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Agouti-related protein in patients with acute and weight-restored anorexia nervosa

Published online by Cambridge University Press:  22 March 2011

J. V. Merle ,
V. Haas ,
R. Burghardt ,
N. Döhler ,
N. Schneider ,
U. Lehmkuhl  and
S. Ehrlich
J. V. Merle
Affiliation:
Charité – Universitätsmedizin Berlin, CVK, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Berlin, Germany
V. Haas
Affiliation:
Charité – Universitätsmedizin Berlin, CVK, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Berlin, Germany Charité – Universitätsmedizin Berlin, ECRC, Franz-Volhard Clinical Research Center, Berlin, Germany
R. Burghardt
Affiliation:
Charité – Universitätsmedizin Berlin, CVK, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Berlin, Germany
N. Döhler
Affiliation:
Charité – Universitätsmedizin Berlin, CVK, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Berlin, Germany
N. Schneider
Affiliation:
Charité – Universitätsmedizin Berlin, CVK, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Berlin, Germany
U. Lehmkuhl
Affiliation:
Charité – Universitätsmedizin Berlin, CVK, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Berlin, Germany
S. Ehrlich*
Affiliation:
Charité – Universitätsmedizin Berlin, CVK, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Berlin, Germany Harvard Medical School, Massachusetts General Hospital, Department of Psychiatry, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, USA Dresden University of Technology, Department of Child and Adolescent Psychiatry, Translational Developmental Neuroscience Section, Dresden, Germany
*
*Address for correspondence: S. Ehrlich, M.D., Massachusetts General Hospital/Harvard Medical School, Athinoula A. Martinos Center for Biomedical Imaging, Psychiatric Neuroimaging Research Program, CNY Building 120, Suite 100, Charlestown, Massachusetts 02129-2000, USA. (Email: stefan@nmr.mgh.harvard.edu)
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Abstract

Background

An imbalance in appetite-regulating neuropeptides of the central nervous system has been associated with anorexia nervosa (AN), but the mechanisms of action are poorly understood. Agouti-related protein (AGRP), an orexigenic mediator of the hypothalamus, increases food intake and decreases energy expenditure in times of negative energy balance. The aim of the present study was to investigate AGRP in acute and fully weight-restored patients with AN, as well as during weight gain.

Method

Plasma AGRP and leptin levels were assessed using an enzyme-linked immunosorbent assay kit in a total of 175 female participants, including 75 patients with acute AN, 37 weight-restored AN patients and 63 healthy controls. Of the patients with acute AN, 33 were reassessed after partial weight gain.

Results

In weight-restored AN patients plasma AGRP levels were similar to those in healthy controls, whereas in patients with acute AN, AGRP was elevated. AGRP was inversely correlated with indicators of undernutrition such as body mass index and plasma leptin. In addition, AGRP levels normalized during weight gain of longitudinally assessed AN patients.

Conclusions

Our results underline the significance of undernutrition and hypoleptinemia for the interpretation of peripheral AGRP concentrations. This provides support for the hypothesis that abnormal AGRP plasma levels in AN patients reflect undernutrition, rather than disease-specific traits.

Keywords

Agouti-related proteinanorexia nervosaleptinneuroendocrinologyundernutrition
Type
Original Articles
Information
Psychological Medicine , Volume 41 , Issue 10 , October 2011 , pp. 2183 - 2192
Copyright
Copyright © Cambridge University Press 2011

