Objective: Anti-lipolytic drugs and exercise are enhancers of growth hormone (GH) secretion. Decreased circulating free fatty acids (FFA) have been proposed to exert ghrelin-GH feedback loop after administration of an anti-lipolytic longer-acting analog of nicotinic acid, Acipimox (OLB, 5-Methylpyrazine-2-carboxylic acid 4-oxide, molecular weight of 154.1 Da). OLB administration strongly suppresses plasma FFA during exercise. Neuroendocrine perturbations of the adipose tissue (AT), gut, and brain peptides may be involved in the etiopathogenesis of eating disorders including bulimia nervosa (BN) and anorexia nervosa. BN is characterized by binge eating, self-induced vomiting or excessive exercise. Approach: To test the hypothesis that treatment with OLB together with exercise vs. exercise alone would induce feedback action of GH, pancreatic polypeptide (PP), peptide tyrosine tyrosine (PYY), and leptin on ghrelin in Czech women with BN and in healthy-weight Czech women (HW). The lipolysis rate (as glycerol release) in subcutaneous abdominal AT was assessed with microdialysis. At an academic medical center, 12 BN and 12 HW (the control group) were randomized to OLB 500 mg 1 h before a single exercise bout (45 min, 2 W/kg of lean body mass [LBM]) once a week vs. identical placebo over a total of 2 weeks. Blood plasma concentrations of GH, PP, PYY, leptin, ghrelin, FFA, glycerol, and concentrations of AT interstitial glycerol were estimated during the test by RIA utilizing 125I-labeled tracer, the electrochemiluminescence technique (ECLIA) or colorimetric kits. Results: OLB administration together with short-term exercise significantly increased plasma GH (P < 0.0001), PP (P < 0.0001), PYY, and leptin concentrations and significantly decreased plasma ghrelin (P < 0.01) concentrations in both groups, whereas short-term exercise with placebo resulted in plasma ghrelin (P < 0.05) decrease exclusively in BN. OLB administration together with short-term exercise significantly lowered local subcutaneous abdominal AT interstitial glycerol (P < 0.0001) to a greater extent in BN. Conclusion: OLB-induced suppression of plasma ghrelin concentrations together with short-term exercise and after the post-exercise recovering phase suggests a potential negative co-feedback of GH, PP, PYY, and leptin on ghrelin secretion to a greater extent in BN. Simultaneously, the exercise-induced elevation in AT interstitial glycerol leading to a higher inhibition of peripheral lipolysis by OLB in BN. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03338387.

1st Faculty of Medicine Eating Disorder Center Psychiatric Clinic Charles University and General University Hospital Prague Czechia

1st Faculty of Medicine Institute of Pathological Physiology Charles University Prague Czechia

1st Faculty of Medicine Institute of Physiology Charles University Prague Czechia

Clinical Department Institute of Endocrinology Prague Czechia

Laboratory of Clinical and Experimental Neuroendocrinology Institute of Endocrinology Prague Czechia

Obesity Management Center Institute of Endocrinology Prague Czechia

Steroid Hormone and Proteofactors Department Institute of Endocrinology Prague Czechia

Zobrazit více v PubMed

Huas C, Godart N, Caille A, Pham-Scottez A, Foulon C, Divac SM, et al. . Mortality and its predictors in severe bulimia nervosa patients. Eur Eat Disord Rev. (2013) 21:15–9. 10.1002/erv.2178 PubMed DOI

Huas C, Caille A, Godart N, Foulon C, Pham-Scottez A, Divac S, et al. . Factors predictive of ten-year mortality in severe anorexia nervosa patients. Acta Psychiatr Scand. (2011) 123:62–70. 10.1111/j.1600-0447.2010.01627.x PubMed DOI

American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-IV- TR) 4th edition. Washington, DC: American Psychiatric Association; (2000).

