Anche se la potente efficacia oressigena della grelina non è ancora presente nelle prime 2-3 settimane postnatali in topi o ratti [120,121], la grelina nei primi mesi di vita post- natale ha un effetto di sviluppo duraturo sui circuiti ipotalamici coinvolti nell' omeostasi energetica, ed influenza il peso corporeo in età adulta [122]. I topi neonati iniettati con un composto anti-grelina tra il quarto (P4) ed il ventiduesimo giorno di vita (P22) registrano una maggiore densità di α-MSH- e AgRP- contenenti assoni che innervano il nucleo paraventricolare. Queste alterazioni strutturali sono accompagnate da difetti metabolici a lungo termine, compreso un elevato peso corporeo, massa grassa, ed iperglicemia. Al contrario, il trattamento di topi adulti con il composto di anti-grelina è relativamente inefficace perché non aumenta la densità delle proiezioni nel nucleo arcuato relative ai topi di controllo. Le iniezioni croniche di grelina esogena in topi neonati selvatici tra P4 e P 12 dimostrano una marcata riduzione della densità di fibre del nucleo arcuato che innervano il nucleo paraventricolare.
Questi risultati suggeriscono che l'attività di sviluppo esercitata dalla grelina sulle proiezioni arcuate è limitata ad una critica finestra neonatale. Curiosamente, la densità delle proiezioni assonali del nucleo arcuato è elevata anche nei cuccioli di topo grelina- KO (knockout), ma questo diventa normale negli animali adulti, indicando che le proiezioni arcuate continuano ad essere plastiche non solo nelle prime fasi di sviluppo, ma anche durante il periodo post svezzamento in risposta agli eventi geneticamente programmati. Il sito di azione per gli effetti di sviluppo da parte della grelina include probabilmente un'azione diretta sui neuroni arcuati. Il nucleo arcuato in sviluppo contiene i più alti livelli di espressione di GHSR e l'esposizione diretta di espianti isolati dall' arcuato alla grelina rende insensibili l'estensione del neurone.
Durante la vita neonatale, la grelina appare quindi agire come segnale inibitorio, influenzando eventi chiave evolutivi nelle stesse vie ipotalamiche in cui conergono i segnali della grelina nei topi maturi. Così, mentre l' obesità ostacola le azioni della
47
grelina in età adulta, gli effetti della grelina postnatale possono anche contrastare l' obesità in età adulta [122].
48
FIGURE
FIGURA 1: L'obesità indotta dalla dieta (DIO) sopprime il sistema Neuroendocrino/grelina
Durante la DIO le cellule secernenti grelina nello stomaco non rispondono più all'azione stimolatoria della Norepinefrina , ne tanto meno all'azione inibitoria del glucosio. Questo porta ad avere livelli più bassi del normale di grelina plasmatica e a delle modifiche postprandiali di deterioramento dei livelli di grelina plasmatica nei topi DIO. Oltre ad alterare la secrezione di grelina, la DIO attenua il trasporto della grelina attraverso la BEE ed altera entrambi i circuiti neuronali NPY e AgRP nel nucleo arcuato ipotalamico (ARC). Con il nucleo arcuato ipotalamico, la grelina fallisce l'attivazione dei neuroni NPY/AgRP, fallisce nell'incremento dell'espressione genica per NPY/AgRP o della secrezione di tali peptidi ed in ultimo fallisce nell'aumento dell'assunzione di cibo nei topi soggetti alla DIO. Recenti studi suggeriscono che la DIO provoca resistenza alla grelina nei circuiti neuronali che regolano i comportamenti motivazionali, sebbene l'origine di questi circuiti rimanga ancora poco conosciuta. Ed è tutt'ora incompreso se la DIO causi resistenza alla grelina nei circuiti deputati alla regolazione di stress e ansia o della produzione di glucosio epatico.
49
FIGURA 2: Un modello teorico che illustra l'ipotesi della resistenza alla grelina La perdita di peso indotta dalla dieta ripristina la sensibilità all'ormone grelina, ed i livelli di grelina nel plasma sono elevati nei soggetti che seguono una dieta per ridurre il peso corporeo.
