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Gastrointestinal hormones and polycystic ovary syndrome

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Abstract

Polycystic ovary syndrome (PCOS) is an endocrine disease of women in reproductive age. It is characterized by anovulation and hyperandrogenism. Most often patients with PCOS have metabolic abnormalities such as dyslipidemia, insulin resistance, and glucose intolerance. It is not surprising that obesity is high prevalent in PCOS. Over 60 % of PCOS women are obese or overweight. Modulation of appetite and energy intake is essential to maintain energy balance and body weight. The gastrointestinal tract, where nutrients are digested and absorbed, plays a central role in energy homeostasis. The signals from the gastrointestinal tract arise from the stomach (ghrelin release), proximal small intestine (CCK release), and distal small intestine (GLP-1 and PYY) in response to food. These hormones are recognized as “appetite regulatory hormones.” Weight loss is the key in the treatments of obese/overweight patients with PCOS. However, current non-pharmacologic management of body weight is hard to achieve. This review highlighted the gastrointestinal hormones, and discussed the potential strategies aimed at modifying hormones for treatment in PCOS.

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References

  1. E.S. Knochenhauer, T.J. Key, M. Kahsar-Miller, W. Waggoner, L.R. Boots, R. Azziz, Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J. Clin. Endocrinol. Metab. 83, 3078–3082 (1998)

    CAS  PubMed  Google Scholar 

  2. E. Diamanti-Kandarakis, C.R. Kouli, A.T. Bergiele, F.A. Filandra, T.C. Tsianateli, G.G. Spina, E.D. Zapanti, M.I. Bartzis, A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J. Clin. Endocrinol. Metab. 84, 4006–4011 (1999)

    CAS  PubMed  Google Scholar 

  3. W.A. March, V.M. Moore, K.J. Willson, D.I. Phillips, R.J. Norman, M.J. Davies, The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum. Reprod. 25, 544–551 (2010)

    PubMed  Google Scholar 

  4. H. Jia, L. Yu, X. Guo, W. Gao, Z. Jiang, Associations of adiponectin gene polymorphisms with polycystic ovary syndrome: a meta-analysis. Endocrine 42, 299–306 (2012)

    CAS  PubMed  Google Scholar 

  5. M. Brower, K. Brennan, M. Pall, R. Azziz, The severity of menstrual dysfunction as a predictor of insulin resistance in PCOS. J. Clin. Endocrinol. Metab. 98, E1967–E1971 (2013)

    CAS  PubMed  Google Scholar 

  6. S.F. Witchel, S.E. Recabarren, F. Gonzalez, E. Diamanti-Kandarakis, K.I. Cheang, A.J. Duleba, R.S. Legro, R. Homburg, R. Pasquali, R.A. Lobo, C.C. Zouboulis, F. Kelestimur, F. Fruzzetti, W. Futterweit, R.J. Norman, D.H. Abbott, Emerging concepts about prenatal genesis, aberrant metabolism and treatment paradigms in polycystic ovary syndrome. Endocrine 42, 526–534 (2012)

    CAS  PubMed Central  PubMed  Google Scholar 

  7. S.S. Lim, R.J. Norman, M.J. Davies, L.J. Moran, The effect of obesity on polycystic ovary syndrome: a systematic review and meta-analysis. Obes. Rev. 14, 95–109 (2013)

    CAS  PubMed  Google Scholar 

  8. N. Kanaya, S. Vonderfecht, S. Chen, Androgen (dihydrotestosterone)-mediated regulation of food intake and obesity in female mice. J.Steroid Biochem. Mol. Biol. 138, 100–106 (2013)

    CAS  PubMed Central  PubMed  Google Scholar 

  9. A.L. Hirschberg, S. Naessen, M. Stridsberg, B. Bystrom, J. Holtet, Impaired cholecystokinin secretion and disturbed appetite regulation in women with polycystic ovary syndrome. Gynecol. Endocrinol. 19, 79–87 (2004)

    CAS  PubMed  Google Scholar 

  10. D. Mahoney, Lifestyle modification intervention among infertile overweight and obese women with polycystic ovary syndrome. J. Am. Assoc. Nurse Pract. (2013). doi:10.1002/2327-6924.12073

    PubMed  Google Scholar 

  11. B.A. Gower, P.C. Chandler-Laney, F. Ovalle, L.L. Goree, R. Azziz, R.A. Desmond, W.M. Granger, A.M. Goss, G.W. Bates, Favourable metabolic effects of a eucaloric lower-carbohydrate diet in women with PCOS. Clin. Endocrinol. 79, 550–557 (2013)

    CAS  Google Scholar 

  12. P.J. Havel, Peripheral signals conveying metabolic information to the brain: short-term and long-term regulation of food intake and energy homeostasis. Exp. Biol. Med. (Maywood) 226, 963–977 (2001)

    CAS  Google Scholar 

  13. R. Deniz, B. Gurates, S. Aydin, H. Celik, I. Sahin, Y. Baykus, Z. Catak, A. Aksoy, C. Citil, S. Gungor, Nesfatin-1 and other hormone alterations in polycystic ovary syndrome. Endocrine 42, 694–699 (2012)

    CAS  PubMed  Google Scholar 

  14. S. Aydin, Multi-functional peptide hormone NUCB2/nesfatin-1. Endocrine 44, 312–325 (2013)

    CAS  PubMed  Google Scholar 

  15. M. Tschop, D.L. Smiley, M.L. Heiman, Ghrelin induces adiposity in rodents. Nature 407, 908–913 (2000)

    CAS  PubMed  Google Scholar 

  16. G. Gomez, E.W. Englander, G.H. Greeley Jr, Nutrient inhibition of ghrelin secretion in the fasted rat. Regul. Pept. 117, 33–36 (2004)

