CoChat
Sign Up
Cited by 40Neuroinflammation and Neurodegeneration MechanismsRegulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic Diseases

The Interplay between Ghrelin and Microglia in Neuroinflammation: Implications for Obesity and Neurodegenerative Diseases

Open access
Russo, Cristina, Valle, Maria Stella, Russo, Antonella, Malaguarnera, Lucia·2022·International Journal of Molecular Sciences
DOI 10.3390/ijms232113432PMC PMC9654207
Open this paper in CoChat — free accountOpen PDF

Abstract

Numerous studies have shown that microglia are capable of producing a wide range of chemokines to promote inflammatory processes within the central nervous system (CNS). These cells share many phenotypical and functional characteristics with macrophages, suggesting that microglia participate in innate immune responses in the brain. Neuroinflammation induces neurometabolic alterations and increases in energy consumption. Microglia may constitute an important therapeutic target in neuroinflammation. Recent research has attempted to clarify the role of Ghre signaling in microglia on the regulation of energy balance, obesity, neuroinflammation and the occurrence of neurodegenerative diseases. These studies strongly suggest that Ghre modulates microglia activity and thus affects the pathophysiology of neurodegenerative diseases. This review aims to summarize what is known from the current literature on the way in which Ghre modulates microglial activity during neuroinflammation and their impact on neurometabolic alterations in neurodegenerative diseases. Understanding the role of Ghre in microglial activation/inhibition regulation could provide promising strategies for downregulating neuroinflammation and consequently for diminishing negative neurological outcomes.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.3390/ijms232113432

Cites

13 of 13 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 129

  1. [1]Cowley M.A. Smith R.G. Diano S. Tschöp M. Pronchuk N. Grove K.L. Strasburger C.J. Bidlingmaier M. Esterman M. Heiman M.L. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis Neuron 2003 37 649 661 10.1016/S0896-6273(03)00063-1 12597862 · DOI · Paper page
  2. [2]Cope E.C. LaMarca E.A. Monari P.K. Olson L.B. Martinez S. Zych A.D. Katchur N.J. Gould E. Microglia Play an Active Role in Obesity-Associated Cognitive Decline J. Neurosci. 2018 38 8889 8904 10.1523/JNEUROSCI.0789-18.2018 30201764 PMC6181311 · DOI
  3. [3]Hattori N. Saito T. Yagyu T. Jiang B.H. Kitagawa K. Inagaki C. GH, GH receptor, GH secretagogue receptor, and ghrelin expression in human T cells, B cells, and neutrophils J. Clin. Endocrinol. Metab. 2001 86 4284 4291 10.1210/jcem.86.9.7866 11549663 · DOI
  4. [4]Sofroniew M.V. Vinters H.V. Astrocytes: Biology and pathology Acta Neuropathol. 2010 119 7 35 10.1007/s00401-009-0619-8 20012068 PMC2799634 · DOI · Paper page
  5. [6]Fan Z. Aman Y. Ahmed I. Chetelat G. Landeau B. Ray Chaudhuri K. Brooks D.J. Edison P. Influence of microglial activation on neuronal function in Alzheimer’s and Parkinson’s disease dementia Alzheimers Dement. 2015 11 608 621.e7 10.1016/j.jalz.2014.06.016 25239737 · DOI · Paper page
  6. [7]Kojima M. Kangawa K. Ghrelin: Structure and function Physiol. Rev. 2005 85 495 522 10.1152/physrev.00012.2004 15788704 · DOI · Paper page
  7. [8]Kojima M. Hosoda H. Date Y. Nakazato M. Matsuo H. Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach Nature 1999 402 656 660 10.1038/45230 10604470 · DOI · Paper page
  8. [9]Russo C. Patanè M. Vicario N. Di Bella V. Cosentini I. Barresi V. Gulino R. Pellitteri R. Russo A. Stanzani S. Olfactory Ensheathing Cells express both Ghrelin and Ghrelin Receptor in vitro: A new hypothesis in favor of a neurotrophic effect Neuropeptides 2020 79 101997 10.1016/j.npep.2019.101997 31784044 · DOI
  9. [10]Kirsz K. Zieba D.A. Ghrelin-mediated appetite regulation in the central nervous system Peptides 2011 32 2256 2264 10.1016/j.peptides.2011.04.010 21524673 · DOI
  10. [11]Yanagi S. Sato T. Kangawa K. Nakazato M. The homeostatic force of ghrelin Cell Metab. 2018 27 786 804 10.1016/j.cmet.2018.02.008 29576534 · DOI