Noi ipotizziamo che la resistenza alla grelina sia un meccanismo fisiologico atto a proteggere un punto di alto peso corporeo raggiunto con l' obesità dieta-indotta (DIO). Il cervello percepisce la riduzione della disponibilità di cibo o la rapida perdita di peso durante una dieta dimagrante come una forma di bilancio energetico negativo, e risponde di conseguenza coinvolgendo il sistema neuroendocrino/grelina affinchè stimoli ed aumenti l'assunzione di cibo e l'aspetto motivazionale per prevenire un ulteriore calo ponderale.
Da un punto di vista evolutivo questo meccanismo abilita la difesa di un peso corporeo raggiunto durante i periodi di relativa abbondanza e reperibilità di cibo.
50
BIBLIOGRAFIA
[1] Briggs, , D.I and Andrews, Z.B., 2011. Metabolic status regulates ghrelin function on energy homeostasis. Neuroendocrinology 93, 48-57
[2] Muller, T.D., et al., 2015. Ghrelin. Mol. Metab. 4, 437-470
[3] Barnett, B.P., et al., 2010. Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science 330, 1689-1692
[4] Briggs, D.I., et al., 2013. Calorie-restricted weight loss reversed high-fat diet- induced ghrelin resistance, which contributes to rebound weight gain in a ghrelin- dependent manner. Endocrinology 154, 709-717
51
[5] Zigman, J.M., et al., 2005. Mice lacking ghrelin receptors resist the development of diet-induced obesity. J.Clin. Invest. 115, 3564-3572
[6] Zorrilla, E.P., et al., 2006. Vaccination against weight gain. Proc. Natl. Acad. Sci.
U.S.A 103, 13226-13231
[7] http://www.nutrizione-salute.com/ Perfezionamento in Biochimica e biologia molecolare
[8] World Health Organization. Fact sheet: obesity e overweight. http://www.who.int/dietphysicalactivity/publications/facts/obesity/en/
[9] MH Tschoep (Ed) Obesitext. http://www.Endotext.org
[10] Moran TH. Gut peptides in the control of food intake. Int. J. Obes. (Lond). 2009; 33 Suppl 1:S7-10.
[11] Kadowaki T., et al. Adiponectin and adiponectin receptors.
Endocr. Rev. 2005; 26(3):439-451.
[12] Oh D.K., et al. Adiponectin in health and disease. Diabetes Obes. Metab. 2007; 9(3):282-289.
[13] Patti M.E., et al. The role of mitochondria in the pathogenesis of type 2 diabetes.
Endocr. Rev. 2010; 31:364-395.
[14] Sparks, J.D., et al. Insulin regulation of triacylglycerol-rich lipoprotein synthesis and secretion. Biochimica et Biophysica Acta. 994; 1215, 9-321.
52
[15] Kelley, D.E., et al. Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss. Am. J. Physiol. Endocrinol. Metab. 1999; 277: E1130–E1141.
[16] Zurlo, F., et al. Low ratio of fat to carbohydrate oxidation as predictor of weight gain: study of 24-h RQ. Am. J. Physiol. Endocrinol. Metab. 1990; 259, E650–E657.
[17] Krief, S., et al. Tissue distribution of beta 3-adrenergic receptor mRNA in man.
J. Clin. Invest. 1993; 91(1):344-9
[18] Van Baak, M.A. The peripheral sympathetic nervous system in human obesity.
Obes. Rev. 2001; 2(1), 3-14.
[19] Bray GA. Sympathetic nervous system, adrenergic receptors, and obesity.
The Journal of Laboratory and Clinical Medicine. 1999; 134, 4-6.
[20] Grujic, D. et al. Beta3-adrenergic receptors on white and brown adipocytes mediate beta3- selective agonist-induced effects on energy expenditure, insulin secretion, and food intake. A study using transgenic and gene knockout mice.
J. Biol. Chem. 1997; 272, 17686-93.
[21] Cannon, B., et al. Brown adipose tissue: function and physiological significance.
