activator, oleoylethanolamide. Because PPAR-alpha regulates fatty acid β-oxidation, we hypothesized that this transcription factor might mediate the oxytocin effects. This was substantiated by the observation that, in contrast to its effects in wild-type mice, oxytocin infusion failed to induce weight loss and fat oxidation in PPAR-alpha-deficient animals. Altogether, these results suggest that oxytocin administration could represent a promising therapeutic approach for the treatment of human obesity and type 2 diabetes.
Gimpl G, Fahrenholz F, (2001) The oxytocin receptor system: structure, function, and regulation. Physiol Rev 81: 629-683.
Arletti R, Benelli A, Bertolini A, (1989) Influence of oxytocin on feeding behavior in the rat. Peptides 10: 89-93.
Swaab DF, Purba JS, Hofman MA, (1995) Alterations in the hypothalamic paraventricular nucleus and its oxytocin neurons (putative satiety cells) in Prader-Willi syndrome: a study of five cases. J Clin Endocrinol Metab 80: 573-579.
Camerino C, (2009) Low sympathetic tone and obese phenotype in oxytocin-deficient mice. Obesity (Silver Spring) 17: 980-984.
Takayanagi Y, Kasahara Y, Onaka T, Takahashi N, Kawada T, et al. (2008) Oxytocin receptor-deficient mice developed late-onset obesity. Neuroreport 19: 951-955.
Zhang G, Bai H, Zhang H, Dean C, Wu Q, et al. (2011) Neuropeptide exocytosis involving synaptotagmin-4 and oxytocin in hypothalamic programming of body weight and energy balance. Neuron 69: 523-535.
Lo Verme J, Gaetani S, Fu J, Oveisi F, Burton K, et al. (2005) Regulation of food intake by oleoylethanolamide. Cell Mol Life Sci 62: 708-716.
Elabd C, Basillais A, Beaupied H, Breuil V, Wagner N, et al. (2008) Oxytocin controls differentiation of human mesenchymal stem cells and reverses osteoporosis. Stem Cells 26: 2399-2407.
Muchmore DB, Little SA, de Haen C, (1981) A dual mechanism of action of ocytocin in rat epididymal fat cells. J Biol Chem 256: 365-372.
Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, et al. (1995) Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol 15: 3012-3022.
Rohner-Jeanrenaud F, Walker CD, Greco-Perotto R, Jeanrenaud B, (1989) Central corticotropin-releasing factor administration prevents the excessive body weight gain of genetically obese (fa/fa) rats. Endocrinology 124: 733-739.
Pequeux C, Hendrick JC, Hagelstein MT, Geenen V, Legros JJ, (2001) Novel plasma extraction procedure and development of a specific enzyme-immunoassay of oxytocin: application to clinical and biological investigations of small cell carcinoma of the lung. Scand J Clin Lab Invest 61: 407-415.
Vettor R, Zarjevski N, Cusin I, Rohner-Jeanrenaud F, Jeanrenaud B, (1994) Induction and reversibility of an obesity syndrome by intracerebroventricular neuropeptide Y administration to normal rats. Diabetologia 37: 1202-1208.
Marsicano G, Wotjak CT, Azad SC, Bisogno T, Rammes G, et al. (2002) The endogenous cannabinoid system controls extinction of aversive memories. Nature 418: 530-534.
Foti M, Porcheron G, Fournier M, Maeder C, Carpentier JL, (2007) The neck of caveolae is a distinct plasma membrane subdomain that concentrates insulin receptors in 3T3-L1 adipocytes. Proc Natl Acad Sci U S A 104: 1242-1247.
Olson AL, Knight JB, Pessin JE, (1997) Syntaxin 4, VAMP2, and/or VAMP3/cellubrevin are functional target membrane and vesicle SNAP receptors for insulin-stimulated GLUT4 translocation in adipocytes. Mol Cell Biol 17: 2425-2435.
Gould BR, Zingg HH, (2003) Mapping oxytocin receptor gene expression in the mouse brain and mammary gland using an oxytocin receptor-LacZ reporter mouse. Neuroscience 122: 155-167.
Tsuda T, Ueno Y, Yoshikawa T, Kojo H, Osawa T, (2006) Microarray profiling of gene expression in human adipocytes in response to anthocyanins. Biochem Pharmacol 71: 1184-1197.
Schaffler A, Binart N, Scholmerich J, Buchler C, (2005) Hypothesis paper Brain talks with fat-evidence for a hypothalamic-pituitary-adipose axis? Neuropeptides 39: 363-367.
Kusui C, Kimura T, Ogita K, Nakamura H, Matsumura Y, et al. (2001) DNA methylation of the human oxytocin receptor gene promoter regulates tissue-specific gene suppression. Biochem Biophys Res Commun 289: 681-686.
Popeijus HE, Saris WH, Mensink RP, (2008) Role of stearoyl-CoA desaturases in obesity and the metabolic syndrome. Int J Obes (Lond) 32: 1076-1082.