  11. [12]Banks W.A. Tschöp M. Robinson S.M. Heiman M.L. Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure J. Pharmacol. Exp. Ther. 2002 302 822 827 10.1124/jpet.102.034827 12130749 · DOI · Paper page
  12. [13]Russo C. Russo A. Pellitteri R. Stanzani S. Hippocampal Ghrelin-positive neurons directly project to arcuate hypothalamic and medial amygdaloid nuclei. Could they modulate food-intake? Neurosci. Lett. 2017 653 126 131 10.1016/j.neulet.2017.05.049 28552455 · DOI
  13. [14]Mani B.K. Shankar K. Zigman J.M. Ghrelin’s Relationship to Blood Glucose Endocrinology 2019 160 1247 1261 10.1210/en.2019-00074 30874792 PMC6482034 · DOI
  14. [15]Hosoda H. Kojima M. Matsuo H. Kangawa K. Ghrelin and des-acyl ghrelin: Two major forms of rat ghrelin peptide in gastrointestinal tissue Biochem. Biophys. Res. Commun. 2000 279 909 913 10.1006/bbrc.2000.4039 11162448 · DOI
  15. [16]Ferens D.M. Yin L. Ohashi-Doi K. Habgood M. Bron R. Brock J.A. Gale J.D. Furness J.B. Evidence for functional ghrelin receptors on parasympathetic preganglionic neurons of micturition control pathways in the rat Clin. Exp. Pharm. Physiol. 2010 37 926 932 10.1111/j.1440-1681.2010.05409.x 20497419 · DOI
  16. [17]Dixit V.D. Schaffer E.M. Pyle R.S. Collins G.D. Sakthivel S.K. Palaniappan R. Lillard J.W. Taub D.D. Jr. Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells J. Clin. Inv. 2004 114 57 66 10.1172/JCI21134 PMC437970 15232612 · DOI
  17. [18]Alvarez-Crespo M. Skibicka K.P. Farkas I. Molnár C.S. Egecioglu E. Hrabovszky E. Liposits Z. Dickson S.L. The amygdala as a neurobiological target for ghrelin in rats: Neuroanatomical, electrophysiological and behavioral evidence PLoS ONE 2012 7 e46321 10.1371/journal.pone.0046321 23071554 PMC3468604 · DOI
  18. [19]Russo C. Russo A. Pellitteri R. Stanzani S. Ghrelin-containing neurons in the olfactory bulb send collateralized projections into medial amygdaloid and arcuate hypothalamic nuclei: Neuroanatomical study Exp. Brain Res. 2018 236 2223 2229 10.1007/s00221-018-5298-z 29845448 · DOI
  19. [20]Delporte C. Structure and physiological actions of ghrelin Scientifica 2013 2013 518909 10.1155/2013/518909 24381790 PMC3863518 · DOI
  20. [21]Taub D.D. Novel connections between the neuroendocrine and immune systems: The ghrelin immunoregulatory network Vitam. Horm. 2008 77 325 346 17983863
  21. [22]Chow K.B. Sun J. Chu K.M. Tai Cheung W. Cheng C.H. Wise H. The truncated ghrelin receptor polypeptide (GHS-R1b) is localized in the endoplasmic reticulum where it forms heterodimers with ghrelin receptors (GHS-R1a) to attenuate their cell surface expression Mol. Cell Endocrinol. 2012 348 247 254 10.1016/j.mce.2011.08.034 21903149 · DOI
  22. [24]Gregor M.F. Hotamisligil G.S. Inflammatory mechanisms in obesity Annu. Rev. Immunol. 2011 29 415 445 10.1146/annurev-immunol-031210-101322 21219177 · DOI · Paper page
  23. [25]Cheyuo C. Wu R. Zhou M. Jacob A. Coppa G. Wang P. Ghrelin suppresses inflammation and neuronal nitric oxide synthase in focal cerebral ischemia via the vagus nerve Shock 2011 35 258 265 10.1097/SHK.0b013e3181f48a37 20720512 · DOI
  24. [26]Miller A.A. Spencer S.J. Obesity and neuroinflammation: A pathway to cognitive impairment Brain Behav. Immun. 2014 42 10 21 10.1016/j.bbi.2014.04.001 24727365 · DOI
  25. [27]Sheikh M.H. Errede M. d’Amati A. Khan N.Q. Fanti S. Loiola R.A. McArthur S. Purvis G.S.D. O’Riordan C.E. Ferorelli D. Impact of metabolic disorders on the structural, functional, and immunological integrity of the blood-brain barrier:Therapeutic avenues FASEB J. 2022 36 e22107 10.1096/fj.202101297R 34939700 · DOI
  26. [28]Ku J.M. Taher M. Chin K.Y. Barsby T. Austin V. Wong C. Andrews Z.B. Spencer S. Miller A.A. Protective actions of des-acylated ghrelin on brain injury and blood-brain barrier disruption after stroke in mice Clin. Sci. 2016 130 1545 1558 10.1042/CS20160077 27303049 · DOI
  27. [29]Kohno D. Gao H.Z. Muroya S. Kikuyama S. Yada T. Ghrelin directly interacts with neuropeptide-Y-containing neurons in the rat arcuate nucleus: Ca2+ signaling via protein kinase A and N-type channel-dependent mechanisms and cross-talk with leptin and orexin Diabetes 2003 52 948 956 10.2337/diabetes.52.4.948 12663466 · DOI
