The GhsrQ343X allele favors the storage of fat by acting on nutrient partitioning

in Journal of Endocrinology
Authors:
Candice Marion Université de Paris, INSERM UMR S-1124, CNRS ERL3649, Paris, France

Search for other papers by Candice Marion in
Current site
Google Scholar
PubMed Close
,
Philippe Zizzari Université de Bordeaux, Neurocentre Magendie, INSERM U1215, Bordeaux, France

Search for other papers by Philippe Zizzari in
Current site
Google Scholar
PubMed Close
,
Raphael G P Denis Université de Paris, BFA, UMR 8251, CNRS, Paris, France

Search for other papers by Raphael G P Denis in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-7677-7460
,
Rim Hassouna Université de Paris, BFA, UMR 8251, CNRS, Paris, France

Search for other papers by Rim Hassouna in
Current site
Google Scholar
PubMed Close
,
Yacine Chebani Université de Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Laboratoire de Physiopathologie des Maladies Psychiatriques, Paris, France

Search for other papers by Yacine Chebani in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0003-2923-8760
,
Thierry Leste-Lasserre Université de Bordeaux, Neurocentre Magendie, INSERM U1215, Bordeaux, France

Search for other papers by Thierry Leste-Lasserre in
Current site
Google Scholar
PubMed Close
,
Hélène Doat Université de Bordeaux, Neurocentre Magendie, INSERM U1215, Bordeaux, France

Search for other papers by Hélène Doat in
Current site
Google Scholar
PubMed Close
,
Gwenaëlle Le Pen Université de Paris, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Laboratoire de Physiopathologie des Maladies Psychiatriques, Paris, France

Search for other papers by Gwenaëlle Le Pen in
Current site
Google Scholar
PubMed Close
,
Daniela Cota Université de Bordeaux, Neurocentre Magendie, INSERM U1215, Bordeaux, France

Search for other papers by Daniela Cota in
Current site
Google Scholar
PubMed Close
,
Florence Noble Université de Paris, INSERM UMR S-1124, CNRS ERL3649, Paris, France

Search for other papers by Florence Noble in
Current site
Google Scholar
PubMed Close
,
Serge Luquet Université de Paris, BFA, UMR 8251, CNRS, Paris, France

Search for other papers by Serge Luquet in
Current site
Google Scholar
PubMed Close
, and
Jacques Pantel Université de Paris, INSERM UMR S-1124, CNRS ERL3649, Paris, France

Search for other papers by Jacques Pantel in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-9015-6281

Correspondence should be addressed to J Pantel: jacques.pantel@inserm.fr

*(C Marion and P Zizzari contributed equally to this work)

DOI:
https://doi.org/10.1530/JOE-20-0576
Volume/Issue:
Volume 251: Issue 3
Article Type:
Research Article
Page Range:
181–194
Online Publication Date:
05 Nov 2021
Copyright:
© Society for Endocrinology 2021
Restricted access
Rent on DeepDyve

Sign up for journal news

The growth hormone secretagogue receptor (GHSR) mediates key properties of the gut hormone ghrelin on metabolism and behavior. Nevertheless, most recent observations also support that the GHSR is a constitutively active G protein-coupled receptor (GPCR) endowed with a sophisticated tuning involving a balance of endogenous ligands. Demonstrating the feasibility of shifting GHSR canonical signaling in vivo, we previously reported that a model with enhanced sensitivity to ghrelin (GhsrQ343X mutant rats) developed fat accumulation and glucose intolerance. Herein, we investigated the contribution of energy homeostasis to the onset of this phenotype, as well as behavioral responses to feeding or pharmacological challenges, by comparing GhsrM/M rats to WT littermate rats: (1) as freely behaving animals and (2) in feeding and locomotor paradigms. Herein, GhsrM/M rats showed enhanced locomotor response to a GHSR agonist while locomotor or anorexigenic responses to amphetamine or cabergoline (dopamine receptor 2 agonist), respectively, were preserved. Ad libitum fedGhsrM/M rats consumed and conditioned for sucrose similarly to littermate control rats . In calorie-restricted conditions, GhsrM/M rats retained food anticipatory activity and maintained better body weight and glycemia. Importantly, prior to fat accumulation, male GhsrM/M rats preferentially used carbohydrates as fuel substrate without alterations of energy intake, energy expenditure or physical activity and showed alterations of the GHSR system (i.e. enhanced ratio of GHSR hormones LEAP2: acyl-ghrelin and increased Ghsr expression in the hypothalamus). Overall, the present study provides proof for the concept that shifted GHSR signaling can specifically alter nutrient partitioning resulting in modified balance of carbohydrate/lipid utilization.