    CAS  PubMed  Google Scholar 

  17. J. Overduin, R.S. Frayo, H.J. Grill, J.M. Kaplan, D.E. Cummings, Role of the duodenum and macronutrient type in ghrelin regulation. Endocrinology 146, 845–850 (2005)

    CAS  PubMed  Google Scholar 

  18. B.A. Parker, S. Doran, J. Wishart, M. Horowitz, I.M. Chapman, Effects of small intestinal and gastric glucose administration on the suppression of plasma ghrelin concentrations in healthy older men and women. Clin. Endocrinol. 62, 539–546 (2005)

    CAS  Google Scholar 

  19. W.A. Blom, A. Stafleu, C. de Graaf, F.J. Kok, G. Schaafsma, H.F. Hendriks, Ghrelin response to carbohydrate-enriched breakfast is related to insulin. Am. J. Clin. Nutr. 81, 367–375 (2005)

    CAS  PubMed  Google Scholar 

  20. Y. Greenman, N. Golani, S. Gilad, M. Yaron, R. Limor, N. Stern, Ghrelin secretion is modulated in a nutrient- and gender-specific manner. Clin. Endocrinol. 60, 382–388 (2004)

    Google Scholar 

  21. A.M. Wren, L.J. Seal, M.A. Cohen, A.E. Brynes, G.S. Frost, K.G. Murphy, W.S. Dhillo, M.A. Ghatei, S.R. Bloom, Ghrelin enhances appetite and increases food intake in humans. J. Clin. Endocrinol. Metab. 86, 5992 (2001)

    CAS  PubMed  Google Scholar 

  22. D.E. Cummings, K. Clement, J.Q. Purnell, C. Vaisse, K.E. Foster, R.S. Frayo, M.W. Schwartz, A. Basdevant, D.S. Weigle, Elevated plasma ghrelin levels in Prader Willi syndrome. Nat. Med. 8, 643–644 (2002)

    CAS  PubMed  Google Scholar 

  23. D.E. Cummings, D.S. Weigle, R.S. Frayo, P.A. Breen, M.K. Ma, E.P. Dellinger, J.Q. Purnell, Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N. Engl. J. Med. 346, 1623–1630 (2002)

    PubMed  Google Scholar 

  24. P.J. Currie, A. Mirza, R. Fuld, D. Park, J.R. Vasselli, Ghrelin is an orexigenic and metabolic signaling peptide in the arcuate and paraventricular nuclei. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289, R353–R358 (2005)

    CAS  PubMed  Google Scholar 

  25. M. Nakazato, N. Murakami, Y. Date, M. Kojima, H. Matsuo, K. Kangawa, S. Matsukura, A role for ghrelin in the central regulation of feeding. Nature 409, 194–198 (2001)

    CAS  PubMed  Google Scholar 

  26. M.A. Cowley, J.L. Smart, M. Rubinstein, M.G. Cerdan, S. Diano, T.L. Horvath, R.D. Cone, M.J. Low, Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484 (2001)

    CAS  PubMed  Google Scholar 

  27. D.E. Cummings, K.E. Foster, Ghrelin-leptin tango in body-weight regulation. Gastroenterology 124, 1532–1535 (2003)

    PubMed  Google Scholar 

  28. A. Moulin, L. Brunel, D. Boeglin, L. Demange, J. Ryan, C. M’Kadmi, S. Denoyelle, J. Martinez, J.A. Fehrentz, The 1,2,4-triazole as a scaffold for the design of ghrelin receptor ligands: development of JMV 2959, a potent antagonist. Amino Acids 44, 301–314 (2013)

    CAS  PubMed  Google Scholar 

  29. G. Arusoglu, G. Koksal, N. Cinar, S. Tapan, D.Y. Aksoy, B.O. Yildiz, Basal and meal-stimulated ghrelin, PYY, CCK levels and satiety in lean women with polycystic ovary syndrome: effect of low-dose oral contraceptive. J. Clin. Endocrinol. Metab. 98, 4475–4482 (2013)

    CAS  PubMed  Google Scholar 

  30. Japur, CC, Diez-Garcia, RW, de Oliveira Penaforte, FR, de Sa, MF, Imbalance between postprandial ghrelin and insulin responses to an ad libitum meal in obese women with polycystic ovary syndrome. Reprod. Sci. (2014) [Epub ahead of print]

  31. I.T. Ozgen, M. Aydin, A. Guven, Y. Aliyazicioglu, Characteristics of polycystic ovarian syndrome and relationship with ghrelin in adolescents. J. Pediatr. Adolesc. Gynecol. 23, 285–289 (2010)

    CAS  PubMed  Google Scholar 

  32. T.M. Barber, F.F. Casanueva, F. Karpe, M. Lage, S. Franks, M.I. McCarthy, J.A. Wass, Ghrelin levels are suppressed and show a blunted response to oral glucose in women with polycystic ovary syndrome. Eur. J. Endocrinol 158, 511–516 (2008)

    CAS  PubMed  Google Scholar 

  33. M. Mitkov, B. Pehlivanov, Orbetzova, M:Serum ghrelin level in women with polycystic ovary syndrome and its relationship with endocrine and metabolic parameters. Gynecol. Endocrinol. 24, 625–630 (2008)

    CAS  PubMed  Google Scholar 

  34. A. Bideci, M.O. Camurdan, E. Yesilkaya, F. Demirel, P. Cinaz, Serum ghrelin, leptin and resistin levels in adolescent girls with polycystic ovary syndrome. J. Obstet. Gynaecol. Res. 34, 578–584 (2008)

    CAS  PubMed  Google Scholar 

  35. M.J. Theodorakis, O. Carlson, S. Michopoulos, M.E. Doyle, M. Juhaszova, K. Petraki, J.M. Egan, Human duodenal enteroendocrine cells: source of both incretin peptides, GLP-1 and GIP. Am. J. Physiol. Endocrinol. Metab. 290, E550–E559 (2006)