  28. [30]Moon M. Kim H.G. Hwang L. Seo J.H. Kim S. Hwang S. Kim S. Lee D. Chung H. Oh M.S. Neuroprotective effect of ghrelin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease by blocking microglial activation Neurotox. Res. 2009 15 332 347 10.1007/s12640-009-9037-x 19384567 · DOI · Paper page
  29. [31]Deng B. Fang F. Yang T. Yu Z. Zhang B. Xie X. Ghrelin inhibits AngII -induced expression of TNF-α, IL-8, MCP-1 in human umbilical vein endothelial cells Int. J. Clin. Exp. 2015 8 579 588 PMC4358487 25785032
  30. [32]Rezaeian F. Wettstein R. Scheuer C. Bäumker K. Bächle A. Vollmar B. Menger M.D. Harder Y. Ghrelin protects musculocutaneous tissue from ischemic necrosis by improving microvascular perfusion. American journal of physiology Am. J. Physiol. Heart Circ. 2012 302 H603 H610 10.1152/ajpheart.00390.2010 22159999 · DOI
  31. [33]Chang L. Niu F. Chen J. Cao X. Liu Z. Bao X. Xu Y. Ghrelin improves muscle function in dystrophin-deficient mdx mice by inhibiting NLRP3 inflammasome activation Life Sci. 2019 232 116654 10.1016/j.lfs.2019.116654 31306657 · DOI
  32. [34]Chorny A. Anderso6-+n P. Gonzalez-Rey E. Delgado M. Ghrelin protects against experimental sepsis by inhibiting high-mobility group box 1 release and by killing bacteria J. Immunol. 2008 180 8369 8377 10.4049/jimmunol.180.12.8369 18523304 · DOI
  33. [35]Mohammed M.S. Sendra S. Lloret J. Bosch I. Systems and WBANs for Controlling Obesity J. Healthc. Eng. 2018 2018 1564748 10.1155/2018/1564748 29599941 PMC5823412 · DOI
  34. [36]Fujita Y. Yamashita T. The Effects of Leptin on Glial Cells in Neurological Diseases Front. Neurosci. 2019 13 828 10.3389/fnins.2019.00828 31447640 PMC6692660 · DOI
  35. [37]Lv Y. Liang T. Wang G. Li Z. Ghrelin, a gastrointestinal hormone, regulates energy balance and lipid metabolism Biosci. Rep. 2018 38 BSR20181061 10.1042/BSR20181061 30177523 PMC6153372 · DOI
  36. [38]Tschöp M. Smiley D.L. Heiman M.L. Ghrelin induces adiposity in rodents Nature 2000 407 908 913 10.1038/35038090 11057670 · DOI · Paper page
  37. [39]Tong J. Prigeon R.L. Davis H.W. Bidlingmaier M. Kahn S.E. Cummings D.E. Tschöp M.H. D’Alessio D. Ghrelin suppresses glucose-stimulated insulin secretion and deteriorates glucose tolerance in healthy humans Diabetes 2010 59 2145 2151 10.2337/db10-0504 20584998 PMC2927935 · DOI
  38. [40]Korbonits M. Grossman A.B. Ghrelin: Update on a novel hormonal system Eur. J. Endocrinol. 2004 151 (Suppl. S1) S67 S70 10.1530/eje.0.151s067 15339247 · DOI
  39. [41]Broglio F. Gottero C. Benso A. Prodam F. Destefanis S. Gauna C. Maccario M. Deghenghi R. van der Lely A.J. Ghigo E. Effects of ghrelin on the insulin and glycemic responses to glucose, arginine, or free fatty acids load in humans J. Clin. Endocrinol. Metab. 2003 88 4268 4272 10.1210/jc.2002-021940 12970297 · DOI
  40. [42]Delhanty P.J. van Kerkwijk A. Huisman M. van de Zande B. Verhoef-Post M. Gauna C. Hofland L. Themmen A.P. van der Lely A.J. Unsaturated fatty acids prevent desensitization of the human growth hormone secretagogue receptor by blocking its internalization. American journal of physiology Endocrinol. Metab. 2010 299 E497 E505 10.1152/ajpendo.00414.2009 20587751 · DOI
  41. [43]Steculorum S.M. Collden G. Coupe B. Croizier S. Lockie S. Andrews Z.B. Jarosch F. Klussmann S. Bouret S.G. Neonatal ghrelin programs development of hypothalamic feeding circuits J. Clin. Investig. 2015 125 846 858 10.1172/JCI73688 25607843 PMC4319433 · DOI
  42. [45]Erdmann J. Lippl F. Wagenpfeil S. Schusdziarra V. Differential association of basal and postprandial plasma ghrelin with leptin, insulin, and type 2 diabetes Diabetes 2005 54 1371 1378 10.2337/diabetes.54.5.1371 15855322 · DOI
  43. [46]Li P. Tiwari H.K. Lin W.Y. Allison D.B. Chung W.K. Leibel R.L. Yi N. Liu N. Genetic association analysis of 30 genes related to obesity in a European American population Int. J. Obes. 2014 38 724 729 10.1038/ijo.2013.140 PMC3909018 23900445 · DOI
  44. [47]Kulkarni V.V. Maday S. Compartment-specific dynamics and functions of autophagy in neurons Dev. Neurobiol. 2018 78 298 310 10.1002/dneu.22562 29197160 PMC5816696 · DOI
  45. [48]Kiriyama Y. Nochi H. The Function of Autophagy in Neurodegenerative Diseases Int. J. Mol. Sci. 2015 16 26797 26812 10.3390/ijms161125990 26569220 PMC4661849 · DOI