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References

Berridge, KC (2009). ‘Liking’ and ‘wanting’ food rewards: brain substrates and roles in eating disorders. Physiology and Behavior 97, 537–550.CrossRefGoogle ScholarPubMed
Dardennes, RM, Zizarri, P, Tolle, V, Foulon, C, Kipman, A, Romo, L, Iancu-Gontard, D, Boni, C, Sinet, PM, Bluet, MT, Estour, B, Mouren, MC, Guelfi, JD, Rouillona, F, Gorwood, P, Epelbaum, J (2007). Family trios analyses of common polymorphisms in the obestatin/ghrelin, BDNF and AGRP genes in patients with anorexia nervosa: association with subtype, body-mass index, severity and age of onset. Psychoneuroendocrinology 32, 106–113.CrossRefGoogle Scholar
Davis, C, Katzman, DK, Kaptein, S, Kirsh, C, Brewer, H, Kalmbach, K, Olmsted, MP, Woodside, DB, Kaplan, AS (1997). The prevalence of high-level exercise in the eating disorders: etiological implications. Comprehensive Psychiatry 38, 321–326.CrossRefGoogle ScholarPubMed
Ebihara, K, Ogawa, Y, Katsuura, G, Numata, Y, Masuzaki, H, Satoh, N, Tamaki, M, Yoshioka, T, Hayase, M, Matsuoka, N, Aizawa-Abe, M, Yoshimasa, Y, Nakao, K (1999). Involvement of agouti-related protein, an endogenous antagonist of hypothalamic melanocortin receptor, in leptin action. Diabetes 48, 2028–2033.CrossRefGoogle ScholarPubMed
Ehrlich, S, Burghardt, R, Schneider, N, Hein, J, Weiss, D, Pfeiffer, E, Lehmkuhl, U, Salbach-Andrae, H (2009). Leptin and its associations with measures of psychopathology in patients with anorexia nervosa. Journal of Neural Transmission 116, 109–115.CrossRefGoogle ScholarPubMed
Ehrlich, S, Franke, L, Scherag, S, Burghardt, R, Schott, R, Schneider, N, Brockhaus, S, Hein, J, Uebelhack, R, Lehmkuhl, U (2010 a). The 5-HTTLPR- polymorphism, platelet serotonin transporter activity and platelet serotonin content in underweight and weight recovered females with anorexia nervosa. European Archives of Psychiatry and Clinical Neuroscience 260, 483–490.CrossRefGoogle ScholarPubMed
Ehrlich, S, Franke, L, Schott, R, Salbach-Andrae, H, Pfeiffer, E, Lehmkuhl, U, Uebelhack, R (2008). Platelet monoamine oxidase activity in underweight and recovered females with anorexia nervosa. Pharmacopsychiatry 41, 226–231.CrossRefGoogle ScholarPubMed
Ehrlich, S, Weiss, D, Burghardt, R, Infante-Duarte, C, Brockhaus, S, Muschler, MA, Bleich, S, Lehmkuhl, U, Frieling, H (2010 b). Promoter specific DNA methylation and gene expression of POMC in acutely underweight and recovered patients with anorexia nervosa. Journal of Psychiatric Research 44, 827–833.CrossRefGoogle ScholarPubMed
Elmquist, JK, Elias, CF, Saper, CB (1999). From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 22, 221–232.CrossRefGoogle ScholarPubMed
Fichter, M, Quadflieg, N (1999). The Structured Interview for Anorexic and Bulimic Disorders for DSM-IV and ICD-10 (SIAB-EX) [in German]. Huber: Bern.Google Scholar
Fichter, M, Quadflieg, N (2001). The structured interview for anorexic and bulimic disorders for DSM-IV and ICD-10 (SIAB-EX): reliability and validity. European Psychiatry 16, 38–48.CrossRefGoogle ScholarPubMed
Fong, TM, Mao, C, MacNeil, T, Kalyani, R, Smith, T, Weinberg, D, Tota, MR, van der Ploeg, LHT (1997). ART (protein product of agouti-related transcript) as an agonist of MC-3 and MC-4 receptors. Biochemical and Biophysical Research Communications 237, 629–631.CrossRefGoogle Scholar
Franke, GH (2002). SCL-90. The Symptom-Checklist of Derogatis – German Version [in German]. Beltz Test GmbH: Göttingen.Google Scholar
Frieling, H, Römer, KD, Scholz, S, Mittelbach, F, Wilhelm, J, De Zwaan, M, Jacoby, GE, Kornhuber, J, Hillemacher, T, Bleich, S (2009). Epigenetic dysregulation of dopaminergic genes in eating disorders. International Journal of Eating Disorders 43, 577–583.CrossRefGoogle Scholar