Physiol. Rev. 2004; 84, 277-359.
[22] Kojima, M. et al., 1999. Ghrelin is a gut-hormone-releasing acylated peptide from stomach. Nature 402, 656-660.
[23] Gutierrez, J.A. et al., 2008. Ghrelin octanoylation mediated by an orphan lipid transferase. Proc. Natl. Acad. Sci. U.S.A 105, 6320-6325
53
[24] Yang, J., et al. 2008. Identification of the Acyltransferas that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 132, 387-396
[25] Howard, A.D., et al. 1996. A Receptor in pituitary and hipothalamus that functions in growth hormone release. Science 273, 974-977
[26] Delhanty, P.J. et al. 2013. Des-acyl ghrelin analogs prevent high-fat-diet-induced dysregulation of glucose homeostasis. FASEB J. 27, 1690-1700
[27] Ku, J.M. et al. 2015. Ghrelin-related peptides exert protective effects in the cerebral circulation of male mice through a nonclassical ghrelin receptor(s).
Endocrinology 1, 280-290
[28] Cummings, D.E., 2006. Ghrelin and the short- and long-term regulation of appetite and body weight. Physiol. Behav. 89, 71-84
[29] Foster-Schubert, K.E. et al. 2008. Acyl and total ghrelin are suppressed strongly by ingested proteins, weakly by lipids, and biphasically by carbohydrates. J. Clin.
Endocrinol. Metab. 93, 1971-1979
[30] Tschop, M., et al., 2001. Post-prandial decrease of circulating human ghrelin levels. J. Endocrinol. Invest. 24, RC19-RC21
[31] Briggs, D.I., et al., 2011. Diet-induced obesity attenuates fasting-induced hyperphagia.
J. Neuroendocrinol. 23, 620-626
[32] Tschop, M. et al. 2001. Circulating ghrelin levels are decreased in human obesity.
54
[33] Zhao, T.J., et al. 2010. Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice.
Proc. Natl. Acad. Sci. U.S.A 107, 7467-7472
[34] Zhao, T.J., et al. 2010. Ghrelin secretion stimulated by β1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice.
Proc. Natl. Acad. Sci. U.S.A 107, 15868-15873
[35] Hansen, T.K., et al. 2002. Weight loss increases circulating levels of ghrelin in human obesity. Clin. Endocrinol. (Oxf.) 56, 203-206
[36] Uchida, A., et al., 2014. Altered ghrelin secretion in mice in response to diet- induced obesity and Roux-en-Y gastric bypass. Mol. Metab. 3, 717-730
[37] Tymitz, K., et al., 2011. Changes in ghrelin levels following bariatric surgery: review of the literature. Obes. Surg. 21, 125-130
[38] Bowers, C.Y., Momany, F., Reynolds, G.A., Chang, D., Hong, A., Chang, K., 1980. Structure-activity relationships of a synthetic pentapeptide that specifically releases growth hormone in vitro. Endocrinology 106, 663-667
[39] Momany, F.A., Bowers, C.Y., Reynolds, G.A., Chang, D., Hong, A., Newlander, K., 1981. Design, synthesis, and biological activity of peptides which release growth
hormone in vitro. Endocrinology 108, 31-39
[40] Smith, R.G., Van der Ploeg, L.H., Howard, A.D., Feighner, S.D., Cheng, K., Hickey, G.J., et al., 1997. Peptidomimetic regulation of growth hormone secretion. Endocrine reviews 18, 621-645
55
hormone-releasing peptide activates hypothalamic arcuate neurons. Neuroscience 53, 303-306
[42] Dickson, S.L., Luckman, S.M., 1997. Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing factor neurons in the rat arcuate nucleus following systemic injection of the GH secretagogue, GH-releasing peptide-6.
Endocrinology 138, 771-777
[43] Blake, A.D., Smith, R.G., 1991. Desensitization studies using perifused rat pituitary cells show that growth hormone-releasing hormone and His-D-Trp-Ala-Trp-D-Phe-Lys- NH2 stimulate growth hormone release through distinct receptor sites.