  46. [49]Wang H. Dou S. Zhu J. Shao Z. Wang C. Cheng B. Ghrelin protects dopaminergic neurons against MPTP neurotoxicity through promoting autophagy and inhibiting endoplasmic reticulum mediated apoptosis Brain Res. 2020 1746 147023 10.1016/j.brainres.2020.147023 32710901 · DOI · Paper page
  47. [51]Ferreira-Marques M. Carvalho A. Cavadas C. Aveleira C.A. PI3K/AKT/MTOR and ERK1/2-MAPK signaling pathways are involved in autophagy stimulation induced by caloric restriction or caloric restriction mimetics in cortical neurons Aging 2021 13 7872 7882 10.18632/aging.202805 33714946 PMC8034898 · DOI
  48. [52]Chung H. Choi J. Park S. Ghrelin protects adult rat hippocampal neural stem cells from excessive autophagy during oxygen-glucose deprivation Endocr. J. 2018 65 63 73 10.1507/endocrj.EJ17-0281 29057768 · DOI
  49. [53]Cecarini V. Bonfili L. Cuccioloni M. Keller J.N. Bruce-Keller A.J. Eleuteri A.M. Effects of Ghrelin on the Proteolytic Pathways of Alzheimer’s Disease Neuronal Cells Mol. Neurobiol. 2016 53 3168 3178 10.1007/s12035-015-9227-x 26033219 · DOI
  50. [54]Cui H. López M. Rahmouni K. The cellular and molecular bases of leptin and ghrelin resistance in obesity. Nature reviews Endocrinology 2017 13 338 351 10.1038/nrendo.2016.222 28232667 PMC8904083 · DOI
  51. [55]Wang H. Dou S. Zhu J. Shao Z. Wang C. Cheng B. Regulatory effects of ghrelin on endoplasmic reticulum stress, oxidative stress, and autophagy: Therapeutic potential Neuropeptides 2021 85 102112 10.1016/j.npep.2020.102112 33333485 · DOI
  52. [56]Zigman J.M. Bouret S.G. Andrews Z.B. Obesity Impairs the Action of the Neuroendocrine Ghrelin System Trends Endocrinol. Metab. 2016 27 54 63 10.1016/j.tem.2015.09.010 26542050 PMC4814209 · DOI
  53. [59]Li Q. Barres B.A. Microglia and macrophages in brain homeostasis and disease. Nature reviews Immunology 2018 18 225 242 10.1038/nri.2017.125 29151590 · DOI · Paper page
  54. [61]Murray P.J. Allen J.E. Biswas S.K. Fisher E.A. Gilroy D.W. Goerdt S. Gordon S. Hamilton J.A. Ivashkiv L.B. Lawrence T. Macrophage activation and polarization: Nomenclature and experimental guidelines Immunity 2014 41 14 20 10.1016/j.immuni.2014.06.008 25035950 PMC4123412 · DOI · Paper page
  55. [62]Chhor V. Le Charpentier T. Lebon S. Oré M.V. Celador I.L. Josserand J. Degos V. Jacotot E. Hagberg H. Sävman K. Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro Brain Behav. Immun. 2013 32 70 85 10.1016/j.bbi.2013.02.005 23454862 PMC3694309 · DOI
  56. [63]Qin C. Zhou L.Q. Ma X.T. Hu Z.W. Yang S. Chen M. Bosco D.B. Wu L.J. Tian D.S. Dual Functions of Microglia in Ischemic Stroke Neurosci. Bull. 2019 35 921 933 10.1007/s12264-019-00388-3 31062335 PMC6754485 · DOI
  57. [64]Hu X. Leak R.K. Shi Y. Suenaga J. Gao Y. Zheng P. Chen J. Microglial and macrophage polarization—New prospects for brain repair. Nature reviews Neurology 2015 11 56 64 10.1038/nrneurol.2014.207 25385337 PMC4395497 · DOI
  58. [67]Cui W. Sun C. Ma Y. Wang S. Wang X. Zhang Y. Inhibition of TLR4 Induces M2 Microglial Polarization and Provides Neuroprotection via the NLRP3 Inflammasome in Alzheimer’s Disease Front. Neurosci. 2020 14 444 10.3389/fnins.2020.00444 32508567 PMC7251077 · DOI
  59. [68]Thaler J.P. Yi C.X. Schur E.A. Guyenet S.J. Hwang B.H. Dietrich M.O. Zhao X. Sarruf D.A. Izgur V. Maravilla K.R. Obesity is associated with hypothalamic injury in rodents and humans J. Clin. Investig. 2012 122 153 162 10.1172/JCI59660 22201683 PMC3248304 · DOI · Paper page
  60. [69]Mendes N.F. Velloso L.A. Perivascular macrophages in high-fat diet-induced hypothalamic inflammation J. Neuroinflammation 2022 19 136 10.1186/s12974-022-02519-6 35681242 PMC9185933 · DOI
  61. [70]Mendes N.F. Kim Y.B. Velloso L.A. Araújo E.P. Hypothalamic Microglial Activation in Obesity: A Mini-Review Front. Neurosci. 2018 12 846 10.3389/fnins.2018.00846 30524228 PMC6262396 · DOI
  62. [71]Banerjee J. Dorfman M.D. Fasnacht R. Douglass J.D. Wyse-Jackson A.C. Barria A. Thaler J.P. CX3CL1 Action on Microglia Protects from Diet-Induced Obesity by Restoring POMC Neuronal Excitability and Melanocortin System Activity Impaired by High-Fat Diet Feeding Int. J. Mol. Sci. 2022 23 6380 10.3390/ijms23126380 35742824 PMC9224384 · DOI
