Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Bariatric Surgery

Ghrelin reductions following bariatric surgery were associated with decreased resting state activity in the hippocampus

Abstract

Background/objective:

Laparoscopic sleeve gastrectomy (LSG) is an effective bariatric surgery to treat obesity, and involves removal of the gastric fundus where ghrelin is mainly produced. Ghrelin stimulates appetite and regulates food intake through its effect on the hypothalamus and hippocampus (HIPP). While ghrelin’s role on the hypothalamus has been explored, little is known about its role on HIPP. We tested the hypothesis that LSG-induced reductions in ghrelin levels would be associated with changes in HIPP activity.

Subjects/methods:

Brain activity was measured with amplitude of low-frequency fluctuations (ALFF) captured with resting-state functional magnetic resonance imaging (fMRI) in 30 obese participants, both before and after 1-month of LSG, and in 26 obese controls without surgery that were studied at baseline and 1-month later. A two-way analysis of variance (ANOVA) was performed to model the group and time effects on ALFF and resting-state functional connectivity.

Results:

One-month post-LSG there were significant decreases in appetite, body mass index (BMI), fasting plasma ghrelin and leptin levels, anxiety, and ALFF in HIPP and ALFF increases in posterior cingulate cortex (PCC, PFWE < 0.05). Decreases in HIPP ALFF correlated positively with decreases in fasting ghrelin and anxiety, and increases in PCC ALFF correlated positively with decreases in anxiety. Seed-voxel correlation analysis showed stronger connectivity between HIPP and insula, and between PCC and dorsolateral prefrontal cortex (DLPFC) post-LSG.

Conclusions:

These findings suggest that ghrelin effects in HIPP modulate connectivity with the insula, which processes interoception and might be relevant to LSG-induced reductions in appetite/anxiety. Role of LSG in PCC and its enhanced connectivity with DLPFC in improving self-regulation following LSG requires further investigation.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Diamantis T, Apostolou KG, Alexandrou A, Griniatsos J, Felekouras E, Tsigris C. Review of long-term weight loss results after laparoscopic sleeve gastrectomy. Surg Obes Relat Dis. 2014;10(1):177–183.

    Article  PubMed  Google Scholar 

  2. Langer FB, Reza HM, Bohdjalian A, Felberbauer FX, Zacherl J,Wenzl E, et al. Sleeve gastrectomy and gastric banding: effects on plasma ghrelin levels. Obes Surg. 2005;15(7):1024–1029.

    Article  CAS  PubMed  Google Scholar 

  3. Papailiou J, Albanopoulos K, Toutouzas KG, Tsigris C, Nikiteas N, Zografos G, Morbid obesity and sleeve gastrectomy: how does it work?. Obes Surg. 2010;20(10):1448–1455.

    Article  PubMed  Google Scholar 

  4. Lean ME, Malkova D, Altered gut and adipose tissue hormones in overweight and obese individuals: cause or consequence?. Int J Obes (Lond). 2016;40(4):622–632.

    Article  CAS  Google Scholar 

  5. Faraj M, Havel PJ, Phelis S, Blank D, Sniderman AD, Cianflone K, Plasma acylation-stimulating protein, adiponectin, leptin, and ghrelin before and after weight loss induced by gastric bypass surgery in morbidly obese subjects. J Clin Endocrinol Metab. 2003;88(4):1594–1602.

    Article  CAS  PubMed  Google Scholar 

  6. Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med. 2002;346(21):1623–1630.

    Article  PubMed  Google Scholar 

  7. Hanusch-Enserer U, Brabant G, Roden M, Ghrelin concentrations in morbidly obese patients after adjustable gastric banding. N Engl J Med. 2003;348(21):2159–2160.

    Article  PubMed  Google Scholar 

  8. Tsoli M, Chronaiou A, Kehagias I, Kalfarentzos F, Alexandrides TK, Hormone changes and diabetes resolution after biliopancreatic diversion and laparoscopic sleeve gastrectomy: a comparative prospective study. Surg Obes Relat Dis. 2013;9(5):667–677.

    Article  PubMed  Google Scholar 

  9. Karamanakos SN, Vagenas K, Kalfarentzos F, Alexandrides TK, Weight loss, appetite suppression, and changes in fasting and postprandial ghrelin and peptide-YY levels after Roux-en-Y gastric bypass and sleeve gastrectomy: a prospective, double blind study. Ann Surg. 2008;247(3):401–407.

    Article  PubMed  Google Scholar 

  10. Andrews ZB. The extra-hypothalamic actions of ghrelin on neuronal function. Trends Neurosci. 2011;34(1):31–40.

    Article  CAS  PubMed  Google Scholar 

  11. Carlini VP, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN, de Barioglio SR. Differential role of the hippocampus, amygdala, and dorsal raphe nucleus in regulating feeding, memory, and anxiety-like behavioral responses to ghrelin. Biochem Biophys Res Commun. 2004;313(3):635–641.