The Journal of Endocrinology 129, 11-19
[44] Bowers, C.Y., Reynolds, G.A., Durham, D., Barrera, C.M., Pezzoli, S.S., Thorner, M.O., 1990. Growth hormone (GH)-releaseing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone. The Journal of Clinical
Endocrinology and Metabolism 70, 975-982
[45] Cheng, K., Chan, W.W., Butler, B., Barreto Jr., A., Smith, R.G, 1991. Evidence for a role of protein Kinase-C in His-D-Trp-Ala-Trp-D-Phe-Lys-NH2-induced growth hormone release from rat primary pituitary cells. Endocrinology 129, 3337-3342
[46] Gnanapavan, S., Kola, B., Bustin, S.A., Morris, D.G., McGee, P., Fairclough, P., et
al.,2002. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor,
GHS-R, in humans. The Journal of Clinical Endocrinology and Metabolism. 87, 2988
[47] Jiang, H., Betancourt, L., Smith, R.G., 2006. Ghrelin amplifies dopamine signaling by cross talk involving formation of growth hormone secretagogue receptor/dopamine receptor subtype 1 heterodimers. Molecular Endocrinology 20, 1772-1785
56
[48] Leung, P.K., Chow, K.B., Lau, P.N., Chu, K.M., Chan, C.B, Cheng, C.H., et al., 2007. The truncated ghrelin receptor polypeptide (GHS-R1b) acts as a dominant- negative mutant of the ghrelin receptor. Cellular Signalling 19, 1011-1022
[49] Guan, X.M, Yu, H., Palyha, O.C., McKee, K.K., Feighner, S.D., Sirinathsinghji, D.J., et al., 1997. Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Research Molecular Brain Research 48, 23-29
[50] Willesen, M.G., Kristensen, P., Romer, J., 1999. Colocalization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat.
Neuroendocrinology 70, 306-316
[51] Zangh, J.V., Ren, P.G., Avsian-Kretchmer, O., Luo, C.W., Rauch, R., Klein, C., et
al., 2005. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on
food intake. Science 310, 996-999
[52] Depoortere, I., 2012. GI functions of GPR39: novel biology. Current Opinion in Pharmacology 12, 647-652
[53] Sakata, I., Yang, J., Lee, C.E, Osborne-Lawrence, S., Rovinsky, S.A., Elmquist, J.K., et al., 2009. Colocalization of ghrelin O-acyltransferase and ghrelin in gastric mucosal cells.
American Journal of Physiology Endocrinology and Metabolism 297, E134-E141
[54] Lim, C.T., Kola, B., Grossman, A., Korbonits, M., 2011. The expression of ghrelin O-acyltransferase (GOAT) in human tissues. Endocrine Journal 58, 707-710
[55] Zhao, T.J., Liang, G., Li, R.L., Xie, X., Sleeman, M.W, Murphy, A.J., et al., 2010. Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of
57
calorie-restricted mice. Proceedings of the National Academy of Sciences of the United
States of America 107, 7467-7472
[56] Kirchner, H., Gutierrez, J.A., Solenberg, P.J, Pfluger, P.T., Czyzyk, T.A., Willency, J.A., et al., 2009. GOAT links dietary lipids with the endocrine control of energy balance.
Nature Medicine 15, 741-745
[57] Yang, J., Zhao, T.J., Goldstein, J.L., Brown, M.S., 2008. Inhibition of ghrelin O- acyltransferase (GOAT) by octanoylated pentapeptides. Proceedings of the National
Academy of Sciences of the United States of America 105, 10750- 10755
[58] Nishi, Y., Hiejima, H., Hosoda, H., Kaiya, H., Mori, K., Fukue, Y., et al., 2005. Ingested medium-chain fatty acids are directly utilized for the acyl modification of ghrelin. Endocrinology 146, 2255-2264
[59] Sakata, I., Nakamura, K., Yamazaki, M., Matsubara, M., Hayashi, Y., Kangawa, K.,
et al., 2002. Ghrelin-producing cells exist as two types of cells, closed and opened-type
cells, in the rat gastrointestinal tract. Peptides 23, 531-536
[60] Armand, M., Hamosh, M., Mehta, N.R., Angelus, P.A., Philpott, J.R., Henderson, T.R., et al., 1996. Effect of human milk or formula on gastric function and fat digestion in the premature infant. Pediatric Research 40, 429-437
[61] Heppner, K.M., Chaudhary, N., Muller, T.D., Kirchner, H., Habegger, K.M., Ottaway, N., et al., 2012. Acylation type determines ghrelin's effects on energy homeostasis in rodents.