  63. [72]Hou Z. Miao Y. Gao L. Pan H. Zhu S. Ghrelin-containing neuron in cerebral cortex and hypothalamus linked with the DVC of brainstem in rat Regul. Pept. 2006 134 126 131 10.1016/j.regpep.2006.02.005 16600402 · DOI
  64. [73]Travagli R.A. Hermann G.E. Browning K.N. Rogers R.C. Brainstem circuits regulating gastric function Annu. Rev. Physiol. 2006 68 279 305 10.1146/annurev.physiol.68.040504.094635 16460274 PMC3062484 · DOI · Paper page
  65. [74]Naznin F. Toshinai K. Waise T.M. NamKoong C. Md Moin A.S. Sakoda H. Nakazato M. Diet-induced obesity causes peripheral and central ghrelin resistance by promoting inflammation J. Endocrinol. 2015 226 81 92 10.1530/JOE-15-0139 26016745 PMC4485401 · DOI
  66. [75]De Luca S.N. Sominsky L. Soch A. Wang H. Ziko I. Rank M.M. Spencer S.J. Conditional microglial depletion in rats leads to reversible anorexia and weight loss by disrupting gustatory circuitry Brain Behav. Immun. 2019 77 77 91 10.1016/j.bbi.2018.12.008 30578932 · DOI
  67. [76]Solfrizzi V. Custodero C. Lozupone M. Imbimbo B.P. Valiani V. Agosti P. Schilardi A. D’Introno A. La Montagna M. Calvani M. Relationships of Dietary Patterns, Foods, and Micro- and Macronutrients with Alzheimer’s Disease and Late-Life Cognitive Disorders: A Systematic Review J. Alzheimer’s Dis. 2017 59 815 849 10.3233/JAD-170248 28697569 · DOI
  68. [77]O’Brien P.D. Hinder L.M. Callaghan B.C. Feldman E.L. Neurological consequences of obesity Lancet. Neurol. 2017 16 465 477 10.1016/S1474-4422(17)30084-4 28504110 PMC5657398 · DOI
  69. [78]Timper K. Brüning J.C. Hypothalamic circuits regulating appetite and energy homeostasis: Pathways to obesity Dis. Model. Mech. 2017 10 679 689 10.1242/dmm.026609 28592656 PMC5483000 · DOI
  70. [79]Thomas K. Beyer F. Lewe G. Zhang R. Schindler S. Schönknecht P. Stumvoll M. Villringer A. Witte A.V. Higher body mass index is linked to altered hypothalamic microstructure Sci. Rep. 2019 9 17373 10.1038/s41598-019-53578-4 31758009 PMC6874651 · DOI
  71. [80]Stillman C.M. Weinstein A.M. Marsland A.L. Gianaros P.J. Erickson K.I. Body-Brain Connections: The Effects of Obesity and Behavioral Interventions on Neurocognitive Aging Front. Aging Neurosci. 2017 9 115 10.3389/fnagi.2017.00115 28507516 PMC5410624 · DOI
  72. [81]Uranga R.M. Keller J.N. The Complex Interactions Between Obesity, Metabolism and the Brain. Frontiers in neuroscience Front. Neurosci. 2019 13 513 10.3389/fnins.2019.00513 31178685 PMC6542999 · DOI
  73. [82]Ballard C. Gauthier S. Corbett A. Brayne C. Aarsland D. Jones E. Alzheimer’s disease Lancet 2011 377 1019 1031 10.1016/S0140-6736(10)61349-9 21371747 · DOI · Paper page
  74. [83]Perry G. Siedlak S.L. Richey P. Kawai M. Cras P. Kalaria R.N. Galloway P.G. Scardina J.M. Cordell B. Greenberg B.D. Association of heparan sulfate proteoglycan with the neurofibrillary tangles of Alzheimer’s disease J. Neurosci. Off. J. Soc. Neurosci. 1991 11 3679 3683 10.1523/JNEUROSCI.11-11-03679.1991 PMC6575552 1941102 · DOI
  75. [84]Stefanis L. α-Synuclein in Parkinson’s disease Cold Spring Harb. Perspect. Med. 2012 2 a009399 10.1101/cshperspect.a009399 22355802 PMC3281589 · DOI · Paper page
  76. [85]Beach T.G. Adler C.H. Zhang N. Serrano G.E. Sue L.I. Driver-Dunckley E. Mehta S.H. Zamrini E.E. Sabbagh M.N. Shill H.A. Severe hyposmia distinguishes neuropathologically confirmed dementia with Lewy bodies from Alzheimer’s disease dementia PLoS ONE 2020 15 e0231720 10.1371/journal.pone.0231720 32320406 PMC7176090 · DOI
  77. [86]Allen N.J. Lyons D.A. Glia as architects of central nervous system formation and function Science 2018 362 181 185 10.1126/science.aat0473 30309945 PMC6292669 · DOI · Paper page
  78. [87]Neher J.J. Cunningham C. Priming Microglia for Innate Immune Memory in the Brain Trends Immunol. 2019 40 358 374 10.1016/j.it.2019.02.001 30833177 · DOI
  79. [88]Patel K. Taub D.D. Role of neuropeptides, hormones, and growth factors in regulating thymopoiesis in middle to old age F1000 Biol. Rep. 2009 1 42 10.3410/B1-42 20948643 PMC2924688 · DOI
  80. [90]Ding S. Xu S. Ma Y. Liu G. Jang H. Fang J. Modulatory Mechanisms of the NLRP3 Inflammasomes in Diabetes Biomolecules 2019 9 850 10.3390/biom9120850 PMC6995523 31835423 · DOI
