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Diet-induced obesity blunts the behavioural effects of ghrelin: studies in a mouse-progressive ratio task

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Abstract

Rational

The ghrelinergic system is implicated in the development of obesity and in modulating central reward systems. It has been reported that diet-induced obesity causes blunted responding on food intake to ghrelin administration, associated with central ghrelin resistance. Here we investigate whether the stimulatory effects of ghrelin on the reward system are altered in diet-induced obese mice.

Methods

Obesity was induced in C57BL/6J mice by feeding high-fat diet for 13 weeks. Mice were trained in an operant fixed and exponential progressive ratio task to respond for sucrose rewards. In an ad libitum fed state, ghrelin and a ghrelin receptor antagonist were administered in the progressive ratio. Alterations in the central ghrelin system in diet-induced obese mice were assessed.

Results

Obese mice showed attenuated acquisition and performance in the fixed and progressive ratio paradigm. Most importantly, diet-induced obesity inhibited the stimulatory effects of ghrelin (2 nmol, 3 nmol/10 g) on progressive ratio responding whereas lean animals presented with increased responding. Administration of the ghrelin-receptor antagonist (D-Lys3)-GHRP-6 (66.6 nmol/10 g) decreased performance in lean but not obese mice. This insensitivity to ghrelin receptor ligands in mice on high-fat diet was further supported by decreased mRNA expression of the ghrelin receptor in the hypothalamus and the nucleus accumbens in obese mice.

Conclusions

This study demonstrates that the modulatory effects of ghrelin receptor ligands are blunted in a mouse model of diet-induced obesity in a progressive ratio task. Thereby, our data extend the previously described ghrelin resistance in these mice from food intake to reward-associated behaviours.

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References

  • Abizaid A, Liu ZW, Andrews ZB, Shanabrough M, Borok E, Elsworth JD, Roth RH, Sleeman MW, Picciotto MR, Tschöp MH, Gao XB, Horvath TL (2006) Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Invest 116:3229–3239

    Article  PubMed  CAS  Google Scholar 

  • Arnold JM, Roberts DC (1997) A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav 57:441–447

    Article  PubMed  CAS  Google Scholar 

  • Asakawa A, Inui A, Kaga T, Katsuura G, Fujimiya M, Fujino MA, Kasuga M (2003) Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut 52:947–952

    Article  PubMed  CAS  Google Scholar 

  • Beck B, Richy S, Stricker-Krongrad A (2004) Feeding response to ghrelin agonist and antagonist in lean and obese Zucker rats. Life Sci 76:473–478

    Article  PubMed  CAS  Google Scholar 

  • Briggs DI, Andrews ZB (2011) Metabolic status regulates ghrelin function on energy homeostasis. Neuroendocrinology 93:48–57

    Article  PubMed  CAS  Google Scholar 

  • Briggs DI, Enriori PJ, Lemus MB, Cowley MA, Andrews ZB (2010) Diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons. Endocrinology 151:4745–4755

    Article  PubMed  CAS  Google Scholar 

  • Cheng KC, Li YX, Asakawa A, Inui A (2010) The role of ghrelin in energy homeostasis and its potential clinical relevance. Int J Mol Med 26:771–778

    PubMed  CAS  Google Scholar 

  • Davis KW, Wellman PJ, Clifford PS (2007) Augmented cocaine conditioned place preference in rats pretreated with systemic ghrelin. Regul Pept 140:148–152

    Article  PubMed  CAS  Google Scholar 

  • Davis JF, Tracy AL, Schurdak JD, Tschöp MH, Lipton JW, Clegg DJ, Benoit SC (2008) Exposure to elevated levels of dietary fat attenuates psychostimulant reward and mesolimbic dopamine turnover in the rat. Behav Neurosci 122:1257–1263

    Article  PubMed  Google Scholar 

  • Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA, Jerlhag E (2011) The role of the central ghrelin system in reward from food and chemical drugs. Mol Cell Endocrinol 340(1):80–87

    Article  PubMed  CAS  Google Scholar 

  • Egecioglu E, Jerlhag E, Salomé N, Skibicka KP, Haage D, Bohlooly-Y M, Andersson D, Bjursell M, Perrissoud D, Engel JA, Dickson SL (2010) Ghrelin increases intake of rewarding food in rodents. Addict Biol 15:304–311

