Changes in Acyl Ghrelin, Des-acyl Ghrelin, and Ratio of Acyl Ghrelin to Total Ghrelin with Short-term Refeeding in Female Inpatients with Restricting-type Anorexia Nervosa

Abstract

Restricting type of anorexia nervosa (AN-R) is a serious disorder affecting adolescents and young adults and decreases quality of life over a long period. Successful weight restoration is an important prognostic factor for disease outcome; however, the underlying mechanism of refeeding resistance, a core psychopathology relevant to ‘ambivalent’ eating behaviors, remains unclear in this disorder. Ghrelin plays an important role in the regulation of growth hormone release, appetite, and energy metabolism. However, the early progress of these patients and changes in the levels of acyl ghrelin and des-acyl ghrelin during treatment were not reported. The purpose of this study was to determine the changes in ghrelin levels (acyl and des-acyl) during early treatment. As a result, des-acyl ghrelin in AN-R patients is higher than in control subjects before the therapy, but it decreases with treatment. The plasma des-acyl ghrelin level in AN-R patients started decreasing more rapidly and in early stage of the hospitalization than ever reported, and after 8 weeks, it is significantly lower than in control subjects. It means that des-acyl ghrelin is sensitive and changeable with their nutrition state. Furthermore, the ratio of the acyl ghrelin to total ghrelin increases with 8 weeks treatment. Eight weeks after, energy intake of the AN-R patients is recovered near the normal range with a daily energy intake of 1 700±93.54 kcal. These findings may be valuable for future AN-R treatments in order to increase acyl ghrelin and decrease des-acyl ghrelin, thereby influencing the refeeding outcome.