Fu J, Gaetani S, Oveisi F, Lo Verme J, Serrano A, et al. (2003) Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 425: 90-93.
Guzman M, Lo Verme J, Fu J, Oveisi F, Blazquez C, et al. (2004) Oleoylethanolamide stimulates lipolysis by activating the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-alpha). J Biol Chem 279: 27849-27854.
Fu J, Oveisi F, Gaetani S, Lin E, Piomelli D, (2005) Oleoylethanolamide, an endogenous PPAR-alpha agonist, lowers body weight and hyperlipidemia in obese rats. Neuropharmacology 48: 1147-1153.
Miyazaki M, Ntambi JM, (2003) Role of stearoyl-coenzyme A desaturase in lipid metabolism. Prostaglandins Leukot Essent Fatty Acids 68: 113-121.
Brown JM, Rudel LL, (2010) Stearoyl-coenzyme A desaturase 1 inhibition and the metabolic syndrome: considerations for future drug discovery. Curr Opin Lipidol 21: 192-197.
Ariyama H, Kono N, Matsuda S, Inoue T, Arai H, (2010) Decrease in membrane phospholipid unsaturation induces unfolded protein response. J Biol Chem.
Miyazaki M, Man WC, Ntambi JM, (2001) Targeted disruption of stearoyl-CoA desaturase1 gene in mice causes atrophy of sebaceous and meibomian glands and depletion of wax esters in the eyelid. J Nutr 131: 2260-2268.
Collins JM, Neville MJ, Hoppa MB, Frayn KN, (2010) De novo lipogenesis and stearoyl-CoA desaturase are coordinately regulated in the human adipocyte and protect against palmitate-induced cell injury. J Biol Chem 285: 6044-6052.
Bjorkstrand E, Eriksson M, Uvnas-Moberg K, (1992) Plasma levels of oxytocin after food deprivation and hypoglycaemia, and effects of 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-oxytocin on blood glucose in rats. Acta Physiol Scand 144: 355-359.
Izzo AA, Piscitelli F, Capasso R, Marini P, Cristino L, et al. (2010) Basal and fasting/refeeding-regulated tissue levels of endogenous PPAR-alpha ligands in Zucker rats. Obesity (Silver Spring) 18: 55-62.
Jeong S, Yoon M, (2009) Fenofibrate inhibits adipocyte hypertrophy and insulin resistance by activating adipose PPARalpha in high fat diet-induced obese mice. Exp Mol Med 41: 397-405.
Dobrzyn P, Sampath H, Dobrzyn A, Miyazaki M, Ntambi JM, (2008) Loss of stearoyl-CoA desaturase 1 inhibits fatty acid oxidation and increases glucose utilization in the heart. Am J Physiol Endocrinol Metab 294: E357-364.
Dobrzyn P, Pyrkowska A, Jazurek M, Szymanski K, Langfort J, et al. (2010) Endurance training-induced accumulation of muscle triglycerides is coupled to upregulation of stearoyl-CoA desaturase 1. J Appl Physiol.
Gaetani S, Fu J, Cassano T, Dipasquale P, Romano A, et al. (2010) The fat-induced satiety factor oleoylethanolamide suppresses feeding through central release of oxytocin. J Neurosci 30: 8096-8101.
Gonzalez-Yanes C, Serrano A, Bermudez-Silva FJ, Hernandez-Dominguez M, Paez-Ochoa MA, et al. (2005) Oleylethanolamide impairs glucose tolerance and inhibits insulin-stimulated glucose uptake in rat adipocytes through p38 and JNK MAPK pathways. Am J Physiol Endocrinol Metab 289: E923-929.
Brunton PJ, Russell JA, (2008) The expectant brain: adapting for motherhood. Nat Rev Neurosci 9: 11-25.
Yogev Y, Visser GH, (2009) Obesity, gestational diabetes and pregnancy outcome. Semin Fetal Neonatal Med 14: 77-84.
Jensen DR, Gavigan S, Sawicki V, Witsell DL, Eckel RH, et al. (1994) Regulation of lipoprotein lipase activity and mRNA in the mammary gland of the lactating mouse. Biochem J 298 (Pt 2): 321-327.
Takagi T, Tanizawa O, Otsuki Y, Sugita N, Haruta M, et al. (1985) Oxytocin in the cerebrospinal fluid and plasma of pregnant and nonpregnant subjects. Horm Metab Res 17: 308-310.
Fuchs AR, Fuchs F, Husslein P, Soloff MS, Fernstrom MJ, (1982) Oxytocin receptors and human parturition: a dual role for oxytocin in the initiation of labor. Science 215: 1396-1398.
Murata T, Murata E, Liu CX, Narita K, Honda K, et al. (2000) Oxytocin receptor gene expression in rat uterus: regulation by ovarian steroids. J Endocrinol 166: 45-52.