Endocrinology 153, 4687-4695
58 2009.
Ghrelin O-acyltransferase (GOAT) has a preference for n-hexanoil-CoA over n-
octanoyl-Coa as an acyl donor. Biochemical and Biophysical research communications 386, 153-158
[63] Janssen, S., Laermans, J., Iwakura, H., Tack, J., Depoortere, I., 2012. Sensing of fatty acids for octanoylation of ghrelin involves a gustatory G-protein. PloS One 7, e40168
[64] Lu, X., et al., 2012. Postprandial inhibition of gastric ghrelin secretion by long- chain fatty acid through GPR120 in isolated gastric ghrelin cells and mice. Am. J.,
Physiol. Gastrointest. Liver Physiol. 303, G367-G376
[65] Sakata, I. et al.,2009. Characterization of a novel ghrelin cell reporter mouse.
Regul. Pept. 155, 91-98
[66] Sakata, I. et al., 2012. Glucose-mediated control of ghrelin release from primary cultures of gastric mucosal cells. Am, J., Physiol. Endocrino. Metab. 302, E1300- E1310
[67] Gagnon, J., and Anini, Y., 2012. Insulin and norepinephrine regulate ghrelin secretion from a rat primary stomach cell culture. Endocrinology 153, 3646-3656
[68] Iwakura, H., et al., 2010. Establishment of a novel ghrelin-producing cell line.
Endocrinology 151, 2940-2945
[69] Engelstoft, M.S., et al., 2013. Seven transmembrane G protein-coupled receptor repertoire of gatsric ghrelin cells. Mol. Metab. 2, 376-392
59
[70] Al Massadi, O., et al., 2010. Macronutrients act directly on the stomach to regulate gastric ghrelin release. J. Endocrinol. Invest. 33, 599-602
[71] Seoane, L.M., et al., 2007. Growth hormone and somatostatin directly inhibit gastric ghrelin secretion. An in vitro organ culture system. Journal of Endocrinological
Investigation 30, RC22-RC25
[72] Iwakura, H., et al., 2011. Oxytocin and dopamine stimulate ghrelin secretion by the ghrelin-producing cell line, MGN3-1 in vitro. Endocrinology 152, 2619-2625
[73] de la Cour, C.D., et al., 2007. Secretion of ghrelin from rat stomach ghrelin cells in response to local microinfusion of candidate messenger compounds: a microdialysis study.
Regul. Pept. 143, 118-126
[74] Williams, D.L., Cummings, D.E., Grill, H.J., Kaplan, J.M., 2003. Meal-related ghrelin suppression requires postgastric feedback. Endocrinology 144, 2765-2767
[75] English, P.J., et al., 2002. Food fails to suppress ghrelin levels in obese humans.
J. Clin. Endocrinol. Metab. 87, 2984
[76] Abdemur, A., et al., 2014. Morphology, localization, and patterns of ghrelin- producing cells in stomachs of a morbidly obese population. Surg. Laparosc. Endosc.
Percutan. Tech.
24, 122-126
[77] Briggs, D.I., et al., 2010. Diet-induced obesity causes ghrelin resistance in arcuate NPY/AgRP neurons. Endocrinology 151, 4745-4755
60 lowering free radicals. Nature 454, 846-851
[79] Nakazato, M., et al., 2001. A role for ghrelin in the central regulation of feeding.