Smitka K, Papezova H, Vondra K, Hill M, Hainer V, Nedvidkova J. The role of “mixed” orexigenic and anorexigenic signals and autoantibodies reacting with appetite-regulating neuropeptides and peptides of the adipose tissue-gut-brain axis: relevance to food intake and nutritional status in patients with anorexia nervosa and bulimia nervosa. Int J Endocrinol. (2013) 2013:483145. 10.1155/2013/483145 PubMed DOI PMC

Troisi A, Di Lorenzo G, Lega I, Tesauro M, Bertoli A, Leo R, et al. . Plasma ghrelin in anorexia, bulimia, and binge-eating disorder: relations with eating patterns and circulating concentrations of cortisol and thyroid hormones. Neuroendocrinology. (2005) 81:259–66. 10.1159/000087923 PubMed DOI

Kojima S, Nakahara T, Nagai N, Muranaga T, Tanaka M, Yasuhara D, et al. . Altered ghrelin and peptide YY responses to meals in bulimia nervosa. Clin Endocrinol. (2005) 62:74–8. 10.1111/j.1365-2265.2004.02176.x PubMed DOI

Naessén S, Carlström K, Holst JJ, Hellström PM, Hirschberg AL. Women with bulimia nervosa exhibit attenuated secretion of glucagon-like peptide 1, pancreatic polypeptide, and insulin in response to a meal. Am J Clin Nutr. (2011) 94:967–72. 10.3945/ajcn.111.014837 PubMed DOI

Al Massadi O, Lear PV, Muller TD, Lopez M, Dieguez C, Tschop MH, et al. . Review of novel aspects of the regulation of ghrelin secretion. Curr Drug Metab. (2014) 15:398–413. 10.2174/1389200215666140505153723 PubMed DOI

Nedvidkova J, Smitka K, Papezova H, Vondra K, Hill M, Hainer V. Acipimox during exercise points to an inhibitory feedback of GH on ghrelin secretion in bulimic and healthy women. Regul Pept. (2011) 167:134–9. 10.1016/j.regpep.2010.12.012 PubMed DOI

Smitka K, Papezova H, Vondra K, Hill M, Hainer V, Nedvidkova J. A higher response of plasma neuropeptide Y, growth hormone, leptin levels and extracellular glycerol levels in subcutaneous abdominal adipose tissue to Acipimox during exercise in patients with bulimia nervosa: single-blind, randomized, microdialysis study. Nutr Metab. (2011) 8:81. 10.1186/1743-7075-8-81 PubMed DOI PMC

Smitka K, Papezova H, Vondra K, Hill M, Hainer V, Nedvidkova J. Short-term exercise combined with Acipimox administration induces an increase in plasma ACTH and its subsequent fall in the recovery phase in bulimic women. Regul Pept. (2013) 182:45–52. 10.1016/j.regpep.2012.12.010 PubMed DOI

Khandekar N, Berning B, Sainsbury A, Lin S. The role of pancreatic polypeptide in the regulation of energy homeostasis. Mol Cell Endocrinol. (2015) 418:33–41. 10.1016/j.mce.2015.06.028 PubMed DOI

Holzer P, Reichmann F, Farzi A. Neuropeptide Y, peptide YY and pancreatic polypeptide in the gut-brain axis. Neuropeptides. (2012) 46:261–74. 10.1016/j.npep.2012.08.005 PubMed DOI PMC

Shintani M, Ogawa Y, Ebihara K, Aizawa-Abe M, Miyanaga F, Takaya K, et al. . Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes. (2001) 50:227–32. 10.2337/diabetes.50.2.227 PubMed DOI

Nway NC, Sitticharoon C, Chatree S, Maikaew P. Correlations between the expression of the insulin sensitizing hormones, adiponectin, visfatin, and omentin, and the appetite regulatory hormone, neuropeptide Y and its receptors in subcutaneous and visceral adipose tissues. Obes Res Clin Pract. (2016) 10:256–63. 10.1016/j.orcp.2015.05.007 PubMed DOI