    CAS  PubMed  Google Scholar 

  36. C.F. Deacon, What do we know about the secretion and degradation of incretin hormones? Regul. Pept. 128, 117–124 (2005)

    CAS  PubMed  Google Scholar 

  37. R. Mentlein, B. Gallwitz, W.E. Schmidt, Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7–36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur. J. Biochem. 214, 829–835 (1993)

    CAS  PubMed  Google Scholar 

  38. R. Mentlein, Dipeptidyl-peptidase IV (CD26)–role in the inactivation of regulatory peptides. Regul. Pept. 85, 9–24 (1999)

    CAS  PubMed  Google Scholar 

  39. L. Hansen, C.F. Deacon, C. Orskov, J.J. Holst, Glucagon-like peptide-1-(7–36)amide is transformed to glucagon-like peptide-1-(9–36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 140, 5356–5363 (1999)

    CAS  PubMed  Google Scholar 

  40. L.A. Scrocchi, T.J. Brown, N. MaClusky, P.L. Brubaker, A.B. Auerbach, A.L. Joyner, D.J. Drucker, Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat. Med. 2, 1254–1258 (1996)

    CAS  PubMed  Google Scholar 

  41. R. Perfetti, J. Zhou, M.E. Doyle, J.M. Egan, Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats. Endocrinology 141, 4600–4605 (2000)

    CAS  PubMed  Google Scholar 

  42. J. Schirra, M. Nicolaus, R. Roggel, M. Katschinski, M. Storr, H.J. Woerle, B. Goke, Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans. Gut 55, 243–251 (2006)

    CAS  PubMed Central  PubMed  Google Scholar 

  43. J.J. Meier, B. Gallwitz, S. Salmen, O. Goetze, J.J. Holst, W.E. Schmidt, M.A. Nauck, Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 88, 2719–2725 (2003)

    CAS  PubMed  Google Scholar 

  44. M.A. Nauck, U. Niedereichholz, R. Ettler, J.J. Holst, C. Orskov, R. Ritzel, W.H. Schmiegel, Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am. J. Physiol. 273, E981–E988 (1997)

    CAS  PubMed  Google Scholar 

  45. J.J. Hwa, L. Ghibaudi, P. Williams, M.B. Witten, R. Tedesco, C.D. Strader, Differential effects of intracerebroventricular glucagon-like peptide-1 on feeding and energy expenditure regulation. Peptides 19, 869–875 (1998)

    CAS  PubMed  Google Scholar 

  46. F. Rodriquez de Fonseca, M. Navarro, E. Alvarez, I. Roncero, J.A. Chowen, O. Maestre, R. Gomez, R.M. Munoz, J. Eng, E. Blazquez, Peripheral versus central effects of glucagon-like peptide-1 receptor agonists on satiety and body weight loss in Zucker obese rats. Metabolism 49, 709–717 (2000)

    CAS  PubMed  Google Scholar 

  47. J.J. Meier, M.A. Nauck, Glucagon-like peptide 1(GLP-1) in biology and pathology. Diabetes Metab. Res. Rev. 21, 91–117 (2005)

    CAS  PubMed  Google Scholar 

  48. E. Naslund, M. Gutniak, S. Skogar, S. Rossner, P.M. Hellstrom, Glucagon-like peptide 1 increases the period of postprandial satiety and slows gastric emptying in obese men. Am. J. Clin. Nutr. 68, 525–530 (1998)

    CAS  PubMed  Google Scholar 

  49. M.A. Nauck, J.J. Meier, Glucagon-like peptide 1 and its derivatives in the treatment of diabetes. Regul. Pept. 128, 135–148 (2005)

    CAS  PubMed  Google Scholar 

  50. M. Nauck, F. Stockmann, R. Ebert, W. Creutzfeldt, Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 29, 46–52 (1986)

    CAS  PubMed  Google Scholar 

  51. J. Ma, A.N. Pilichiewicz, C. Feinle-Bisset, J.M. Wishart, K.L. Jones, M. Horowitz, C.K. Rayner, Effects of variations in duodenal glucose load on glycaemic, insulin, and incretin responses in type 2 diabetes. Diabet. Med. 29, 604–608 (2012)

    CAS  PubMed  Google Scholar 

  52. L.R. Ranganath, J.M. Beety, L.M. Morgan, J.W. Wright, R. Howland, V. Marks, Attenuated GLP-1 secretion in obesity: cause or consequence? Gut 38, 916–919 (1996)

    CAS  PubMed Central  PubMed  Google Scholar 

  53. S. Madsbad, The role of glucagon-like peptide-1 impairment in obesity and potential therapeutic implications. Diabet. Obes. Metab. 16, 9–21 (2014)

    CAS  Google Scholar 

  54. F.K. Knop, K. Aaboe, T. Vilsboll, A. Volund, J.J. Holst, T. Krarup, S. Madsbad, Impaired incretin effect and fasting hyperglucagonaemia characterizing type 2 diabetic subjects are early signs of dysmetabolism in obesity. Diabet. Obes. Metab. 14, 500–510 (2012)

    CAS  Google Scholar 

  55. T. Vilsboll, T. Krarup, J. Sonne, S. Madsbad, A. Volund, A.G. Juul, J.J. Holst, Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 88, 2706–2713 (2003)

    CAS  PubMed  Google Scholar 

  56. C. Verdich, S. Toubro, B. Buemann, L. Madsen, J. Juul, J. Holst, A. Astrup, The role of postprandial releases of insulin and incretin hormones in meal-induced satiety–effect of obesity and weight reduction. Int. J. Obes. Relat. Metab. Disord. 25, 1206–1214 (2001)

    CAS  PubMed  Google Scholar 

  57. Y. Anini, P.L. Brubaker, Role of leptin in the regulation of glucagon-like peptide-1 secretion. Diabetes 52, 252–259 (2003)