  81. [91]Xiong W. Meng X.F. Zhang C. NLRP3 Inflammasome in Metabolic-Associated Kidney Diseases: An Update Front. Immunol. 2021 12 714340 10.3389/fimmu.2021.714340 34305953 PMC8297462 · DOI
  82. [92]Yang Y. Ye Y. Kong C. Su X. Zhang X. Bai W. He X. MiR-124 Enriched Exosomes Promoted the M2 Polarization of Microglia and Enhanced Hippocampus Neurogenesis After Traumatic Brain Injury by Inhibiting TLR4 Pathway Neurochem. Res. 2019 44 811 828 10.1007/s11064-018-02714-z 30628018 · DOI
  83. [93]Baatar D. Patel K. Taub D.D. The effects of ghrelin on inflammation and the immune system Mol. Cell. Endocrinol. 2011 340 44 58 10.1016/j.mce.2011.04.019 21565248 · DOI
  84. [94]Wang Q. Lin P. Li P. Feng L. Ren Q. Xie X. Xu J. Ghrelin protects the heart against ischemia/reperfusion injury via inhibition of TLR4/NLRP3 inflammasome pathway Life Sci. 2017 186 50 58 10.1016/j.lfs.2017.08.004 28782532 · DOI
  85. [95]Liu F. Li Z. He X. Yu H. Feng J. Ghrelin Attenuates Neuroinflammation and Demyelination in Experimental Autoimmune Encephalomyelitis Involving NLRP3 Inflammasome Signaling Pathway and Pyroptosis Front. Pharmacol. 2019 10 1320 10.3389/fphar.2019.01320 31780940 PMC6851267 · DOI
  86. [96]Xu Y. Jin M.Z. Yang Z.Y. Jin W.L. Microglia in neurodegenerative diseases Neural Regen. Res. 2021 16 270 280 10.4103/1673-5374.290881 32859774 PMC7896205 · DOI
  87. [97]Burguillos M.A. Deierborg T. Kavanagh E. Persson A. Hajji N. Garcia-Quintanilla A. Cano J. Brundin P. Englund E. Venero J.L. Caspase signalling controls microglia activation and neurotoxicity Nature 2011 472 319 324 10.1038/nature09788 21389984 · DOI · Paper page
  88. [98]Dong X.Y. Xu J. Tang S.Q. Li H.Y. Jiang Q.Y. Zou X.T. Ghrelin and its biological effects on pigs Peptides 2009 30 1203 1211 10.1016/j.peptides.2009.03.001 19463757 · DOI
  89. [99]de Sousa V.L. Araújo S.B. Antonio L.M. Silva-Queiroz M. Colodeti L.C. Soares C. Barros-Aragão F. Mota-Araujo H.P. Alves V.S. Coutinho-Silva R. Innate immune memory mediates increased susceptibility to Alzheimer’s disease-like pathology in sepsis surviving mice Brain Behav. Immun. 2021 95 287 298 10.1016/j.bbi.2021.04.001 33838250 · DOI
  90. [100]Selkoe D.J. Alzheimer’s disease: Genes, proteins, and therapy Physiol. Rev. 2001 81 741 766 10.1152/physrev.2001.81.2.741 11274343 · DOI · Paper page
  91. [101]Zhu M. Wang X. Sun L. Schultzberg M. Hjorth E. Can. inflammation be resolved in Alzheimer’s disease? Ther. Adv. Neurol. Disord. 2018 11 1756286418791107 10.1177/1756286418791107 30116300 PMC6088473 · DOI
  92. [102]Panza F. Frisardi V. Seripa D. Imbimbo B.P. Sancarlo D. D’Onofrio G. Addante F. Paris F. Pilotto A. Solfrizzi V. Metabolic syndrome, mild cognitive impairment, and dementia Curr. Alzheimer Res. 2011 8 492 509 10.2174/156720511796391818 21605050 · DOI
  93. [103]Dinel A.L. André C. Aubert A. Ferreira G. Layé S. Castanon N. Cognitive and emotional alterations are related to hippocampal inflammation in a mouse model of metabolic syndrome PLoS ONE 2011 6 e24325 10.1371/journal.pone.0024325 21949705 PMC3174932 · DOI
  94. [104]Cai W. Ramdas M. Zhu L. Chen X. Striker G.E. Vlassara H. Oral advanced glycation endproducts (AGEs) promote insulin resistance and diabetes by depleting the antioxidant defenses AGE receptor-1 and sirtuin 1 Proc. Natl. Acad. Sci. USA 2012 109 15888 15893 10.1073/pnas.1205847109 22908267 PMC3465382 · DOI
  95. [105]Kaiser J. Krippeit-Drews P. Drews G. Acyl-Ghrelin Influences Pancreatic β-Cell Function by Interference with KATP Channels Diabetes 2021 70 423 435 10.2337/db20-0231 33154069 · DOI
  96. [106]Page L.C. Gastaldelli A. Gray S.M. D’Alessio D.A. Tong J. Interaction of GLP-1 and Ghrelin on Glucose Tolerance in Healthy Humans Diabetes 2018 67 1976 1985 10.2337/db18-0451 30065032 PMC6152343 · DOI
  97. [107]Lewitt M.S. The Role of the Growth Hormone/Insulin-Like Growth Factor System in Visceral Adiposity Biochem. Insights. 2017 10 1178626417703995 10.1177/1178626417703995 28469442 PMC5404904 · DOI
  98. [108]Kunath N. van Groen T. Allison D.B. Kumar A. Dozier-Sharpe M. Kadish I. Ghrelin agonist does not foster insulin resistance but improves cognition in an Alzheimer’s disease mouse model Sci. Rep. 2015 5 11452 10.1038/srep11452 26090621 PMC4473679 · DOI