Zhang W, Cline MA, Gilbert ER. Hypothalamus-adipose tissue crosstalk: neuropeptide Y and the regulation of energy metabolism. Nutr Metab. (2014) 11:27. 10.1186/1743-7075-11-27 PubMed DOI PMC

Arosio M, Ronchi CL, Gebbia C, Cappiello V, Beck-Peccoz P, Peracchi M. Stimulatory effects of ghrelin on circulating somatostatin and pancreatic polypeptide levels. J Clin Endocrinol Metab. (2003) 88:701–4. 10.1210/jc.2002-021161 PubMed DOI

Tovar SA, Seoane LM, Caminos JE, Nogueiras R, Casanueva FF, Diéguez C. Regulation of peptide YY levels by age, hormonal and nutritional status. Obes Res. (2004) 12:1944–50. 10.1038/oby.2004.244 PubMed DOI

Lloyd B, Ravi P, Mendes N, Klibanski A, Misra M. Peptide YY levels across pubertal stages and associations with growth hormone. J Clin Endocrinol Metab. (2010) 95:2957–62. 10.1210/jc.2009-2496 PubMed DOI PMC

Alexander SPH, Mathie A, Peters JA. Guide to receptors and channels (GRAC). 7TM receptors: nicotinic acid family. Br J Pharmacol. (2009) 158(Suppl. 1):S77 10.1111/j.1476-5381.2009.00501_48.x DOI

Carlson LA. Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review. J Intern Med. (2005) 258:94–114. 10.1111/j.1365-2796.2005.01528.x PubMed DOI

Ren N, Kaplan R, Hernandez M, Cheng K, Jin L, Taggart AK, et al. . Phenolic acids suppress adipocyte lipolysis via activation of the nicotinic acid receptor GPR109A (HM74a/PUMA-G). J Lipid Res. (2009) 50:908–14. 10.1194/jlr.M800625-JLR200 PubMed DOI PMC

Offermanns S, Colletti SL, Lovenberg TW, Semple G, Wise A, IJzerman AP. International union of basic and clinical pharmacology. LXXXII: nomenclature and classification of hydroxy- carboxylic acid receptors (GPR81, GPR109A, and GPR109B). Pharmacol Rev. (2011) 63:269–90. 10.1124/pr.110.003301 PubMed DOI

Engelstoft MS, Park WM, Sakata I, Kristensen LV, Husted AS, Osborne-Lawrence S, et al. . Seven transmembrane G protein coupled receptor repertoire of gastric ghrelin cells. Mol Metab. (2013) 2:376–92. 10.1016/j.molmet.2013.08.006 PubMed DOI PMC

Cai TQ, Ren N, Jin L, Cheng K, Kash S, Chen R, et al. . Role of GPR81 in lactate-mediated reduction of adipose lipolysis. Biochem Biophys Res Commun. (2008) 377:987–91. 10.1016/j.bbrc.2008.10.088 PubMed DOI

Kirkland JB, Meyer-Ficca ML. Niacin. Adv Food Nutr Res. (2018) 83:83–149. 10.1016/bs.afnr.2017.11.003 PubMed DOI

Alarcon P, Manosalva C, Carretta MD, Hidalgo AI, Figueroa CD, Taubert A, et al. . Fatty and hydroxycarboxylic acid receptors: the missing link of immune response and metabolism in cattle. Vet Immunol Immunopathol. (2018) 201:77–87. 10.1016/j.vetimm.2018.05.009 PubMed DOI

Wang-Fisher YL, Han J, Guo W. Acipimox stimulates leptin production from isolated rat adipocytes. J Endocrinol. (2002) 174:267–72. 10.1677/joe.0.1740267 PubMed DOI

Lauring B, Taggart AK, Tata JR, Dunbar R, Caro L, Cheng K, et al. . Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression. Sci Transl Med. (2012) 4:148ra115. 10.1126/scitranslmed.3003877 PubMed DOI