    Article  PubMed  CAS  Google Scholar 

  • Egecioglu E, Skibicka KP, Hansson C, Alvarez-Crespo M, Friberg PA, Jerlhag E, Engel JA, Dickson SL (2011) Hedonic and incentive signals for body weight control. Rev Endocr Metab Disord 12(3):141–151

    Article  PubMed  CAS  Google Scholar 

  • El-Ghundi M, O’Dowd BF, Erclik M, George SR (2003) Attenuation of sucrose reinforcement in dopamine D1 receptor deficient mice. Eur J Neurosci 17:851–862

    Article  PubMed  Google Scholar 

  • Field BC, Chaudhri OB, Bloom SR (2009) Obesity treatment: novel peripheral targets. Br J Clin Pharmacol 68:830–843

    Article  PubMed  CAS  Google Scholar 

  • Finger BC, Dinan TG, Cryan JF (2010) Progressive Ratio Responding in an Obese Mouse Model: Effects of Fenfluramine. Neuropharmacology 59:619–626

    Article  PubMed  CAS  Google Scholar 

  • Finger BC, Dinan TG, Cryan JF (2011a) Behavioural satiety sequence in a genetic mouse model of obesity: effects of ghrelin receptor ligands. Behav Pharmacol. doi:10.1097/FBP.0b013e32834afee6

  • Finger BC, Dinan TG, Cryan JF (2011b) High-fat diet selectively protects against the effects of chronic social stress in the mouse. Neuroscience. doi:10.1016/j.neuroscience.2011.06.072

  • Finger BC, Schellekens H, Dinan TG, Cryan JF (2011c) Is there altered sensitivity to ghrelin receptor ligands in leptin deficient mice?: Importance of satiety state and time of day. Psychopharmacology (Berl) 216:421–429

    Article  CAS  Google Scholar 

  • Haney M, Rubin E, Foltin RW (2011) Aripiprazole maintenance increases smoked cocaine self-administration in humans. Psychopharmacology (Berl) 216(3):379–387

    Article  CAS  Google Scholar 

  • Hodos W (1961) Progressive ratio as a measure of reward strength. Science 134:943–944

    Article  PubMed  CAS  Google Scholar 

  • Jerlhag E, Engel JA (2011) Ghrelin receptor antagonism attenuates nicotine-induced locomotor stimulation, accumbal dopamine release and conditioned place preference in mice. Drug Alcohol Depend 117(2–3):126–131

    Article  PubMed  CAS  Google Scholar 

  • Jerlhag E, Egecioglu E, Dickson SL, Andersson M, Svensson L, Engel JA (2006) Ghrelin stimulates locomotor activity and accumbal dopamine-overflow via central cholinergic systems in mice: implications for its involvement in brain reward. Addict Biol 11:45–54

    Article  PubMed  CAS  Google Scholar 

  • Jerlhag E, Egecioglu E, Dickson SL, Svensson L, Engel JA (2008) Alpha-conotoxin MII-sensitive nicotinic acetylcholine receptors are involved in mediating the ghrelin-induced locomotor stimulation and dopamine overflow in nucleus accumbens. Eur Neuropsychopharmacol 18:508–518

    Article  PubMed  CAS  Google Scholar 

  • Jerlhag E, Egecioglu E, Landgren S, Salomé N, Heilig M, Moechars D, Datta R, Perrissoud D, Dickson SL, Engel JA (2009) Requirement of central ghrelin signaling for alcohol reward. Proc Natl Acad Sci USA 106:11318–11323

    Article  PubMed  CAS  Google Scholar 

  • Jerlhag E, Egecioglu E, Dickson SL, Engel JA (2010) Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference. Psychopharmacology (Berl) 211:415–422

    Article  CAS  Google Scholar 

  • Kenny PJ (2011) Reward mechanisms in obesity: new insights and future directions. Neuron 69:664–679

    Article  PubMed  CAS  Google Scholar 

  • Kirchner H, Tong J, Tschöp MH, Pfluger PT (2010) Ghrelin and PYY in the regulation of energy balance and metabolism: lessons from mouse mutants. Am J Physiol Endocrinol Metab 298:E909–E919

    Article  PubMed  CAS  Google Scholar 

  • Kitazawa T, De Smet B, Verbeke K, Depoortere I, Peeters TL (2005) Gastric motor effects of peptide and non-peptide ghrelin agonists in mice in vivo and in vitro. Gut 54:1078–1084