Supplementary Materials

    • Supplementary Figure 1: Glycemia fluctuations across feeding conditions. GhsrM/M and GhsrWT/WT male rats at 15 weeks of age (n=6-8/genotype). Data represent mean ± SEM.
    • Supplementary Figure 2: Diurnal and nocturnal meal patterns of Ghsr<sup>M/M</sup> and Ghsr<sup>WT/WT</sup> rats during ad libitum-feeding and refeeding. (A-B) Mean meal size during light (A) and dark (B) phases. (C-D) Total chow ingested during light (C) and dark (D) phases. (E-F) Total time spent eating during light (E) and dark (F) phases. (G-H) Number of meals during light (G) and dark (H) phases. (I-J) Mean meal duration in light (I) and dark (J) phases. (K-L) Inter-meal interval during light (K) and dark (L) phases. (M-N) Meal ingestion rate in light (M) and dark (N) phases (n=12/genotype). Data represent mean ± SEM.
    • Supplementary Figure 3: Decreased fat oxydation in Ghsr<sup>M/M</sup> rats across feeding conditions. (A-C) Daily pattern of fat oxydation during adlibitum feeding (A), 24h fasting (B) and 24h refeeding (C). Data represent mean ± SEM. (D) 24-h cumulative fat oxydation (n=12/genotype). Data were analyzed by 2-way ANOVA (E) Relative cumulative frequency curves for ad libitum fed Ghsr<sup>M/M</sup> and Ghsr<sup>WT/WT</sup> rats (dots) and curve fits (full lines) reveal higher EC50 (0.947 vs. 0.933) and a lower 1/Hill slope value (0.067 vs. 0.074) for GhsrM/M rats compared to GhsrWT/WT rats (F-test; p<0.001 for both parameters). * p<0.05; *** p<0.001.
    • Supplementary Materials
    • Supplementary Table 1. Primers sequence for real time PCR analysis
    • Supplementary Table 2. House keeping gene primers sequence for real time PCR analysis

Journal of Endocrinology is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 1335 102 0
PDF Downloads 230 17 0

 

  • Collapse
  • Expand
Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© Society for Endocrinology 2021
Page(s):
14
Article Type:
Research Article
Received Date:
22 Sep 2021
Accepted Date:
28 Sep 2021
Print Publication Date:
01 Dec 2021
Online Publication Date:
05 Nov 2021
Keywords:
ghrelin; GHSR; mutant rat; energy metabolism; food intake

  • Abizaid A, Liu ZW, Andrews ZB, Shanabrough M, Borok E, Elsworth JD, Roth RH, Sleeman MW, Picciotto MR & Tschop MH et al.2006 Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. Journal of Clinical Investigation 116 3229–3239. (https://doi.org/10.1172/JCI29867)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Al-Massadi O, Muller T, Tschop M, Dieguez C & Nogueiras R 2018 Ghrelin and LEAP-2: rivals in energy metabolism. Trends in Pharmacological Sciences 39 685–694. (https://doi.org/10.1016/j.tips.2018.06.004)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Anderberg RH, Hansson C, Fenander M, Richard JE, Dickson SL, Nissbrandt H, Bergquist F & Skibicka KP 2016 The stomach-derived hormone ghrelin increases impulsive behavior. Neuropsychopharmacology 41 1199–1209. (https://doi.org/10.1038/npp.2015.297)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Andrews ZB 2019 The next big LEAP2 understanding ghrelin function. Journal of Clinical Investigation 129 3542–3544. (https://doi.org/10.1172/JCI131023)