  99. [109]Hirosumi J. Tuncman G. Chang L. Görgün C.Z. Uysal K.T. Maeda K. Karin M. Hotamisligil G.S. A central role for JNK in obesity and insulin resistance Nature 2002 420 333 336 10.1038/nature01137 12447443 · DOI · Paper page
  100. [110]Bomfim T.R. Forny-Germano L. Sathler L.B. Brito-Moreira J. Houzel J.C. Decker H. Silverman M.A. Kazi H. Melo H.M. McClean P.L. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease- associated Aβ oligomers J. Clin. Investig. 2012 122 1339 1353 10.1172/JCI57256 22476196 PMC3314445 · DOI
  101. [111]Pinkney J. The role of ghrelin in metabolic regulation Curr. Opin. Clin. Nutr. Metab. Care. 2014 17 497 502 10.1097/MCO.0000000000000101 25111866 · DOI
  102. [112]Lee J. Lim E. Kim Y. Li E. Park S. Ghrelin attenuates kainic acid-induced neuronal cell death in the mouse hippocampus J. Endocrinol. 2010 205 263 270 10.1677/JOE-10-0040 20351014 · DOI
  103. [113]Lee J.Y. Choi H.Y. Yune T.Y. MMP-3 secreted from endothelial cells of blood vessels after spinal cord injury activates microglia, leading to oligodendrocyte cell death Neurobiol. Dis. 2015 82 141 151 10.1016/j.nbd.2015.06.002 26079709 · DOI
  104. [114]Heneka M.T. Carson M.J. El Khoury J. Landreth G.E. Brosseron F. Feinstein D.L. Jacobs A.H. Wyss-Coray T. Vitorica J. Ransohoff R.M. Neuroinflammation in Alzheimer’s disease Lancet Neurol. 2015 14 388 405 10.1016/S1474-4422(15)70016-5 25792098 PMC5909703 · DOI · Paper page
  105. [115]Pan X.D. Zhu Y.G. Lin N. Zhang J. Ye Q.Y. Huang H.P. Chen X.C. Microglial phagocytosis induced by fibrillar β-amyloid is attenuated by oligomeric β-amyloid: Implications for Alzheimer’s disease Mol. Neurodegener. 2011 6 45 10.1186/1750-1326-6-45 21718498 PMC3149591 · DOI · Paper page
  106. [116]Collins R.F. Touret N. Kuwata H. Tandon N.N. Grinstein S. Trimble W.S. Uptake of oxidized low density lipoprotein by CD36 occurs by an actin-dependent pathway distinct from macropinocytosis J. Biol. Chem. 2009 284 30288 30297 10.1074/jbc.M109.045104 19740737 PMC2781584 · DOI
  107. [118]Bulgarelli I. Tamiazzo L. Bresciani E. Rapetti D. Caporali S. Lattuada D. Locatelli V. Torsello A. Desacyl-ghrelin and synthetic GH-secretagogues modulate the production of inflammatory cytokines in mouse microglia cells stimulated by beta-amyloid fibrils J. Neurosci. Res. 2009 87 2718 2727 10.1002/jnr.22088 19382238 · DOI
  108. [119]Granado M. Priego T. Martín A.I. Villanúa M.A. López-Calderón A. Anti-inflammatory effect of the ghrelin agonist growth hormone-releasing peptide-2 (GHRP-2) in arthritic rats Am. J. Physiol. Endocrinol. Metab. 2005 288 E486 E492 10.1152/ajpendo.00196.2004 15507538 · DOI
  109. [120]Dhurandhar E.J. Allison D.B. van Groen T. Kadish I. Hunger in the absence of caloric restriction improves cognition and attenuates Alzheimer’s disease pathology in a mouse model PLoS ONE 2013 8 e60437 10.1371/journal.pone.0060437 23565247 PMC3614512 · DOI · Paper page
  110. [121]Martins I. Gomes S. Costa R.O. Otvos L. Oliveira C.R. Resende R. Pereira C.M. Leptin and ghrelin prevent hippocampal dysfunction induced by Aβ oligomers Neuroscience 2013 241 41 51 10.1016/j.neuroscience.2013.02.062 23506735 · DOI
  111. [122]Chaney A. Williams S.R. Boutin H. In vivo molecular imaging of neuroinflammation in Alzheimer’s disease J. Neurochem. 2019 149 438 451 10.1111/jnc.14615 30339715 PMC6563454 · DOI
  112. [124]Leung E. Guo L. Bu J. Maloof M. El Khoury J. Geula C. Microglia activation mediates fibrillar amyloid-β toxicity in the aged primate cortex Neurobiol. Aging 2011 32 387 397 10.1016/j.neurobiolaging.2009.02.025 19349094 PMC2888944 · DOI
  113. [125]McGrattan A.M. McGuinness B. McKinley M.C. Kee F. Passmore P. Woodside J.V. McEvoy C.T. Diet and Inflammation in Cognitive Ageing and Alzheimer’s Disease Curr. Nutr. Rep. 2019 8 53 65 10.1007/s13668-019-0271-4 30949921 PMC6486891 · DOI
  114. [126]Santos V.V. Stark R. Rial D. Silva H.B. Bayliss J.A. Lemus M.B. Davies J.S. Cunha R.A. Prediger R.D. Andrews Z.B. Acyl ghrelin improves cognition, synaptic plasticity deficits and neuroinflammation following amyloid β (Aβ1-40) administration in mice J. Neuroendocrinol. 2017 29 12476 10.1111/jne.12476 28380673 · DOI