    CAS  PubMed  Google Scholar 

  58. J.G. Barrera, D.A. Sandoval, D.A. D’Alessio, R.J. Seeley, GLP-1 and energy balance: an integrated model of short-term and long-term control. Nat. Rev. Endocrinol. 7, 507–516 (2011)

    CAS  PubMed Central  PubMed  Google Scholar 

  59. R. Gama, F. Norris, J. Wright, L. Morgan, S. Hampton, S. Watkins, V. Marks, The entero-insular axis in polycystic ovarian syndrome. Ann. Clin. Biochem. 33(Pt 3), 190–195 (1996)

    PubMed  Google Scholar 

  60. C. Pontikis, M.P. Yavropoulou, K.A. Toulis, K. Kotsa, K. Kazakos, A. Papazisi, A. Gotzamani-Psarakou, J.G. Yovos, The incretin effect and secretion in obese and lean women with polycystic ovary syndrome: a pilot study. J. Women’s Health 20, 971–976 (2011)

    Google Scholar 

  61. J. Vrbikova, M. Hill, B. Bendlova, T. Grimmichova, K. Dvorakova, K. Vondra, G. Pacini, Incretin levels in polycystic ovary syndrome. Eur. J. Endocrinol. 159, 121–127 (2008)

    CAS  PubMed  Google Scholar 

  62. J.F. Rehfeld, G. Sun, T. Christensen, J.G. Hillingso, The predominant cholecystokinin in human plasma and intestine is cholecystokinin-33. J. Clin. Endocrinol. Metab. 86, 251–258 (2001)

    CAS  PubMed  Google Scholar 

  63. R.A. Liddle, I.D. Goldfine, M.S. Rosen, R.A. Taplitz, J.A. Williams, Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding, and relationship to gallbladder contraction. J. Clin. Invest. 75, 1144–1152 (1985)

    CAS  PubMed Central  PubMed  Google Scholar 

  64. T.H. Moran, K.P. Kinzig, Gastrointestinal satiety signals II. Cholecystokinin. Am. J. Physiol. Gastrointest. Liver Physiol. 286, G183–G188 (2004)

    CAS  PubMed  Google Scholar 

  65. R.A. Liddle, Regulation of cholecystokinin secretion in humans. J. Gastroenterol. 35, 181–187 (2000)

    CAS  PubMed  Google Scholar 

  66. C. Feinle, M. D’Amato, N.W. Read, Cholecystokinin-A receptors modulate gastric sensory and motor responses to gastric distension and duodenal lipid. Gastroenterology 110, 1379–1385 (1996)

    CAS  PubMed  Google Scholar 

  67. W. Schwizer, J. Borovicka, P. Kunz, R. Fraser, C. Kreiss, M. D’Amato, G. Crelier, P. Boesiger, M. Fried, Role of cholecystokinin in the regulation of liquid gastric emptying and gastric motility in humans: studies with the CCK antagonist loxiglumide. Gut 41, 500–504 (1997)

    CAS  PubMed Central  PubMed  Google Scholar 

  68. C.K. Rayner, H.S. Park, S.M. Doran, I.M. Chapman, M. Horowitz, Effects of cholecystokinin on appetite and pyloric motility during physiological hyperglycemia. Am. J. Physiol. Gastrointest. Liver Physiol. 278, G98–G104 (2000)

    CAS  PubMed  Google Scholar 

  69. J. Glatzle, Y. Wang, D.W. Adelson, T.J. Kalogeris, T.T. Zittel, P. Tso, J.Y. Wei, H.E. Raybould, Chylomicron components activate duodenal vagal afferents via a cholecystokinin A receptor-mediated pathway to inhibit gastric motor function in the rat. J. Physiol. 550, 657–664 (2003)

    CAS  PubMed Central  PubMed  Google Scholar 

  70. J.G. Gutierrez, W.Y. Chey, V.P. Dinoso, Actions of cholecystokinin and secretin on the motor activity of the small intestine in man. Gastroenterology 67, 35–41 (1974)

    CAS  PubMed  Google Scholar 

  71. J. Gibbs, R.C. Young, G.P. Smith, Cholecystokinin elicits satiety in rats with open gastric fistulas. Nature 245, 323–325 (1973)

    CAS  PubMed  Google Scholar 

  72. T.H. Moran, P.J. Ameglio, G.J. Schwartz, P.R. McHugh, Blockade of type A, not type B, CCK receptors attenuates satiety actions of exogenous and endogenous CCK. Am. J. Physiol. 262, R46–R50 (1992)

    CAS  PubMed  Google Scholar 

  73. T.H. Moran, S. Bi, Hyperphagia and obesity in OLETF rats lacking CCK-1 receptors. Philos. Trans. R. Soc. Lond. B Biol. Sci. 361, 1211–1218 (2006)

    CAS  PubMed Central  PubMed  Google Scholar 

  74. K. Meereis-Schwanke, H. Klonowski-Stumpe, L. Herberg, C. Niederau, Long-term effects of CCK-agonist and -antagonist on food intake and body weight in Zucker lean and obese rats. Peptides 19, 291–299 (1998)

    CAS  PubMed  Google Scholar 

  75. L. Wang, M.D. Barachina, V. Martinez, J.Y. Wei, Y. Tache, Synergistic interaction between CCK and leptin to regulate food intake. Regul. Pept. 92, 79–85 (2000)

    CAS  PubMed  Google Scholar 

  76. I.M. Brennan, T.J. Little, K.L. Feltrin, A.J. Smout, J.M. Wishart, M. Horowitz, C. Feinle-Bisset, Dose-dependent effects of cholecystokinin-8 on antropyloroduodenal motility, gastrointestinal hormones, appetite, and energy intake in healthy men. Am. J. Physiol. Endocrinol. Metab. 295, E1487–E1494 (2008)

    CAS  PubMed  Google Scholar 

  77. C. Beglinger, L. Degen, D. Matzinger, M. D’Amato, J. Drewe, Loxiglumide, a CCK-A receptor antagonist, stimulates calorie intake and hunger feelings in humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280, R1149–R1154 (2001)