  • Blum ID, Patterson Z, Khazall R, Lamont EW, Sleeman MW, Horvath TL & Abizaid A 2009 Reduced anticipatory locomotor responses to scheduled meals in ghrelin receptor deficient mice. Neuroscience 164 351–359. (https://doi.org/10.1016/j.neuroscience.2009.08.009)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • 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. (https://doi.org/10.1210/en.2010-0556)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bulbul M, Babygirija R, Zheng J, Ludwig K, Xu H, Lazar J & Takahashi T 2011 Food intake and interdigestive gastrointestinal motility in ghrelin receptor mutant rats. Journal of Gastroenterology 46 469–478. (https://doi.org/10.1007/s00535-010-0366-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chebani Y, Marion C, Zizzari P, Chettab K, Pastor M, Korostelev M, Geny D, Epelbaum J, Tolle V & Morisset-Lopez S et al.2016 Enhanced responsiveness of GhsrQ343X rats to ghrelin results in enhanced adiposity without increased appetite. Science Signaling 9 ra39. (https://doi.org/10.1126/scisignal.aae0374)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Clegg DJ, Brown LM, Zigman JM, Kemp CJ, Strader AD, Benoit SC, Woods SC, Mangiaracina M & Geary N 2007 Estradiol-dependent decrease in the orexigenic potency of ghrelin in female rats. Diabetes 56 1051–1058. (https://doi.org/10.2337/db06-0015)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Clifford PS, Rodriguez J, Schul D, Hughes S, Kniffin T, Hart N, Eitan S, Brunel L, Fehrentz JA & Martinez J et al.2012 Attenuation of cocaine-induced locomotor sensitization in rats sustaining genetic or pharmacologic antagonism of ghrelin receptors. Addiction Biology 17 956–963. (https://doi.org/10.1111/j.1369-1600.2011.00339.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Currie PJ, Mirza A, Fuld R, Park D & Vasselli JR 2005 Ghrelin is an orexigenic and metabolic signaling peptide in the arcuate and paraventricular nuclei. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 289 R353–R358. (https://doi.org/10.1152/ajpregu.00756.2004)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Damian M, Marie J, Leyris JP, Fehrentz JA, Verdie P, Martinez J, Baneres JL & Mary S 2012 High constitutive activity is an intrinsic feature of ghrelin receptor protein: a study with a functional monomeric GHS-R1a receptor reconstituted in lipid discs. Journal of Biological Chemistry 287 3630–3641. (https://doi.org/10.1074/jbc.M111.288324)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Davis JF, Choi DL, Clegg DJ & Benoit SC 2011 Signaling through the ghrelin receptor modulates hippocampal function and meal anticipation in mice. Physiology and Behavior 103 39–43. (https://doi.org/10.1016/j.physbeh.2010.10.017)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Davis JF, Perello M, Choi DL, Magrisso IJ, Kirchner H, Pfluger PT, Tschoep M, Zigman JM & Benoit SC 2012 GOAT induced ghrelin acylation regulates hedonic feeding. Hormones and Behavior 62 598–604. (https://doi.org/10.1016/j.yhbeh.2012.08.009)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Disse E, Bussier AL, Veyrat-Durebex C, Deblon N, Pfluger PT, Tschop MH, Laville M & Rohner-Jeanrenaud F 2010 Peripheral ghrelin enhances sweet taste food consumption and preference, regardless of its caloric content. Physiology and Behavior 101 277–281. (https://doi.org/10.1016/j.physbeh.2010.05.017)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Galgani J & Ravussin E 2008 Energy metabolism, fuel selection and body weight regulation. International Journal of Obesity 32 (Supplement 7) S109–S119. (https://doi.org/10.1038/ijo.2008.246)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ge X, Yang H, Bednarek MA, Galon-Tilleman H, Chen P, Chen M, Lichtman JS, Wang Y, Dalmas O & Yin Y et al.2018 LEAP2 is an endogenous antagonist of the ghrelin receptor. Cell Metabolism 27 461 .e6–469.e6. (https://doi.org/10.1016/j.cmet.2017.10.016)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Holst B, Cygankiewicz A, Jensen TH, Ankersen M & Schwartz TW 2003 High constitutive signaling of the ghrelin receptor – identification of a potent inverse agonist. Molecular Endocrinology 17 2201–2210. (https://doi.org/10.1210/me.2003-0069)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC & Anderson J et al.1996 A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273 