    Article  CAS  PubMed  Google Scholar 

  12. Diano S, Farr SA, Benoit SC, McNay EC, Da SI, Horvath B, et al. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neurosci. 2006;9(3):381–388.

    Article  CAS  PubMed  Google Scholar 

  13. Kanoski SE, Grill HJ. Hippocampus contributions to food intake control: mnemonic, neuroanatomical, and endocrine mechanisms. Biol Psychiatry. 2017;81(9):748–756.

    Article  PubMed  Google Scholar 

  14. Hsu TM, Hahn JD, Konanur VR, Noble EE, Suarez AN, Thai J, et al. Hippocampus ghrelin signaling mediates appetite through lateral hypothalamic orexin pathways. Elife. 2015;4:e11190.

  15. Mani BK, Walker AK, Lopez SE, Raingo J, Lee CE, Perello M, et al. Neuroanatomical characterization of a growth hormone secretagogue receptor-green fluorescent protein reporter mouse. J Comp Neurol. 2014;522(16):3644–3666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kanoski SE, Fortin SM, Ricks KM, Grill HJ. Ghrelin signaling in the ventral hippocampus stimulates learned and motivational aspects of feeding via PI3K-Akt signaling. Biol Psychiatry. 2013;73(9):915–923.

    Article  CAS  PubMed  Google Scholar 

  17. Schanze A, Reulbach U, Scheuchenzuber M, Groschl M, Kornhuber J, Kraus T. Ghrelin and eating disturbances in psychiatric disorders. Neuropsychobiology. 2008;57(3):126–130.

    Article  CAS  PubMed  Google Scholar 

  18. Jacka FN, Cherbuin N, Anstey KJ, Sachdev P, Butterworth P. Western diet is associated with a smaller hippocampus: a longitudinal investigation. BMC Med. 2015;13:215.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Raji CA, Ho AJ, Parikshak NN, Becker JT, Lopez OL, Kuller LH, et al. Brain structure and obesity. Hum Brain Mapp. 2010;31(3):353–364.

    PubMed  Google Scholar 

  20. Zhang Y, Ji G, Xu M, Cai W, Zhu Q, Qian L, et al. Recovery of brain structural abnormalities in morbidly obese patients after bariatric surgery. Int J Obes (Lond). 2016;40(10):1558–1565.

    Article  CAS  Google Scholar 

  21. Cherbuin N, Sargent-Cox K, Fraser M, Sachdev P, Anstey KJ. Being overweight is associated with hippocampal atrophy: the PATH Through Life Study. Int J Obes (Lond). 2015;39(10):1509–1514.

    Article  CAS  Google Scholar 

  22. Stoeckel LE, Weller RE, Cook ER, Twieg DB, Knowlton RC, Cox JE. Widespread reward-system activation in obese women in response to pictures of high-calorie foods. Neuroimage . 2008;41(2):636–647.

    Article  PubMed  Google Scholar 

  23. Martin LE, Holsen LM, Chambers RJ, Bruce AS, Brooks WM, Zarcone JR, et al. Neural mechanisms associated with food motivation in obese and healthy weight adults. Obes (Silver Spring). 2010;18(2):254–260.

    Article  Google Scholar 

  24. DelParigi A, Chen K, Salbe AD, Reiman EM, Tataranni PA. Sensory experience of food and obesity: a positron emission tomography study of the brain regions affected by tasting a liquid meal after a prolonged fast. Neuroimage. 2005;24(2):436–443.

    Article  PubMed  Google Scholar 

  25. Bragulat V, Dzemidzic M, Bruno C, Cox CA, Talavage T, Considine RV, et al. Food-related odor probes of brain reward circuits during hunger: a pilot FMRI study. Obes (Silver Spring). 2010;18(8):1566–1571.

    Article  Google Scholar 

  26. Min DK, Tuor UI, Chelikani PK. Gastric distention induced functional magnetic resonance signal changes in the rodent brain. Neuroscience . 2011;179:151–158.

    Article  CAS  PubMed  Google Scholar 

  27. Wang GJ, Yang J, Volkow ND, Telang F, Ma Y, Zhu W, et al. Gastric stimulation in obese subjects activates the hippocampus and other regions involved in brain reward circuitry. Proc Natl Acad Sci USA. 2006;103(42):15641–15645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gariepy G, Nitka D, Schmitz N. The association between obesity and anxiety disorders in the population: a systematic review and meta-analysis. Int J Obes (Lond). 2010;34(3):407–419.

    Article  CAS  Google Scholar 

  29. Goldstone AP, Prechtl CG, Scholtz S, Miras AD, Chhina N, Durighel G, et al. Ghrelin mimics fasting to enhance human hedonic, orbitofrontal cortex, and hippocampal responses to food. Am J Clin Nutr. 2014;99(6):1319–1330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32(1):50–55.

    Article  CAS  PubMed  Google Scholar 

  31. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gearhardt AN, Corbin WR, Brownell KD. Preliminary validation of the Yale Food Addiction Scale. Appetite. 2009;52(2):430–436.

