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Mechanisms of the Anti-Obesity Effects of Oxytocin in Diet-Induced Obese Rats

By Nicolas Deblon, Christelle Veyrat-Durebex, Lucie Bourgoin, Aurélie Caillon, Anne-Lise Bussier, Stefania Petrosino, Fabiana Piscitelli, Jean-Jacques Legros, Vincent Geenen, Michelangelo Foti, Walter Wahli, Vincenzo Di Marzo and Françoise Rohner-Jeanrenaud

Abstract

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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3181274
Provided by: PubMed Central

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Citations

  1. (1989). A
  2. (1981). A dual mechanism of action of ocytocin in rat epididymal fat cells.
  3. (1995). Alterations in the hypothalamic paraventricular nucleus and its oxytocin neurons (putative satiety cells) in Prader-Willi syndrome: a study of five cases.
  4. (2010). Basal and fasting/refeeding-regulated tissue levels of endogenous PPAR-alpha ligands in Zucker rats.
  5. (1989). Central corticotropin-releasing factor administration prevents the excessive body weight gain of genetically obese (fa/fa) rats.
  6. (2010). De novo lipogenesis and stearoyl-CoA desaturase are coordinately regulated in the human adipocyte and protect against palmitate-induced cell injury.
  7. (2010). Decrease in membrane phospholipid unsaturation induces unfolded protein response.
  8. (2001). DNA methylation of the human oxytocin receptor gene promoter regulates tissuespecific gene suppression.
  9. (2010). Endurance training-induced accumulation of muscle triglycerides is coupled to upregulation of stearoyl-CoA desaturase 1.
  10. (2009). Fenofibrate inhibits adipocyte hypertrophy and insulin resistance by activating adipose PPARalpha in high fat diet-induced obese mice.
  11. (2005). Hypothesis paper Brain talks with fat–evidence for a hypothalamic-pituitary-adipose axis?
  12. (1994). Induction and reversibility of an obesity syndrome by intracerebroventricular neuropeptide Y administration to normal rats.
  13. (2008). Loss of stearoyl-CoA desaturase 1 inhibits fatty acid oxidation and increases glucose utilization in the heart.
  14. (2009). Low sympathetic tone and obese phenotype in oxytocindeficient mice.
  15. (2003). Mapping oxytocin receptor gene expression in the mouse brain and mammary gland using an oxytocin receptor-LacZ reporter mouse.
  16. (2006). Microarray profiling of gene expression in human adipocytes in response to anthocyanins.
  17. (2011). Neuropeptide exocytosis involving synaptotagmin-4 and oxytocin in hypothalamic programming of body weight and energy balance.
  18. (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.
  19. (2009). Obesity, gestational diabetes and pregnancy outcome.
  20. (2005). Oleylethanolamide impairs glucose tolerance and inhibits insulin-stimulated glucose uptake in rat adipocytes through p38 and JNK MAPK pathways.
  21. (2003). Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 425: 90–93. 2 3 .G u z m a nM ,L oV e r m eJ ,F uJ ,O v e i s iF ,B l a z q u e zC ,e ta l
  22. (2008). Oxytocin controls differentiation of human mesenchymal stem cells and reverses osteoporosis.
  23. (1985). Oxytocin in the cerebrospinal fluid and plasma of pregnant and nonpregnant subjects.
  24. (2000). Oxytocin receptor gene expression in rat uterus: regulation by ovarian steroids.
  25. (2008). Oxytocin receptor-deficient mice developed late-onset obesity.
  26. (1982). Oxytocin receptors and human parturition: a dual role for oxytocin in the initiation of labor.
  27. (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.
  28. (2005). Regulation of food intake by oleoylethanolamide.
  29. (1994). Regulation of lipoprotein lipase activity and mRNA in the mammary gland of the lactating mouse.
  30. (2008). Role of stearoyl-CoA desaturases in obesity and the metabolic syndrome.
  31. (2003). Role of stearoyl-coenzyme A desaturase in lipid metabolism.
  32. (2010). Stearoyl-coenzyme A desaturase 1 inhibition and the metabolic syndrome: considerations for future drug discovery.
  33. (1997). Syntaxin 4, VAMP2, and/or VAMP3/ cellubrevin are functional target membrane and vesicle SNAP receptors for insulin-stimulated GLUT4 translocation in adipocytes.
  34. (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.
  35. (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.
  36. (2002). The endogenous cannabinoid system controls extinction of aversive memories.
  37. (2008). The expectant brain: adapting for motherhood.
  38. (2010). The fatinduced satiety factor oleoylethanolamide suppresses feeding through central release of oxytocin.
  39. (2007). The neck of caveolae is a distinct plasma membrane subdomain that concentrates insulin receptors in 3T3-L1 adipocytes.
  40. (2001). The oxytocin receptor system: structure, function, and regulation.