974–977. (https://doi.org/10.1126/science.273.5277.974)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Inoue H, Kangawa N, Kinouchi A, Sakamoto Y, Kimura C, Horikawa R, Shigematsu Y, Itakura M, Ogata T & Fujieda K et al.2011 Identification and functional analysis of novel human growth hormone secretagogue receptor (GHSR) gene mutations in Japanese subjects with short stature. Journal of Clinical Endocrinology and Metabolism 96 E373–E378. (https://doi.org/10.1210/jc.2010-1570)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jerlhag E, Egecioglu E, Dickson SL, Douhan A, Svensson L & Engel JA 2007 Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens. Addiction Biology 12 6–16. (https://doi.org/10.1111/j.1369-1600.2006.00041.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Joly-Amado A, Denis RG, Castel J, Lacombe A, Cansell C, Rouch C, Kassis N, Dairou J, Cani PD & Ventura-Clapier R et al.2012 Hypothalamic AgRP-neurons control peripheral substrate utilization and nutrient partitioning. EMBO Journal 31 4276–4288. (https://doi.org/10.1038/emboj.2012.250)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kanoski SE, Fortin SM, Ricks KM & Grill HJ 2013 Ghrelin signaling in the ventral hippocampus stimulates learned and motivational aspects of feeding via PI3K-Akt signaling. Biological Psychiatry 73 915–923. (https://doi.org/10.1016/j.biopsych.2012.07.002)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kern A, Albarran-Zeckler R, Walsh HE & Smith RG 2012 Apo-ghrelin receptor forms heteromers with DRD2 in hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism. Neuron 73 317–332. (https://doi.org/10.1016/j.neuron.2011.10.038)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H & Kangawa K 1999 Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402 656–660. (https://doi.org/10.1038/45230)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Laermans J, Vancleef L, Tack J & Depoortere I 2015 Role of the clock gene Bmal1 and the gastric ghrelin-secreting cell in the circadian regulation of the ghrelin-GOAT system. Scientific Reports 5 16748. (https://doi.org/10.1038/srep16748)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lamont EW, Patterson Z, Rodrigues T, Vallejos O, Blum ID & Abizaid A 2012 Ghrelin-deficient mice have fewer orexin cells and reduced cFOS expression in the mesolimbic dopamine pathway under a restricted feeding paradigm. Neuroscience 218 12–19. (https://doi.org/10.1016/j.neuroscience.2012.05.046)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Landgren S, Simms JA, Thelle DS, Strandhagen E, Bartlett SE, Engel JA & Jerlhag E 2011 The ghrelin signalling system is involved in the consumption of sweets. PLoS ONE 6 e18170. (https://doi.org/10.1371/journal.pone.0018170)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • LeSauter J, Hoque N, Weintraub M, Pfaff DW & Silver R 2009 Stomach ghrelin-secreting cells as food-entrainable circadian clocks. PNAS 106 13582–13587. (https://doi.org/10.1073/pnas.0906426106)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lin L, Saha PK, Ma X, Henshaw IO, Shao L, Chang BH, Buras ED, Tong Q, Chan L & McGuinness OP et al.2011 Ablation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues. Aging Cell 10 996–1010. (https://doi.org/10.1111/j.1474-9726.2011.00740.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lockie SH, Dinan T, Lawrence AJ, Spencer SJ & Andrews ZB 2015 Diet-induced obesity causes ghrelin resistance in reward processing tasks. Psychoneuroendocrinology 62 114–120. (https://doi.org/10.1016/j.psyneuen.2015.08.004)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ma X, Lin L, Qin G, Lu X, Fiorotto M, Dixit VD & Sun Y 2011 Ablations of ghrelin and ghrelin receptor exhibit differential metabolic phenotypes and thermogenic capacity during aging. PLoS ONE 6 e16391. (https://doi.org/10.1371/journal.pone.0016391)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • MacKay H, Charbonneau VR, St-Onge V, Murray E, Watts A, Wellman MK & Abizaid A 2016 Rats with a truncated ghrelin receptor (GHSR) do not respond to ghrelin, and show reduced intake of palatable, high-calorie food. Physiology and Behavior 163 88–96. (https://doi.org/10.1016/j.physbeh.2016.04.048)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mani BK & Zigman JM 2017 Ghrelin as a survival hormone. Trends in Endocrinology and Metabolism 28 843–854. (https://doi.org/10.1016/j.tem.2017.10.001)