Key words

eating disorders - energy intake - hospitalization - gut hormone

References

• 1 Steinhausen HC. The outcome of anorexia nervosa in the 20^th century.  Am J Psychiatry. 2002;  159 1284-1293
• 2 Harada T, Nakahara T, Yasuhara D, Kojima S, Sagiyama K, Amitani H, Laviano A, Naruo T, Inui A. Obestatin, Acyl Ghrelin, and Des-acyl Ghrelin Responses to an Oral Glucose Tolerance Test in the Restricting Type of Anorexia Nervosa.  Biol Psychiatry. 2008;  63 245-247
• 3 Yasuhara D, Naruo T, Nagai N, Muranaga T, Nakahara T, Tanaka M, Kojima S, Sagiyama K, Masuda A, Inui A. Glucose Tolerance Predicts Short-term Refeeding Outcome in Females With Anorexia Nervosa.  Psychosom Med. 2005;  67 669-676
• 4 Yasuhara D, Naruo T, Nagai N, Tanaka M, Muranaga T, Nozoe S. Insulinogenic index at 15 min as a marker of nutritional rehabilitation in anorexia nervosa.  Am J Clin Nutr. 2003;  77 292-299
• 5 Inui A. Eating behavior in anorexia nervosa – an excess of both orexigenic and anorexigenic signaling?.  Mol Psychiatry. 2001;  6 620-624
• 6 Yasuhara D, Hashiguchi T, Kawahara K, Nakahara T, Harada T, Taguchi H, Yamada S, Maruyama I, Inui A. High mobility group box 1 and refeeding-resistance in anorexia nervosa.  Mol Psychiatry. 2007;  12 976-977
• 7 Bechtold DA, Ivanov TR, Luckman SM. Appetite-modifying actions of pro-neuromedin U-derived peptides.  Am J Physiol Endocrinol Metab. 2009;  297 545-551
• 8 Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach.  Nature. 1999;  402 656-660
• 9 Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, Mori K, Komatsu Y, Usui T, Shimatsu A, Ogawa Y, Hosoda K, Akamizu T, Kojima M, Kangawa K, Nakao K. Ghrelin strongly stimulates growth hormone release in humans.  J Clin Endocrinol Metab. 2000;  85 4908-4911
• 10 Tschöp M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents.  Nature. 2000;  407 908-913
• 11 Inui A. Ghrelin: An orexigenic and somatotrophic signal from the stomach.  Nat Rev Neurosci. 2001;  2 551-560
• 12 Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, Nozoe S, Kangawa K, Matsukura S. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion.  J Clin Endocrinol Metab. 2002;  87 240-244
• 13 Tanaka M, Tatebe Y, Nakahara T, Yasuhara D, Sagiyama K, Muranaga T, Ueno H, Nkazato M, Nozoe S, Naruo T. Eating pattern and the effect of oral glucose on ghrelin and insulin secretion in patients with anorexia nervosa.  Clin Endocrinol (Oxf). 2003;  59 574-579
• 14 Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N, Makino S, Fujimiya M, Niijima A, Fujino MA, Kasuga M. Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin.  Gastroenterology. 2001;  120 337-345
• 15 Molfino A, Laviano A, Chiappini MG, Rossi Fanelli F, Muscaritoli M. Is des-acyl ghrelin contributing to uremic anorexia?.  Am J Clin Nutr. 2007;  86 1550-1551
• 16 Hotta M, Ohwada R, Katakami H, Shibasaki T, Hizuka N, Takano K. Plasma level of intact and degraded ghrelin and their responses to glucose infusion in anorexia nervosa.  J Clin Endocrinol Metab. 2004;  89 5707-5712
• 17 Tamura H, Kamegai J, Shimizu T, Ishii S, Sugihara H, Oikawa S. Ghrelin stimulates GH but not food intake in arcuate nucleus ablated rats.  Endocrinology. 2002;  143 3268-3275
• 18 Asakawa A, Inui A, Fujimiya M, Sakamaki R, Shinfuku N, Ueta Y, Meguid MM, Kasuga M. Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin.  Gut. 2005;  54 18-24
• 19 Chen CY, Inui A, Asakawa A, Fujino K, Kato I, Chen CC, Ueno N, Fujimiya M. Des-acyl Ghrelin Acts by CRF Type 2 Receptors to Disrupt Fasted Stomach Motility in Conscious Rats.  Gastroenterology. 2005;  129 8-25
• 20 Inhoff T, Mönnikes H, Noetzel S, Stengel A, Goebel M, Dinh QT, Riedl A, Bannert N, Wisser AS, Widenmann B, Klapp BF, Taché Y, Kobelt P. Desacyl ghrelin inhibits the orexigenic effect of peripherally injected ghrelin in rats.  Peptides. 2008;  29 2159-2168
• 21 Støving RK, Andries A, Brixen K, Flyvbjerg A, Hørder K, Frystyk J. Leptin, ghrelin, and endocannabinoids: Potential therapeutic targets in anorexia nervosa.  J Psychiatr Res. 2009;  43 671-679
• 22 Janas-Kozik M, Krupka-Matuszczyk I, Malinowska-Kolodziej I, Lewin-Kowalik J. Total ghrelin plasma level in patients with the restrictive type of anorexia nervosa.  Regul Pept. 2007;  5; 140 43-46
• 23 American Psychiatric Association. .Diagnostic and Statistical Manual of Mental Disorders. 4th ed (DSM-IV), Washington, DC; 1994
• 24 Yasuhara D, Nakahara T, Harada T, Inui A. Olanzapine-induced hyperglycemia in anorexia nervosa.  Am J Psychiatry. 2007;  164 528-529
• 25 Broom DR, Batterham RL, King JA, Stensel DJ. Influence of resistance and aerobic exercise on hunger, circulating levels of acylated ghrelin, and peptide YY in healthy males.  Am J Physiol Regul Integ Comp Physiol. 2009;  296 29-35
• 26 Kawai K, Yamanaka T, Yamashita S, Gondo M, Morita C, Arimura C, Nozaki T, Takii M, Kubo C. Somatic and psychological factors related to the body mass index of patients with anorexia nervosa.  Eat Weight Disord. 2008;  13 198-204
• 27 Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the Acyltransferase that Octanoylates Ghrelin, an Appetite-Stimulating Peptide Hormone.  Cell. 2008;  8 387-396

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