Nature 409, 194-198
[80] Andrews, Z.B., et al., 2011. Central mechanisms involved in the orexigenic actions of ghrelin. Peptides 32, 2248-2255
[81] Abizaid, A., et al., 2006. Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J. Clin. Invest. 116, 3229-3239
[82] Chuang, J.C., et al., 2011. Ghrelin mediates stress-induced food-reward behaviour in mice. J. Clin. Invest. 121, 2684-2692
[83] Perello, M., et al., 2010. Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner. Biol. Psychiatry 67, 880-886
[84] Hewson, A.K., et al., 2002. The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic. Diabetes 51, 3412-3419
[85] Scott, V., et al., 2007. Rapid changes in the sensitivity of arcuate nucleus neurons to central ghrelin in relation to feeding status. Physiol. Behav. 90, 180-185
[86] Briggs, D.I., et al., 2014. Evidence that diet-induced hyperleptinemia, but not hypotalamic gliosis, causes ghrelin resistance in NPY/AgRP neurons of male mice.
Endocrinology 155, 2411-2422
[87] Kohno, D., et al., 2007. Leptin suppresses ghrelin-induced activation of
61
phosphodiesterase 3-mediated pathway. Endocrinology 148, 2251-2263
[88] Perello, M., et al., 2012. Functional implications of limited leptin receptor and ghrelin receptor coexpression in the brain. J. Comp. Neurol. 520, 281-294
[89] Schwartz, M.W., et al., 1992. Inhibition of hypotalamic neuropeptide Y gene expression by insulin. Endocrinology 130, 3608-3616
[90] Konner, A.C., et al., 2007. Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metab. 5, 438-449
[91] Pardini, A.W., et al., 2006. Distribution of insulin receptor substrate-2 in brain areas involved in energy homeostasis. Brain Res. 1112, 169-178
[92] Stark, R., et al.,2015. Acyl ghrelin acts in the brain to control liver function and peripheral glucose homeostasis in male mice. Endocrinology 156, 858-868
[93] Li, R.L., et al., 2012. Profound hypoglycemia in starved, ghrelin-deficient mice is caused by decreased gluconeogenesis and reversed by lactate or fatty acids.
J. Biol. Chem. 287, 17942-17950
[94] McFarlane, M.R., et al., 2014. Induced ablation of ghrelin cells in adult mice does not decrease food intake, body weight, or response to high-fat diet. Cell Metab. 20, 54- 60
[95] Schaeffer, M., et al., 2013. Rapid sensing of circulating ghrelin by hypotalamic appetite-modifying neurons. Proc. Natl. Acad. Sci. U.S.A 110, 1512-1517
[96] Banks, W.A., et al., 2008. Effects of triglycerides, obesity, and starvation on ghrelin transport across the blood-brain barrier. Peptides 29, 2061-2065
62
[97] Perreault, M., et al., 2004. Resistance to the orexigenic effect of ghrelin in dietary- induced obesity in mice: reversal upon weight loss. Int. J. Obes. Relat. Metab. Disord. 28,879-885
[98] Martin, N.M., et al., 2004. Pre-obese and obese agouti mice are sensitive to anorectic effects of peptide YY (3-36) but resistant to ghrelin. Int. J. Obes. Relat.
Metab. Disord.
28, 886-893
[99] Gardiner, J.V., et al., 2010. The hyperphagic effect of ghrelin is inhibited in mice by a diet high in fat. Gastroenterology 138, 2468-2476
[100] Naznin, F., et al., 2015. Diet-induced obesity causes peripheral and central ghrelin resistance by promoting inflammation. J. Endocrinol. 226, 81-92
[101] Kim, M.S., et al., 2006. Role of hypothalamic Foxo1 in the regulation of food intake and energy homeostasis. Nat. Neurosci. 9, 901-906
[102] Thaler, J.P., et al., 2012. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122, 153-162
[103] Perello, M., and Zigman, J.M., 2012. The role of ghrelin in reward-based eating.