  • Mani BK, Puzziferri N, He Z, Rodriguez JA, Osborne-Lawrence S, Metzger NP, Chhina N, Gaylinn B, Thorner MO & Thomas EL et al.2019 LEAP2 changes with body mass and food intake in humans and mice. Journal of Clinical Investigation 129 3909–3923. (https://doi.org/10.1172/JCI125332)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • M’Kadmi C, Cabral A, Barrile F, Giribaldi J, Cantel S, Damian M, Mary S, Denoyelle S, Dutertre S & Peraldi-Roux S et al.2019 N-terminal liver-expressed antimicrobial peptide 2 (LEAP2) region exhibits inverse agonist activity toward the ghrelin receptor. Journal of Medicinal Chemistry 62 965–973. (https://doi.org/10.1021/acs.jmedchem.8b01644)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Muller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, Batterham RL, Benoit SC, Bowers CY & Broglio F et al.2015 Ghrelin. Molecular Metabolism 4 437–460. (https://doi.org/10.1016/j.molmet.2015.03.005)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K & Matsukura S 2001 A role for ghrelin in the central regulation of feeding. Nature 409 194–198. (https://doi.org/10.1038/35051587)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Naleid AM, Grace MK, Cummings DE & Levine AS 2005 Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens. Peptides 26 2274–2279. (https://doi.org/10.1016/j.peptides.2005.04.025)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pantel J, Legendre M, Cabrol S, Hilal L, Hajaji Y, Morisset S, Nivot S, Vie-Luton MP, Grouselle D & de Kerdanet M et al.2006 Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. Journal of Clinical Investigation 116 760–768. (https://doi.org/10.1172/JCI25303)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pantel J, Legendre M, Nivot S, Morisset S, Vie-Luton MP, le Bouc Y, Epelbaum J & Amselem S 2009 Recessive isolated growth hormone deficiency and mutations in the ghrelin receptor. Journal of Clinical Endocrinology and Metabolism 94 4334–4341. (https://doi.org/10.1210/jc.2009-1327)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • 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. Biological Psychiatry 67 880–886. (https://doi.org/10.1016/j.biopsych.2009.10.030)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Perello M, Cabral A, Cornejo MP, De Francesco PN, Fernandez G & Uriarte M 2019 Brain accessibility delineates the central effects of circulating ghrelin. Journal of Neuroendocrinology 31 e12677. (https://doi.org/10.1111/jne.12677)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pugliese-Pires P, Fortin JP, Arthur T, Latronico AC, de Mendonca BB, Villares SM, Arnhold IJ, Kopin AS & Jorge AA 2011 Novel inactivating mutations in the growth hormone secretatogue receptor gene (GHSR) in patients with constitutional delay of growth and puberty. European Journal of Endocrinology 165 233–241.(https://doi.org/10.1530/EJE-11-0168)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Riachi M, Himms-Hagen J & Harper ME 2004 Percent relative cumulative frequency analysis in indirect calorimetry: application to studies of transgenic mice. Canadian Journal of Physiology and Pharmacology 82 1075–1083. (https://doi.org/10.1139/y04-117)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Skibicka KP, Hansson C, Alvarez-Crespo M, Friberg PA & Dickson SL 2011 Ghrelin directly targets the ventral tegmental area to increase food motivation. Neuroscience 180 129–137. (https://doi.org/10.1016/j.neuroscience.2011.02.016)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Skibicka KP, Hansson C, Egecioglu E & Dickson SL 2012 Role of ghrelin in food reward: impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression. Addiction Biology 17 95–107. (https://doi.org/10.1111/j.1369-1600.2010.00294.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Theander-Carrillo C, Wiedmer P, Cettour-Rose P, Nogueiras R, Perez-Tilve D, Pfluger P, Castaneda TR, Muzzin P, Schurmann A & Szanto I et al.2006 Ghrelin action in the brain controls adipocyte metabolism. Journal of Clinical Investigation 116 1983–1993. (https://doi.org/10.1172/JCI25811)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tordoff MG, Alarcon LK & Lawler MP 2008 Preferences of 14 rat strains for 17 taste compounds. Physiology and Behavior 95 308–332. (https://doi.org/10.1016/j.physbeh.2008.06.010)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Torz LJ, Osborne-Lawrence S, Rodriguez J, He Z, Cornejo MP, Mustafa ER, Jin C, Petersen N, Hedegaard MA & Nybo M et al.2020 Metabolic insights from a GHSR-A203E mutant mouse model. Molecular Metabolism 39 101004. (https://doi.org/10.1016/j.molmet.2020.101004)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tschop M, Smiley DL & Heiman ML 2000 Ghrelin induces adiposity in rodents. Nature 407 908–913. (https://doi.org/10.1038/35038090)

  • Wang Q, Liu C, Uchida A, Chuang JC, Walker A, Liu T, Osborne-Lawrence S, Mason BL, Mosher C & Berglund ED et al.2014 Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin. Molecular Metabolism 3 64–72. (https://doi.org/10.1016/j.molmet.2013.10.001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zigman JM, Jones JE, Lee CE, Saper CB & Elmquist JK 2006 Expression of ghrelin receptor mRNA in the rat and the mouse brain. Journal of Comparative Neurology 494 528–548. (https://doi.org/10.1002/cne.20823)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zigman JM, Bouret SG & Andrews ZB 2016 Obesity impairs the action of the neuroendocrine ghrelin system. Trends in Endocrinology and Metabolism 27 54–63. (https://doi.org/10.1016/j.tem.2015.09.010)

    • PubMed
    • Search Google Scholar
    • Export Citation