Gavrila, A, Chan, JL, Miller, LC, Heist, K, Yiannakouris, N, Mantzoros, CS (2005). Circulating melanin-concentrating hormone, agouti-related protein, and α-melanocyte stimulating hormone levels in relation to body composition: alterations in response to food deprivation and recombinant human leptin administration. Journal of Clinical Endocrinology and Metabolism 90, 1047–1054.CrossRefGoogle ScholarPubMed
Goto, K, Inui, A, Takimoto, Y, Yuzuriha, H, Asakawa, A, Kawamura, Y, Tsuji, H, Takahara, Y, Takeyama, C, Katsuura, G, Kasuga, M (2003). Acute intracerebroventricular administration of either carboxyl-terminal or amino-terminal fragments of agouti-related peptide produces a long-term decrease in energy expenditure in rats. International Journal of Molecular Medicine 12, 379–383.Google ScholarPubMed
Graham, M, Shutter, JR, Sarmiento, U, Sarosi, I, Stark, KL (1997). Overexpression of Agrt leads to obesity in transgenic mice. Nature Genetics 17, 273–274.CrossRefGoogle ScholarPubMed
Hagan, MM, Rushing, PA, Schwartz, MW, Yagaloff, KA, Burn, P, Woods, SC, Seeley, RJ (1999). Role of the CNS melanocortin system in the response to overfeeding. Journal of Neuroscience 19, 2362–2367.CrossRefGoogle ScholarPubMed
Hebebrand, J, Muller, TD, Holtkamp, K, Herpertz-Dahlmann, B (2007). The role of leptin in anorexia nervosa: clinical implications. Molecular Psychiatry 12, 23–35.CrossRefGoogle ScholarPubMed
Hillebrand, JJ, Kas, MJ, Adan, RA (2006 a). To eat or not to eat; regulation by the melanocortin system. Physiology and Behavior 89, 97–102.CrossRefGoogle ScholarPubMed
Hillebrand, JJ, Kas, MJH, Scheurink, AJW, van Dijk, G, Adan, RAH (2006 b). AGRP (83-132) and SHU9119 differently affect activity-based anorexia. European Neuropsychopharmacology 16, 403–412.CrossRefGoogle ScholarPubMed
Hoggard, N, Johnstone, AM, Faber, P, Gibney, ER, Elia, M, Lobley, G, Rayner, V, Horgan, G, Hunter, L, Bashir, S, Stubbs, RJ (2004). Plasma concentrations of α-MSH, AgRP and leptin in lean and obese men and their relationship to differing states of energy balance perturbation. Clinical Endocrinology (Oxford) 61, 31–39.CrossRefGoogle ScholarPubMed
Inui, A (2001). Eating behavior in anorexia nervosa – an excess of both orexigenic and anorexigenic signalling? Molecular Psychiatry 6, 620–624.CrossRefGoogle ScholarPubMed
Kas, MJH, van Dijk, G, Scheurink, AJW, Adan, RAH (2003). Agouti-related protein prevents self-starvation. Molecular Psychiatry 23, 197–203.Google Scholar
Katsuki, A, Sumida, Y, Gabazza, EC, Murashima, S, Tanaka, T, Furuta, M, Araki-Sasaki, R, Hori, Y, Nakatani, K, Yano, Y, Adachi, Y (2001). Plasma levels of agouti-related protein are increased in obese men. Journal of Clinical Endocrinology and Metabolism 86, 1921–1924.CrossRefGoogle ScholarPubMed
Kaye, WH, Fudge, JL, Paulus, M (2009). New insights into symptoms and neurocircuit function of anorexia nervosa. Nature Reviews Neuroscience 10, 573–584.CrossRefGoogle ScholarPubMed
Kromeyer-Hauschild, K, Wabitsch, M, Kunze, D (2001). Percentile for the body-mass-index of children and youths using various German samples [in German]. Monatsschrift Kinderheilkunde 149, 807–818.CrossRefGoogle Scholar
Li, JY, Finniss, S, Yang, YK, Zeng, Q, Qu, SY, Barsh, G, Dickinson, C, Gantz, I (2000). Agouti-related protein-like immunoreactivity: characterization of release from hypothalamic tissue and presence in serum. Endocrinology 41, 1942–1950.CrossRefGoogle Scholar
Lu, XY, Nicholson, JR, Akil, H, Watson, SJ (2001). Time course of short-term and long-term orexigenic effects of agouti-related protein (86-132). Neuroreport 12, 1281–1284.CrossRefGoogle ScholarPubMed
Marks, DL, Boucher, N, Lanouette, CM, Pérusse, L, Brookhart, G, Comuzzie, AG, Chagnon, YC, Cone, RD (2004). Ala67Thr polymorphism in the agouti-related peptide gene is associated with inherited leanness in humans. American Journal of Medical Genetics 126, 267–271.CrossRefGoogle Scholar