    CAS  PubMed  Google Scholar 

  78. F.P. O’Harte, M.H. Mooney, C.M. Kelly, P.R. Flatt, Glycated cholecystokinin-8 has an enhanced satiating activity and is protected against enzymatic degradation. Diabetes 47, 1619–1624 (1998)

    PubMed  Google Scholar 

  79. I.A. Montgomery, N. Irwin, P.R. Flatt, Beneficial effects of (pGlu-Gln)-CCK-8 on energy intake and metabolism in high fat fed mice are associated with alterations of hypothalamic gene expression. Hormon. Metab. Res. 45(6), 471–473 (2013)

    CAS  Google Scholar 

  80. N. Irwin, I.A. Montgomery, R.C. Moffett, P.R. Flatt, Chemical cholecystokinin receptor activation protects against obesity-diabetes in high fat fed mice and has sustainable beneficial effects in genetic ob/ob mice. Biochem. Pharmacol. 85, 81–91 (2013)

    CAS  PubMed  Google Scholar 

  81. N. Irwin, P.R. Flatt, Enteroendocrine hormone mimetics for the treatment of obesity and diabetes. Curr. Opin. Pharmacol. 13, 989–995 (2013)

    CAS  PubMed  Google Scholar 

  82. N. Irwin, P. Frizelle, F.P. O’Harte, P.R. Flatt, (pGlu-Gln)-CCK-8[mPEG]: a novel, long-acting, mini-PEGylated cholecystokinin (CCK) agonist that improves metabolic status in dietary-induced diabetes. Biochim. et Biophys. Acta 1830, 4009–4016 (2013)

    CAS  Google Scholar 

  83. B. Bidzinska-Speichert, A. Lenarcik, U. Tworowska-Bardzinska, R. Slezak, G. Bednarek-Tupikowska, A. Milewicz, Pro12Ala PPAR gamma2 gene polymorphism in PCOS women: the role of compounds regulating satiety. Gynecol. Endocrinol. 28, 195–198 (2012)

    PubMed  Google Scholar 

  84. J. Wen, S.F. Phillips, M.G. Sarr, L.J. Kost, Holst, JJ:PYY and GLP-1 contribute to feedback inhibition from the canine ileum and colon. Am. J. Physiol. 269, G945–G952 (1995)

    CAS  PubMed  Google Scholar 

  85. R.P. Vincent, C.W. le Roux, The satiety hormone peptide YY as a regulator of appetite. J. Clin. Pathol. 61, 548–552 (2008)

    CAS  PubMed  Google Scholar 

  86. M.S. Huda, J.P. Wilding, J.H. Pinkney, Gut peptides and the regulation of appetite. Obes. Rev. 7, 163–182 (2006)

    CAS  PubMed  Google Scholar 

  87. L. Degen, S. Oesch, M. Casanova, S. Graf, S. Ketterer, J. Drewe, C. Beglinger, Effect of peptide YY3-36 on food intake in humans. Gastroenterology 129, 1430–1436 (2005)

    CAS  PubMed  Google Scholar 

  88. H.C. Lin, W.Y. Chey, X. Zhao, Release of distal gut peptide YY (PYY) by fat in proximal gut depends on CCK. Peptides 21, 1561–1563 (2000)

    CAS  PubMed  Google Scholar 

  89. G.A. Eberlein, V.E. Eysselein, M. Schaeffer, P. Layer, D. Grandt, H. Goebell, W. Niebel, M. Davis, T.D. Lee, J.E. Shively et al., A new molecular form of PYY: structural characterization of human PYY(3–36) and PYY(1–36). Peptides 10, 797–803 (1989)

    CAS  PubMed  Google Scholar 

  90. R.L. Conter, J.J. Roslyn, I.L. Taylor, Effects of peptide YY on gallbladder motility. Am. J. Physiol. 252, G736–G741 (1987)

    CAS  PubMed  Google Scholar 

  91. N. Vrang, A.N. Madsen, M. Tang-Christensen, G. Hansen, P.J. Larsen, PYY(3–36) reduces food intake and body weight and improves insulin sensitivity in rodent models of diet-induced obesity. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R367–R375 (2006)

    CAS  PubMed  Google Scholar 

  92. T.H. Moran, U. Smedh, K.P. Kinzig, K.A. Scott, S. Knipp, E.E. Ladenheim, Peptide YY(3–36) inhibits gastric emptying and produces acute reductions in food intake in rhesus monkeys. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R384–R388 (2005)

    CAS  PubMed  Google Scholar 

  93. N.M. Neary, C.J. Small, M.R. Druce, A.J. Park, S.M. Ellis, N.M. Semjonous, C.L. Dakin, K. Filipsson, F. Wang, A.S. Kent, G.S. Frost, M.A. Ghatei, S.R. Bloom, Peptide YY3-36 and glucagon-like peptide-17–36 inhibit food intake additively. Endocrinology 146, 5120–5127 (2005)

    CAS  PubMed  Google Scholar 

  94. R.L. Batterham, M.A. Cowley, C.J. Small, H. Herzog, M.A. Cohen, C.L. Dakin, A.M. Wren, A.E. Brynes, M.J. Low, M.A. Ghatei, R.D. Cone, S.R. Bloom, Gut hormone PYY(3-36) physiologically inhibits food intake. Nature 418, 650–654 (2002)

    CAS  PubMed  Google Scholar 

  95. R.L. Batterham, M.A. Cohen, S.M. Ellis, C.W. Le Roux, D.J. Withers, G.S. Frost, M.A. Ghatei, S.R. Bloom, Inhibition of food intake in obese subjects by peptide YY3-36. N. Engl. J. Med. 349, 941–948 (2003)