    Article  PubMed  CAS  Google Scholar 

  • Landgren S, Simms JA, Hyytiä P, Engel JA, Bartlett SE, Jerlhag E (2011a) Ghrelin receptor (GHS-R1A) antagonism suppresses both operant alcohol self-administration and high alcohol consumption in rats. Addict Biol. doi:10.1111/j.1369-1600.2010.00280.x

  • Landgren S, Simms JA, Thelle DS, Strandhagen E, Bartlett SE, Engel JA, Jerlhag E (2011b) The ghrelin signalling system is involved in the consumption of sweets. PLoS One 6:e18170

    Article  PubMed  CAS  Google Scholar 

  • Lutter M, Nestler EJ (2009) Homeostatic and hedonic signals interact in the regulation of food intake. J Nutr 139:629–632

    Article  PubMed  CAS  Google Scholar 

  • Mobini S, Chiang TJ, Ho MY, Bradshaw CM, Szabadi E (2000) Comparison of the effects of clozapine, haloperidol, chlorpromazine and d-amphetamine on performance on a time-constrained progressive ratio schedule and on locomotor behaviour in the rat. Psychopharmacology (Berl) 152:47–54

    Article  CAS  Google Scholar 

  • Perello M, Sakata I, Birnbaum S, Chuang JC, Osborne-Lawrence S, Rovinsky SA, Woloszyn J, Yanagisawa M, Lutter M, Zigman JM (2010) Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner. Biol Psychiatry 67:880–886

    Article  PubMed  CAS  Google Scholar 

  • Pulman KJ, Fry WM, Cottrell GT, Ferguson AV (2006) The subfornical organ: a central target for circulating feeding signals. J Neurosci 26:2022–2030

    Article  PubMed  CAS  Google Scholar 

  • Richardson NR, Roberts DC (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66:1–11

    Article  PubMed  CAS  Google Scholar 

  • Rickard JF, Body S, Zhang Z, Bradshaw CM, Szabadi E (2009) Effect of reinforcer magnitude on performance maintained by progressive-ratio schedules. J Exp Anal Behav 91:75–87

    Article  PubMed  CAS  Google Scholar 

  • Roane HS (2008) On the applied use of progressive-ratio schedules of reinforcement. J Appl Behav Anal 41:155–161

    Article  PubMed  Google Scholar 

  • Rodgers RJ, Holch P, Tallett AJ (2010) Behavioural satiety sequence (BSS): Separating wheat from chaff in the behavioural pharmacology of appetite. Pharmacol Biochem Behav 97:3–14

    Article  PubMed  CAS  Google Scholar 

  • Sabino V, Cottone P, Blasio A, Iyer MR, Steardo L, Rice KC, Conti B, Koob GF, Zorrilla EP (2011) Activation of σ-Receptors Induces Binge-like Drinking in Sardinian Alcohol-Preferring Rats. Neuropsychopharmacology 36:1207–1218

    Article  PubMed  CAS  Google Scholar 

  • Schellekens H, Dinan TG, Cryan JF (2010) Lean mean fat reducing “ghrelin” machine: hypothalamic ghrelin and ghrelin receptors as therapeutic targets in obesity. Review. Neuropharmacology 58:2–16

    Article  PubMed  CAS  Google Scholar 

  • Schiöth HB, Muceniece R, Wikberg JE (1997) Characterization of the binding of MSH-B, HB-228, GHRP-6 and 153N-6 to the human melanocortin receptor subtypes. Neuropeptides 31:565–571

    Article  PubMed  Google Scholar 

  • Skibicka KP, Hansson C, Alvarez-Crespo M, Friberg PA, Dickson SL (2011a) Ghrelin directly targets the ventral tegmental area to increase food motivation. Neuroscience 180:129–137

    Article  PubMed  CAS  Google Scholar 

  • Skibicka KP, Hansson C, Egecioglu E, Dickson SL (2011b) Role of ghrelin in food reward: impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression. Addict Biol. doi:10.1111/j.1369-1600.2010.00294.x

  • Sofuoglu M, Mooney M, Kosten T, Waters A, Hashimoto K (2011) Minocycline attenuates subjective rewarding effects of dextroamphetamine in humans. Psychopharmacology (Berl) 213:61–68

    Article  CAS  Google Scholar 

  • Stoops WW (2008) Reinforcing effects of stimulants in humans: sensitivity of progressive-ratio schedules. Exp Clin Psychopharmacol 16:503–512