Shomali T, Mosleh N, Kamalpour M. Screening of different organs of rats for HCA2 receptor mRNA. Int J Mol Cell Med. (2014) 3:126–9. PubMed PMC

Stilling RM, van de Wouw M, Clarke G, Stanton C, Dinan TG, Cryan JF. The neuropharmacology of butyrate: The bread and butter of the microbiota-gut-brain axis? Neurochem Int. (2016) 99:110–32. 10.1016/j.neuint.2016.06.011 PubMed DOI

Strumia R. Dermatologic signs in patients with eating disorders. Am J Clin Dermatol. (2005) 6:165–73. 10.2165/00128071-200506030-00003 PubMed DOI

Ormsbee MJ, Choi MD, Medlin JK, Geyer GH, Trantham LH, Dubis GS, et al. . Regulation of fat metabolism during resistance exercise in sedentary lean and obese men. J Appl Physiol. (2009) 106:1529–37. 10.1152/japplphysiol.91485.2008 PubMed DOI

Bartak V, Vybiral S, Papezova H, Dostalova I, Pacak K, Nedvidkova J. Basal and exercise induced sympathetic nervous activity and lipolysis in adipose tissue of patients with anorexia nervosa. Eur J Clin Invest. (2004) 34:371–7. 10.1111/j.1365-2362.2004.01344.x PubMed DOI

Islam H, Townsend LK, McKie GL, Medeiros PJ, Gurd BJ, Hazell TJ. Potential involvement of lactate and interleukin-6 in the appetite-regulatory hormonal response to an acute exercise bout. J Appl Physiol. (2017) 123:614–23. 10.1152/japplphysiol.00218.2017 PubMed DOI PMC

Jürimäe J, Jürimäe T, Purge P. Plasma ghrelin is altered after maximal exercise in elite male rowers. Exp Biol Med. (2007) 232:904–9. PubMed

Ueda SY, Yoshikawa T, Katsura Y, Usui T, Nakao H, Fujimoto S. Changes in gut hormone levels and negative energy balance during aerobic exercise in obese young males. J Endocrinol. (2009) 201:151–9. 10.1677/JOE-08-0500 PubMed DOI

Mani BK, Castorena CM, Osborne-Lawrence S, Vijayaraghavan P, Metzger NP, Elmquist JK, et al. . Ghrelin mediates exercise endurance and the feeding response post-exercise. Mol Metab. (2018) 9:114–30. 10.1016/j.molmet.2018.01.006 PubMed DOI PMC

Iwakura H, Kangawa K, Nakao K. The regulation of circulating ghrelin - with recent updates from cell-based assays. Endocr J. (2015) 62:107–22. 10.1507/endocrj.EJ14-0419 PubMed DOI

Müller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, et al. Ghrelin. Mol Metab. (2015) 4:437–60. 10.1016/j.molmet.2015.03.005 PubMed DOI PMC

Hazell TJ, Islam H, Townsend LK, Schmale MS, Copeland JL. Effects of exercise intensity on plasma concentrations of appetite-regulating hormones: potential mechanisms. Appetite. (2016) 98:80–8. 10.1016/j.appet.2015.12.016 PubMed DOI

Vestergaard ET, Dall R, Lange KH, Kjaer M, Christiansen JS, Jorgensen JO. The ghrelin response to exercise before and after growth hormone administration. JClin Endocrinol Metab. (2007) 92:297–303. 10.1210/jc.2006-1435 PubMed DOI

Qi X, Reed J, Englander EW, Chandrashekar V, Bartke A, Greeley GH, Jr. Evidence that growth hormone exerts a feedback effect on stomach ghrelin production and secretion. Exp Biol Med. (2003) 228:1028–32. 10.1177/153537020322800907 PubMed DOI