    CAS  PubMed  Google Scholar 

  96. C.R. Abbott, C.J. Small, A.R. Kennedy, N.M. Neary, A. Sajedi, M.A. Ghatei, S.R. Bloom, Blockade of the neuropeptide Y Y2 receptor with the specific antagonist BIIE0246 attenuates the effect of endogenous and exogenous peptide YY(3–36) on food intake. Brain Res. 1043, 139–144 (2005)

    CAS  PubMed  Google Scholar 

  97. C.W. le Roux, R.L. Batterham, S.J. Aylwin, M. Patterson, C.M. Borg, K.J. Wynne, A. Kent, R.P. Vincent, J. Gardiner, M.A. Ghatei, S.R. Bloom, Attenuated peptide YY release in obese subjects is associated with reduced satiety. Endocrinology 147, 3–8 (2006)

    PubMed  Google Scholar 

  98. C.L. Roth, P.J. Enriori, K. Harz, J. Woelfle, M.A. Cowley, T. Reinehr, Peptide YY is a regulator of energy homeostasis in obese children before and after weight loss. J. Clin. Endocrinol. Metab. 90, 6386–6391 (2005)

    CAS  PubMed  Google Scholar 

  99. E. Naslund, P. Gryback, P.M. Hellstrom, H. Jacobsson, J.J. Holst, E. Theodorsson, L. Backman, Gastrointestinal hormones and gastric emptying 20 years after jejunoileal bypass for massive obesity. Int. J. Obes. Relat. Metab. Disord. 21, 387–392 (1997)

    CAS  PubMed  Google Scholar 

  100. S.L. Pedersen, P.G. Sasikumar, S. Chelur, B. Holst, A. Artmann, K.J. Jensen, N. Vrang, Peptide hormone isoforms: N-terminally branched PYY3–36 isoforms give improved lipid and fat-cell metabolism in diet-induced obese mice. J. Pept. Sci. 16, 664–673 (2010)

    CAS  PubMed  Google Scholar 

  101. M.L. Addison, J.S. Minnion, J.C. Shillito, K. Suzuki, T.M. Tan, B.C. Field, N. Germain-Zito, C. Becker-Pauly, M.A. Ghatei, S.R. Bloom, K.G. Murphy, A role for metalloendopeptidases in the breakdown of the gut hormone, PYY 3–36. Endocrinology 152, 4630–4640 (2011)

    CAS  PubMed  Google Scholar 

  102. T. Tsilchorozidou, R.L. Batterham, G.S. Conway, Metformin increases fasting plasma peptide tyrosine tyrosine (PYY) in women with polycystic ovarian syndrome (PCOS). Clin. Endocrinol. 69, 936–942 (2008)

    CAS  Google Scholar 

  103. K. Zwirska-Korczala, K. Sodowski, S.J. Konturek, D. Kuka, M. Kukla, T. Brzozowski, W. Cnota, E. Wozniak-Grygiel, J. Jaworek, R. Buldak, B. Rybus-Kalinowska, M. Fryczowski, Postprandial response of ghrelin and PYY and indices of low-grade chronic inflammation in lean young women with polycystic ovary syndrome. J. Physiol. Pharmacol. 59(Suppl 2), 161–178 (2008)

    PubMed  Google Scholar 

  104. H. Lee, J.Y. Oh, Y.A. Sung, H. Chung, Is insulin resistance an intrinsic defect in asian polycystic ovary syndrome? Yonsei Med. J. 54, 609–614 (2013)

    CAS  PubMed Central  PubMed  Google Scholar 

  105. D. Panidis, K. Tziomalos, E. Papadakis, C. Vosnakis, P. Chatzis, I. Katsikis, Lifestyle intervention and anti-obesity therapies in the polycystic ovary syndrome: impact on metabolism and fertility. Endocrine 44, 583–590 (2013)

    CAS  PubMed  Google Scholar 

  106. R.L. Thomson, J.D. Buckley, M. Noakes, P.M. Clifton, R.J. Norman, G.D. Brinkworth, The effect of a hypocaloric diet with and without exercise training on body composition, cardiometabolic risk profile, and reproductive function in overweight and obese women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 93, 3373–3380 (2008)

    CAS  PubMed  Google Scholar 

  107. K.A. Marsh, K.S. Steinbeck, F.S. Atkinson, P. Petocz, J.C. Brand-Miller, Effect of a low glycemic index compared with a conventional healthy diet on polycystic ovary syndrome. Am. Erican J. Clin. Nutr. 92, 83–92 (2010)

    CAS  Google Scholar 

  108. F. Esfahanian, M.M. Zamani, R. Heshmat, F. Moini nia, Effect of metformin compared with hypocaloric diet on serum C-reactive protein level and insulin resistance in obese and overweight women with polycystic ovary syndrome. J. Obstet. Gynaecol. Res. 39, 806–813 (2013)

    PubMed  Google Scholar 

  109. S.E. Kasim-Karakas, W.M. Cunningham, A. Tsodikov, Relation of nutrients and hormones in polycystic ovary syndrome. Am. J. Clin. Nutr. 85, 688–694 (2007)

    CAS  PubMed  Google Scholar 

  110. A. Karamanlis, R. Chaikomin, S. Doran, M. Bellon, F.D. Bartholomeusz, J.M. Wishart, K.L. Jones, M. Horowitz, C.K. Rayner, Effects of protein on glycemic and incretin responses and gastric emptying after oral glucose in healthy subjects. Am. J. Clin. Nutr. 86, 1364–1368 (2007)

    CAS  PubMed  Google Scholar 

  111. N. Phelan, A. O’Connor, T. Kyaw Tun, N. Correia, G. Boran, H.M. Roche, J. Gibney, Hormonal and metabolic effects of polyunsaturated fatty acids in young women with polycystic ovary syndrome: results from a cross-sectional analysis and a randomized, placebo-controlled, crossover trial. Am. J. Clin. Nutr. 93, 652–662 (2011)