Biol. Psychiatry 72, 347-353
[104] Perello, M., and Dickson, S.L., 2015. Ghrelin signalling on food reward: a salient link between the gut and the mesolimbic system. J. Neuroendocrinol. 27, 424-434
[105] Lockie, S.H., et al., 2015. Diet-induced obesity causes ghrelin resistance in reward processing tasks. Psychoneuroendocrinology 62, 114-120
63
[106] Finger, B.C., et al., 2012. Diet-induced obesity blunts the behavioural effects of ghrelin :studies in a mouse-progressive ratio task. Psychopharmacology 220, 173-181
[107] Dietrich, M.O., et al., 2012. AgRP neurons regulate development of dopamine neuronal plasticity and nonfood-associated behaviors. Nat. Neurosci. 15, 1108-1110
[108] Krashes, M.J., et al., 2011. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J. Clin. Invest. 121, 1424-1428
[109] Collden, G., et al., 2015. Neonatal overnutrition causes early alterations in the central response to peripheral ghrelin. Mol. Metab. 4, 15-24
[110] Borer, K.T., et al., 2009. Appetite responds to changes in meal content, whereas ghrelin, leptin and insulin track changes in energy availability. J. Clin. Endocrinol.
Metab.
94, 2290-2298
[111] Leidy, H.J., et al., 2004. Circulating ghrelin is sensitive to changes in body weight during a diet and exercise program in normal-weight young women. J. Clin.
Endocrinol. Metab. 89, 2659-2664
[112] Sumithran, P., et al., 2011. Long-term persistence of hormonal adaptations to weight loss. N. Engl. J. Med. 365, 1597-1604
[113] Hooper, L.E., et al., 2010. Frequent intentional weight loss is associated with higher ghrelin and lower glucose and androgen levels in postmenopausal women.
Nutr. Res. 30, 163-170
64
sniffing in rodents and humans. J. Neurosci. 31, 5841-5846
[115] Keen-Rhinehart, E. and Bartness, T.J., 2007. MTII attenuates ghrelin- and food deprivation-induced increases in food hoarding and food intake. Horm. Behav. 52, 612- 620
[116] Diano, S., et al., 2006. Ghrelin controls Hippocampal spine synapse density and memory performance. Nat. Neurosci. 9, 381-388
[117] Lutter, M., et al., 2008. The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat. Neurosci. 11, 752-753
[118] Spencer, S.J., et al., 2012. Ghrelin regulates the hypothalamic-pituitary-adrenal axis and restricts anxiety after acute stress. Biol. Psychiatry 72, 457-465
[119] Skibicka, K.P., et al., 2011. Ghrelin directly targets the ventral tegmental area to increase food motivation. Neuroscience 180, 129-137
[120] Piao, H., et al., 2008. Ghrelin stimulates milk intake by affecting adult type feeding behaviour in postnatal rats. J. Neuroendocrinol. 20, 330-334
[121] Steculorum, S.M., and Bouret, S.G., 2011. Developmental effects of ghrelin.
Peptides 32, 2362-2366
[122] Steculorum, S.M., et al., 2025. Neonatal ghrelin programs development of hypothalamic feeding circuits. J. Clin. Invest. 125, 846-858
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RINGRAZIAMENTI
E pensare che fino a poco tempo fa vedevo lontanissimo il traguardo. Quasi irraggiungibile. E adesso riuscire a concludere con qualche bella parola che esprima tutte le mie sensazioni questo percorso diventa la parte più difficile della mia tesi. Sono stati anni difficili per me quelli dell’Università. Belli, perché hanno accompagnato l’ardore della giovinezza, le avventure più pazze, le amicizie inaspettate, nate nelle aule che ospitavano i primi corsi, cercando di farsi largo tra i primi esami, ridendo di nomi impronunciabili di molecole, piante o farmaci. Lo sconforto e lo smarrimento iniziali di fronte ad un nuovo arduo esame e la sensazione di felicità e libertà subito dopo averlo superato. Belli, ma difficili. Ci vuole tanta, troppa energia per remare controcorrente. A volte il mare appare più tranquillo, la corrente sembra concederti spazio e tregua, ma poi