Zhang QJ, Yang CC, Zhang SY, Zhang LH, Li J. Alteration of NPY in hypothalamus and its correlation with leptin and ghrelin during the development of T2DM in a rat model. Springerplus. (2016) 5:913. 10.1186/s40064-016-3555-9 PubMed DOI PMC

Lissett CA, Clayton PE, Shalet SM. The acute leptin response to GH. J Clin Endocrinol Metab. (2001) 86:4412–5. 10.1210/jcem.86.9.7796 PubMed DOI

Verhulst PJ, Janssen S, Tack J, Depoortere I. Role of the AMP-activated protein kinase (AMPK) signaling pathway in the orexigenic effects of endogenous ghrelin. Regul Pept. (2012) 173:27–35. 10.1016/j.regpep.2011.09.001 PubMed DOI

Kalra SP, Ueno N, Kalra PS. Stimulation of appetite by ghrelin is regulated by leptin restraint: peripheral and central sites of action. J Nutr. (2005) 135:1331–5. 10.1093/jn/135.5.1331 PubMed DOI

Asakawa A, Inui A, Yuzuriha H, Ueno N, Katsuura G, Fujimiya M, et al. . Characterization of the effects of pancreatic polypeptide in the regulation of energy balance. Gastroenterology. (2003) 124:1325–36. 10.1016/S0016-5085(03)00216-6 PubMed DOI

Takahashi H, Kurose Y, Suzuki Y, Kojima M, Yamaguchi T, Yoshida Y, et al. . Changes in blood pancreatic polypeptide and ghrelin concentrations in response to feeding in sheep. J Anim Sci. (2010) 88:2103–7. 10.2527/jas.2009-1920 PubMed DOI

Batterham RL, Cohen MA, Ellis SM, Le Roux CW, Withers DJ, Frost GS, et al. . Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med. (2003) 349:941–8. 10.1056/NEJMoa030204 PubMed DOI

Consitt LA, Bloomer RJ, Wideman L. The effect of exercise type on immunofunctional and traditional growth hormone. Eur J Appl Physiol. (2007) 100:321–30. 10.1007/s00421-007-0431-x PubMed DOI

Gormsen LC, Nielsen C, Gjedsted J, Gjedde S, Vestergaard ET, Christiansen JS, et al. . Effects of free fatty acids, growth hormone and growth hormone receptor blockade on serum ghrelin levels in humans. Clin Endocrinol. (2007) 66:641–5. 10.1111/j.1365-2265.2007.02786.x PubMed DOI

Vestergaard ET, Jessen N, Møller N, Jørgensen JO. Acyl ghrelin induces insulin resistance independently of GH, cortisol, and free fatty acids. Sci Rep. (2017) 7:42706. 10.1038/srep42706 PubMed DOI PMC

Richman JG, Kanemitsu-Parks M, Gaidarov I, Cameron JS, Griffin P, Zheng H, et al. Nicotinic acid receptor agonists differentially activate downstream effectors. J Biol Chem. (2007) 22:8028–36. 10.1074/jbc.M701866200 PubMed DOI

Carlson LA, Oro L. The effect of nicotinic acid on the plasma free fatty acid; demonstration of a metabolic type of sympathicolysis. Acta Med Scand. (1962) 172:641–5. 10.1111/j.0954-6820.1962.tb07203.x PubMed DOI

Chai JT, Digby JE, Choudhury RP. GPR109A and vascular inflammation. Curr Atheroscler Rep. (2013) 15:325. 10.1007/s11883-013-0325-9 PubMed DOI PMC

Lafontan M, Langin D. Lipolysis and lipid mobilization in human adipose tissue. Prog Lipid Res. (2009) 48:275–97. 10.1016/j.plipres.2009.05.001 PubMed DOI

Current Aspects of the Role of Autoantibodies Directed Against Appetite-Regulating Hormones and the Gut Microbiome in Eating Disorders

Zobrazit více v PubMed

ClinicalTrials.gov
NCT03338387