    CAS  PubMed  Google Scholar 

  112. Y.H. Zheng, X.H. Wang, M.H. Lai, H. Yao, H. Liu, H.X. Ma, Effectiveness of abdominal acupuncture for patients with obesity-type polycystic ovary syndrome: a randomized controlled trial. J. Altern. Complement. Med. 19, 740–745 (2013)

    PubMed  Google Scholar 

  113. H. Zhang, Y. Peng, Z. Liu, S. Li, Z. Lv, L. Tian, J. Zhu, X. Zhao, M. Chen, Effects of acupuncture therapy on abdominal fat and hepatic fat content in obese children: a magnetic resonance imaging and proton magnetic resonance spectroscopy study. J. Altern. Complement. Med. 17, 413–420 (2011)

    PubMed  Google Scholar 

  114. B. Xu, J.H. Yuan, Z.C. Liu, M. Chen, X.J. Wang, Effect of acupuncture on plasma peptide YY in the patient of simple obesity. Zhongguo zhen jiu (Chin. Acupunct. Moxib.) 25, 837–840 (2005)

    CAS  Google Scholar 

  115. F. Gucel, B. Bahar, C. Demirtas, S. Mit, C. Cevik, Influence of acupuncture on leptin, ghrelin, insulin and cholecystokinin in obese women: a randomised, sham-controlled preliminary trial. Acupunct. Med. 30, 203–207 (2012)

    PubMed  Google Scholar 

  116. H. Abdi, B. Zhao, M. Darbandi, M. Ghayour-Mobarhan, S. Tavallaie, A.A. Rahsepar, S.M. Parizadeh, M. Safariyan, M. Nemati, M. Mohammadi, P. Abbasi-Parizad, S. Darbandi, S. Akhlaghi, G.A. Ferns, The effects of body acupuncture on obesity: anthropometric parameters, lipid profile, and inflammatory and immunologic markers. Sci.World. J. 2012, 603539 (2012)

    Google Scholar 

  117. S.H. Cho, J.S. Lee, L. Thabane, J. Lee, Acupuncture for obesity: a systematic review and meta-analysis. Int. J. Obes. 33, 183–196 (2009)

    CAS  Google Scholar 

  118. K.M. Hoeger, L. Kochman, N. Wixom, K. Craig, R.K. Miller, D.S. Guzick, A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Fertil. Steril. 82, 421–429 (2004)

    CAS  PubMed  Google Scholar 

  119. J. Xiao, S. Chen, C. Zhang, S. Chang, The effectiveness of metformin ovulation induction treatment in patients with PCOS: a systematic review and meta-analysis. Gynecol. Endocrinol. 28, 956–960 (2012)

    CAS  PubMed  Google Scholar 

  120. M. Shaker, Z.I. Mashhadani, A.A. Mehdi, Effect of Treatment with Metformin on Omentin-1, Ghrelin and other Biochemical, Clinical Features in PCOS Patients. Oman Med. J. 25, 289–293 (2010)

    PubMed Central  PubMed  Google Scholar 

  121. P.F. Svendsen, L. Nilas, S. Madsbad, J.J. Holst, Incretin hormone secretion in women with polycystic ovary syndrome: roles of obesity, insulin sensitivity, and treatment with metformin. Metabolism 58, 586–593 (2009)

    CAS  PubMed  Google Scholar 

  122. W. Wei, H. Zhao, A. Wang, M. Sui, K. Liang, H. Deng, Y. Ma, Y. Zhang, H. Zhang, Y. Guan, A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur. J. Endocrinol. 166, 99–105 (2012)

    CAS  PubMed  Google Scholar 

  123. Y. An, Z. Sun, Y. Zhang, B. Liu, Y. Guan, M. Lu, The use of berberine for women with polycystic ovary syndrome undergoing IVF treatment. Clin. Endocrinol. 80, 425–431 (2014)

    CAS  Google Scholar 

  124. X. Zhang, Y. Zhao, M. Zhang, X. Pang, J. Xu, C. Kang, M. Li, C. Zhang, Z. Zhang, Y. Zhang, X. Li, G. Ning, L. Zhao, Structural changes of gut microbiota during berberine-mediated prevention of obesity and insulin resistance in high-fat diet-fed rats. PloS One 7, e42529 (2012)

    CAS  PubMed Central  PubMed  Google Scholar 

  125. W. Xie, D. Gu, J. Li, K. Cui, Y. Zhang, Effects and action mechanisms of berberine and Rhizoma coptidis on gut microbes and obesity in high-fat diet-fed C57BL/6 J mice. PloS One 6, e24520 (2011)

    CAS  PubMed Central  PubMed  Google Scholar 

  126. T. Vilsboll, M. Christensen, A.E. Junker, F.K. Knop, L.L. Gluud, Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. Br. Med. J. 344, d7771 (2012)

    Google Scholar 

  127. M. Monami, I. Dicembrini, N. Marchionni, C.M. Rotella, E. Mannucci, Effects of glucagon-like peptide-1 receptor agonists on body weight: a meta-analysis. Exp. Diabetes Res. 2012, 672658 (2012)

    PubMed Central  PubMed  Google Scholar 

  128. A.S. Kelly, K.D. Rudser, B.M. Nathan, C.K. Fox, A.M. Metzig, B.J. Coombes, A.K. Fitch, E.M. Bomberg, M.J. Abuzzahab, The effect of glucagon-like peptide-1 receptor agonist therapy on body mass index in adolescents with severe obesity: a randomized, placebo-controlled, clinical trial. J. Am. Med. Assoc. Pediatr. 167, 355–360 (2013)