  115. [127]Moon M. Choi J.G. Nam D.W. Hong H.S. Choi Y.J. Oh M.S. Mook-Jung I. Ghrelin ameliorates cognitive dysfunction and neurodegeneration in intrahippocampal amyloid-β1-42 oligomer-injected mice J. Alzheimer’s Dis. 2011 23 147 159 10.3233/JAD-2010-101263 20930280 · DOI
  116. [128]Seminara R.S. Jeet C. Biswas S. Kanwal B. Iftikhar W. Sakibuzzaman M. Rutkofsky I.H. The Neurocognitive Effects of Ghrelin-induced Signaling on the Hippocampus: A Promising Approach to Alzheimer’s Disease Cureus 2018 10 e3285 10.7759/cureus.3285 30443455 PMC6235652 · DOI
  117. [129]Stoyanova I.I. Ghrelin: A link between ageing, metabolism and neurodegenerative disorders Neurobiol. Dis. 2014 72 Pt A 72 83 10.1016/j.nbd.2014.08.026 25173805 · DOI
  118. [130]Fearnley J.M. Lees A.J. Ageing and Parkinson’s disease: Substantia nigra regional selectivity Brain J. Neurol. 1991 114 Pt 5 2283 2301 10.1093/brain/114.5.2283 1933245 · DOI · Paper page
  119. [131]Subhramanyam C.S. Wang C. Hu Q. Dheen S.T. Microglia-mediated neuroinflammation in neurodegenerative diseases Semin. Cell Dev. Biol. 2019 94 112 120 10.1016/j.semcdb.2019.05.004 31077796 · DOI
  120. [132]Spillantini M.G. Schmidt M.L. Lee V.M. Trojanowski J.Q. Jakes R. Goedert M. Alpha-synuclein in Lewy bodies Nature 1997 388 839 840 10.1038/42166 9278044 · DOI · Paper page
  121. [133]Sergi D. Renaud J. Simola N. Martinoli M.G. Diabetes, a Contemporary Risk for Parkinson’s Disease: Epidemiological and Cellular Evidences Front. Aging Neurosci. 2019 11 302 10.3389/fnagi.2019.00302 31787891 PMC6856011 · DOI
  122. [134]Pagano G. Polychronis S. Wilson H. Giordano B. Ferrara N. Niccolini F. Politis M. Diabetes mellitus and Parkinson disease Neurology 2018 90 e1654 e1662 10.1212/WNL.0000000000005475 29626177 · DOI
  123. [135]Kam T.I. Hinkle J.T. Dawson T.M. Dawson V.L. Microglia and astrocyte dysfunction in parkinson’s disease Neurobiol. Dis. 2020 144 105028 10.1016/j.nbd.2020.105028 32736085 PMC7484088 · DOI
  124. [137]Fiszer U. Michałowska M. Baranowska B. Wolińska-Witort E. Jeske W. Jethon M. Piaścik-Gromada M. Marcinowska-Suchowierska E. Leptin and ghrelin concentrations and weight loss in Parkinson’s disease Acta Neurol. Scand. 2010 121 230 236 10.1111/j.1600-0404.2009.01185.x 20028343 · DOI
  125. [138]Bayliss J.A. Lemus M. Santos V.V. Deo M. Elsworth J.D. Andrews Z.B. Acylated but not des-acyl ghrelin is neuroprotective in an MPTP mouse model of Parkinson’s disease J. Neurochem. 2016 137 460 471 10.1111/jnc.13576 26872221 PMC4836972 · DOI
  126. [139]Morgan A.H. Rees D.J. Andrews Z.B. Davies J.S. Ghrelin mediated neuroprotection—A possible therapy for Parkinson’s disease? Neuropharmacology 2018 136 Pt B 317 326 10.1016/j.neuropharm.2017.12.027 29277488 · DOI
  127. [140]Schellekens H. Dinan T.G. Cryan J.F. Taking two to tango: A role for ghrelin receptor heterodimerization in stress and reward Front. Neurosci. 2013 7 148 10.3389/fnins.2013.00148 24009547 PMC3757321 · DOI
  128. [141]Gao H.M. Jiang J. Wilson B. Zhang W. Hong J.S. Liu B. Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: Relevance to Parkinson’s disease J. Neurochem. 2002 81 1285 1297 10.1046/j.1471-4159.2002.00928.x 12068076 · DOI
  129. [142]Dixit V.D. Taub D.D. Ghrelin and immunity: A young player in an old field Exp. Gerontol. 2005 40 900 910 10.1016/j.exger.2005.09.003 16233968 · DOI

Cited by

Sorted by citations

Authors
Russo, C., Valle, M. S., Russo, A., & Malaguarnera, L.
Affiliations
University of Catania (IT)
Corresponding author
Malaguarnera, Lucia
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2022-11-03
Volume
23
Issue
21
Pages
13432
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms232113432
PMC
PMC9654207
OpenAlex
W4309090970
Cited by
40
References
13
Citations by year
2026: 8 · 2025: 10 · 2024: 13 · 2023: 9
FWCI
0.82
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Università di Catania
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
ghrelin, microglia, neuroinflammation, obesity, neurodegenerative diseases, energy balance, neurometabolism, microglial activation, chemokines
MeSH terms
Neuroinflammatory Diseases, Humans, Inflammation, Obesity, Microglia, Neurodegenerative Diseases, Ghrelin

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review