Mayer, L, Walsh, BT, Pierson, RN Jr., Heymsfield, SB, Gallagher, D, Wang, J, Parides, MK, Leibel, RL, Warren, MP, Killory, E, Glasofer, D (2005). Body fat redistribution after weight gain in women with anorexia nervosa. American Journal of Clinical Nutrition 81, 1286–1291.CrossRefGoogle ScholarPubMed
Mizuno, TM, Mobbs, CV (1999). Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology 140, 814–817.CrossRefGoogle ScholarPubMed
Monteleone, P, Castaldo, E, Maj, M (2008). Neuroendocrine dysregulation of food intake in eating disorders. Regulatory Peptides 149, 39–50.CrossRefGoogle ScholarPubMed
Monteleone, P, Di Lieto, A, Tortorella, A, Longobardi, N, Maj, M (2000). Circulating leptin in patients with anorexia nervosa, bulimia nervosa or binge-eating disorder: relationship to body weight, eating patterns, psychopathology and endocrine changes. Psychiatry Research 94, 121–129.CrossRefGoogle ScholarPubMed
Monteleone, P, Martiadis, V, Colurcio, B, Maj, M (2002). Leptin secretion is related to chronicity and severity of the illness in bulimia nervosa. Psychosomatic Medicine 64, 874–879.Google ScholarPubMed
Moriya, J, Takimoto, Y, Yoshiuchi, K, Shimosawa, T, Akabayashi, A (2006). Plasma agouti-related protein levels in women with anorexia nervosa. Psychoneuroendocrinology 31, 1057–1061.CrossRefGoogle ScholarPubMed
Nijenhuis, WA, Oosterom, J, Adan, RA (2001). AgRP(83-132) acts as an inverse agonist on the human-melanocortin-receptor 4. Molecular Endocrinology 15, 164–171.Google Scholar
Ollmann, MM, Wilson, BD, Yang, YK, Kerns, JA, Chen, Y, Gantz, I, Barsh, GS (1997). Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–138.CrossRefGoogle ScholarPubMed
Rathner, G, Waldherr, K (1997). Eating Disorder Inventory-2. A German validation with standards for female and male youths [in German]. Zeitschrift für Klinische Psychologie, Psychiatrie und Psychotherapie 45, 157–182.Google Scholar
Rossi, M, Kim, MS, Morgan, DGA, Small, CJ, Edwards, CMB, Sunter, D, Abusnana, S, Goldstone, AP, Russell, SH, Stanley, SA, Smith, DM, Yagaloff, K, Ghatei, MA, Bloom, SR (1998). A C-terminal fragment of agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology 139, 4428–4431.CrossRefGoogle ScholarPubMed
Salbach-Andrae, H, Lenz, K, Simmendinger, N, Klinkowski, N, Lehmkuhl, U, Pfeiffer, E (2008). Psychiatric comorbidities among female adolescents with anorexia nervosa. Child Psychiatry and Human Development 39, 261–272.CrossRefGoogle ScholarPubMed
Shen, CP, Wu, KK, Shearman, LP, Camacho, R, Tota, MR, Fong, TM, van der Ploeg, LHT (2002). Plasma agouti-related protein level: a possible correlation with fasted and fed states in humans and rats. Journal of Neuroendocrinology 14, 607–610.CrossRefGoogle Scholar
Shutter, JR, Graham, M, Kinsey, AC, Scully, S, Lüthy, R, Stark, KL (1997). Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice. Genes & Development 11, 593–602.CrossRefGoogle ScholarPubMed
Vink, T, Hinney, A, van Elburg, AA, van Goozen, SHM, Sandkuijl, LA, Sinke, RJ, Herpertz-Dahlmann, BM, Hebebrand, J, Remschmidt, H, van Engeland, H, Adan, RAH (2001). Association between an agouti-related protein gene polymorphism and anorexia nervosa. Molecular Psychiatry 6, 325–328.CrossRefGoogle ScholarPubMed
Yang, YK, Thompson, DA, Dickinson, CJ, Wilken, J, Barsh, GS, Kent, SBH, Gantz, I (1999). Characterization of agouti-related protein binding to melanocortin receptors. Molecular Endocrinology 13, 148–155.CrossRefGoogle ScholarPubMed
Zhang, F, Chen, Y, Heiman, M, Dimarchi, R (2005). Leptin: structure, function and biology. Vitamins and Hormones 71, 345–372.CrossRefGoogle ScholarPubMed
Zhang, F, Proenca, R, Maffei, M, Barone, M, Leopold, L, Friedman, JM (1994). Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432.CrossRefGoogle ScholarPubMed