    Google Scholar 

  129. Gallwitz, B, Extra-pancreatic effects of incretin-based therapies. Endocrine. (2014) [Epub ahead of print]

  130. C. Verdich, A. Flint, J.P. Gutzwiller, E. Naslund, C. Beglinger, P.M. Hellstrom, S.J. Long, L.M. Morgan, J.J. Holst, A. Astrup, A meta-analysis of the effect of glucagon-like peptide-1 (7–36) amide on ad libitum energy intake in humans. J. Clin. Endocrinol. Metab. 86, 4382–4389 (2001)

    CAS  PubMed  Google Scholar 

  131. A.S. Kelly, A.M. Metzig, K.D. Rudser, A.K. Fitch, C.K. Fox, B.M. Nathan, M.M. Deering, B.L. Schwartz, M.J. Abuzzahab, L.M. Gandrud, A. Moran, C.J. Billington, Schwarzenberg, SJ:Exenatide as a weight-loss therapy in extreme pediatric obesity: a randomized, controlled pilot study. Obesity 20, 364–370 (2012)

    CAS  PubMed Central  PubMed  Google Scholar 

  132. R.A. DeFronzo, R.E. Ratner, J. Han, D.D. Kim, M.S. Fineman, A.D. Baron, Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 28, 1092–1100 (2005)

    CAS  PubMed  Google Scholar 

  133. M. Davies, R. Pratley, M. Hammer, A.B. Thomsen, R. Cuddihy, Liraglutide improves treatment satisfaction in people with Type 2 diabetes compared with sitagliptin, each as an add on to metformin. Diabet. Med. 28, 333–337 (2011)

    CAS  PubMed  Google Scholar 

  134. J. Rosenstock, L.J. Klaff, S. Schwartz, J. Northrup, J.H. Holcombe, K. Wilhelm, M. Trautmann, Effects of exenatide and lifestyle modification on body weight and glucose tolerance in obese subjects with and without pre-diabetes. Diabetes Care 33, 1173–1175 (2010)

    CAS  PubMed Central  PubMed  Google Scholar 

  135. K. Elkind-Hirsch, O. Marrioneaux, M. Bhushan, D. Vernor, R. Bhushan, Comparison of single and combined treatment with exenatide and metformin on menstrual cyclicity in overweight women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 93, 2670–2678 (2008)

    CAS  PubMed  Google Scholar 

  136. S.M. Jensterle, T. Kocjan, M. Pfeifer, N.A. Kravos, A. Janez, Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin. Eur. J. Endocrinol. 170, 451–459 (2014)

    Google Scholar 

  137. H.F. Escobar-Morreale, Surgical management of metabolic dysfunction in PCOS. Steroids 77, 312–316 (2012)

    CAS  PubMed  Google Scholar 

  138. H.F. Escobar-Morreale, J.I. Botella-Carretero, F. Alvarez-Blasco, J. Sancho, J.L. San Millan, The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery. J. Clin. Endocrinol. Metab. 90, 6364–6369 (2005)

    CAS  PubMed  Google Scholar 

  139. G.M. Eid, D.R. Cottam, L.M. Velcu, S.G. Mattar, M.T. Korytkowski, G. Gosman, P. Hindi, P.R. Schauer, Effective treatment of polycystic ovarian syndrome with Roux-en-Y gastric bypass. Surg. Obes. Relat. Dis. 1, 77–80 (2005)

    PubMed  Google Scholar 

  140. R. Morinigo, V. Moize, M. Musri, A.M. Lacy, S. Navarro, J.L. Marin, S. Delgado, R. Casamitjana, J. Vidal, Glucagon-like peptide-1, peptide YY, hunger, and satiety after gastric bypass surgery in morbidly obese subjects. J. Clin. Endocrinol. Metab. 91, 1735–1740 (2006)

    CAS  PubMed  Google Scholar 

  141. S. Evans, Z. Pamuklar, J. Rosko, P. Mahaney, N. Jiang, C. Park, A. Torquati, Gastric bypass surgery restores meal stimulation of the anorexigenic gut hormones glucagon-like peptide-1 and peptide YY independently of caloric restriction. Surg. Endosc. 26, 1086–1094 (2012)

    PubMed Central  PubMed  Google Scholar 

  142. M.B. Mumphrey, L.M. Patterson, H. Zheng, H.R. Berthoud, Roux-en-Y gastric bypass surgery increases number but not density of CCK-, GLP-1-, 5-HT-, and neurotensin-expressing enteroendocrine cells in rats. Neurogastroenterol. Motil. 25, e70–e79 (2013)

    CAS  PubMed Central  PubMed  Google Scholar 

  143. J. Korner, M. Bessler, L.J. Cirilo, I.M. Conwell, A. Daud, N.L. Restuccia, S.L. Wardlaw, Effects of Roux-en-Y gastric bypass surgery on fasting and postprandial concentrations of plasma ghrelin, peptide YY, and insulin. J. Clin. Endocrinol. Metab. 90, 359–365 (2005)

    CAS  PubMed  Google Scholar 

  144. C.W. le Roux, R. Welbourn, M. Werling, A. Osborne, A. Kokkinos, A. Laurenius, H. Lonroth, L. Fandriks, M.A. Ghatei, S.R. Bloom, T. Olbers, Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass. Ann. Surg. 246, 780–785 (2007)

    PubMed  Google Scholar 

  145. C.N. Ochner, E. Stice, E. Hutchins, L. Afifi, A. Geliebter, J. Hirsch, J. Teixeira, Relation between changes in neural responsivity and reductions in desire to eat high-calorie foods following gastric bypass surgery. Neuroscience 209, 128–135 (2012)

    CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grant from the Shanghai Jiaotong University, School of Medicine, Science and Technology Fund (Grant No. 12XJ10015).

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  1. Division of Endocrinology and Metabolism, Department of Internal Medicine, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China

    Jing Ma, Tzu Chun Lin & Wei Liu

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Ma, J., Lin, T.C. & Liu, W. Gastrointestinal hormones and polycystic ovary syndrome. Endocrine 47, 668–678 (2014). https://doi.org/10.1007/s12020-014-0275-1

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