    Article  PubMed  Google Scholar 

  • Stoops WW, Lile JA, Glaser PE, Hays LR, Rush CR (2010) Intranasal cocaine functions as reinforcer on a progressive ratio schedule in humans. Eur J Pharmacol 644:101–105

    Article  PubMed  CAS  Google Scholar 

  • Takahashi N, Patel HR, Qi Y, Dushay J, Ahima RS (2002) Divergent effects of leptin in mice susceptible or resistant to obesity. Horm Metab Res 34:691–697

    Article  PubMed  CAS  Google Scholar 

  • Temple JL, Legierski CM, Giacomelli AM, Salvy SJ, Epstein LH (2008) Overweight children find food more reinforcing and consume more energy than do nonoverweight children. Am J Clin Nutr 87:1121–1127

    PubMed  CAS  Google Scholar 

  • Tessari M, Catalano A, Pellitteri M, Di Francesco C, Marini F, Gerrard PA, Heidbreder CA, Melotto S (2007) Correlation between serum ghrelin levels and cocaine-seeking behaviour triggered by cocaine-associated conditioned stimuli in rats. Addict Biol 12:22–29

    Article  PubMed  CAS  Google Scholar 

  • Tschöp M, Heiman ML (2001) Rodent obesity models: an overview. Exp Clin Endocrinol Diabetes 109:307–319

    Article  PubMed  Google Scholar 

  • Vlachou S, Markou A (2010) GABAB receptors in reward processes. Adv Pharmacol 58:315–371

    Article  PubMed  CAS  Google Scholar 

  • Volkow ND, O’Brien CP (2007) Issues for DSM-V: should obesity be included as a brain disorder? Am J Psychiatry 164:708–710

    Article  PubMed  Google Scholar 

  • Volkow ND, Wise RA (2005) How can drug addiction help us understand obesity? Nat Neurosci 8:555–560

    Article  PubMed  CAS  Google Scholar 

  • Volkow ND, Wang GJ, Fowler JS, Telang F (2008) Overlapping neuronal circuits in addiction and obesity: evidence of systems pathology. Philos Trans R Soc Lond B Biol Sci 363:3191–3200

    Article  PubMed  Google Scholar 

  • Vucetic Z, Reyes TM (2010) Central dopaminergic circuitry controlling food intake and reward: implications for the regulation of obesity. Wiley Interdiscip Rev Syst Biol Med 2:577–593

    PubMed  CAS  Google Scholar 

  • Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W, Netusil N, Fowler JS (2001) Brain dopamine and obesity. Lancet 357:354–357

    Article  PubMed  CAS  Google Scholar 

  • Wellman PJ, Davis KW, Nation JR (2005) Augmentation of cocaine hyperactivity in rats by systemic ghrelin. Regul Pept 125:151–154

    Article  PubMed  CAS  Google Scholar 

  • Yi CX, Heppner K, Tschöp MH (2011) Ghrelin in eating disorders. Mol Cell Endocrinol 340(1):29–34

    Article  PubMed  CAS  Google Scholar 

  • Yildiz BO, Suchard MA, Wong ML, McCann SM, Licinio J (2004) Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity. Proc Natl Acad Sci USA 101:10434–10439

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The work described herein was supported by Enterprise Ireland under Grant Number CC20080001. JFC and TGD are also supported in part by Science Foundation Ireland in the form of a centre grant (Alimentary Pharmabiotic Centre). The centre is also funded by GlaxoSmithKline. JFC is funded by European Community’s Seventh Framework Programme; Grant Number: FP7/2007-2013, Grant Agreement 201714.

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Authors and Affiliations

  1. Food for Health Ireland, University College Cork, Cork, Ireland

    Beate C. Finger, Timothy G. Dinan & John F. Cryan

  2. School of Pharmacy, University College Cork, Cork, Ireland

    Beate C. Finger

  3. Department of Psychiatry, University College Cork, Cork, Ireland

    Timothy G. Dinan

  4. Department of Anatomy, University College Cork, Western Road, Cork, Ireland

    John F. Cryan

  5. Laboratory of NeuroGastroenterology, Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland

    Timothy G. Dinan & John F. Cryan

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  1. Beate C. Finger
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  2. Timothy G. Dinan
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Correspondence to John F. Cryan.

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Finger, B.C., Dinan, T.G. & Cryan, J.F. Diet-induced obesity blunts the behavioural effects of ghrelin: studies in a mouse-progressive ratio task. Psychopharmacology 220, 173–181 (2012). https://doi.org/10.1007/s00213-011-2468-0

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