    Article  PubMed  Google Scholar 

  33. Clark SM, Saules KK. Validation of the Yale Food Addiction Scale among a weight-loss surgery population. Eat Behav. 2013;14(2):216–219.

    Article  PubMed  Google Scholar 

  34. Zhang Y, Wang J, Zhang G, Zhu Q, Cai W, Tian J, et al. The neurobiological drive for overeating implicated in Prader-Willi syndrome. Brain Res. 2015;1620:72–80.

    Article  CAS  PubMed  Google Scholar 

  35. Power JD, Barnes KA, Snyder AZ, Schlaggar BL, Petersen SE. Spurious but systematic correlations in functional connectivity MRI networks arise from subject motion. Neuroimage. 2012;59(3):2142–2154.

    Article  PubMed  Google Scholar 

  36. Power JD, Mitra A, Laumann TO, Snyder AZ, Schlaggar BL, Petersen SE. Methods to detect, characterize, and remove motion artifact in resting state fMRI. Neuroimage. 2014;84:320–341.

    Article  PubMed  Google Scholar 

  37. Zang YF, He Y, Zhu CZ, Cao QJ, Sui MQ, Liang M, et al. Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI. Brain Dev. 2007;29(2):83–91.

    Article  PubMed  Google Scholar 

  38. Zhou Y, Wang Z, Zuo XN, Zhang H, Wang Y, Jiang T, et al. Hyper-coupling between working memory task-evoked activations and amplitude of spontaneous fluctuations in first-episode schizophrenia. Schizophr Res. 2014;159(1):80–9.

    Article  PubMed  Google Scholar 

  39. Weiler M, Teixeira CV, Nogueira MH, de Campos BM, Damasceno BP, Cendes F, et al. Differences and the relationship in default mode network intrinsic activity and functional connectivity in mild Alzheimer’s disease and amnestic mild cognitive impairment. Brain Connect. 2014;4(8):567–74.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Yao N, Pang S, Cheung C, Chang RS, Lau KK, Suckling J, et al. Resting activity in visual and corticostriatal pathways in Parkinson’s disease with hallucinations. Park Relat Disord. 2015;21(2):131–7.

    Article  Google Scholar 

  41. Zhang Y, Zhu C, Chen H, Duan X, Lu F, Li M, et al. Frequency-dependent alterations in the amplitude of low-frequency fluctuations in social anxiety disorder. J Affect Disord. 2015;174:329–35.

    Article  PubMed  Google Scholar 

  42. Liu CH, Ma X, Song LP, Tang LR, Jing B, Zhang Y, et al. Alteration of spontaneous neuronal activity within the salience network in partially remitted depression. Brain Res. 2014;1599:93–102.

    Article  PubMed  Google Scholar 

  43. Wei X, Shen H, Ren J, Li X, Xu X, Yang R, et al. Altered resting-state connectivity in college students with nonclinical depressive symptoms. PLOS ONE. 2014;9(12):e114603.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Ball SG, Lipsius S, Escobar R. Validation of the geriatric anxiety inventory in a duloxetine clinical trial for elderly adults with generalized anxiety disorder. Int Psychogeriatr. 2015;27(9):1533–1539.

    Article  PubMed  Google Scholar 

  45. Frank S, Kullmann S, Veit R. Food related processes in the insular cortex. Front Hum Neurosci. 2013;7:499.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Northoff G, Heinzel A, de Greck M, Bermpohl F, Dobrowolny H, Panksepp J. Self-referential processing in our brain – a meta-analysis of imaging studies on the self. Neuroimage. 2006;31(1):440–457.

    Article  PubMed  Google Scholar 

  47. Tomasi D, Volkow ND. Association between functional connectivity hubs and brain networks. Cereb Cortex. 2011;21(9):2003–2013.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, Shulman GL. A default mode of brain function. Proc Natl Acad Sci USA. 2001;98(2):676–682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kullmann S, Heni M, Veit R, Ketterer C, Schick F, Haring HU, et al. The obese brain: association of body mass index and insulin sensitivity with resting state network functional connectivity. Hum Brain Mapp. 2012;33(5):1052–1061.

    Article  PubMed  Google Scholar 

  50. Legget KT, Wylie KP, Cornier MA, Melanson EL, Paschall CJ, Tregellas JR. Exercise-related changes in between-network connectivity in overweight/obese adults. Physiol Behav. 2016;158:60–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Koechlin E. Prefrontal executive function and adaptive behavior in complex environments. Curr Opin Neurobiol. 2016;37:1–6.

    Article  CAS  PubMed  Google Scholar 

  52. Pearce AL, Mackey E, Cherry J, Olson A, You X, Magge SN, et al. Effect of adolescent bariatric surgery on the brain and cognition: a pilot study. Obes (Silver Spring). 2017;25(11):1852–1860.

    Article  Google Scholar 

  53. Orellana ER, Jamis C, Horvath N, Hajnal A. Effect of vertical sleeve gastrectomy on alcohol consumption and preferences in dietary obese rats and mice: a plausible role for altered ghrelin signaling. Brain Res Bull. 2017;S0361-9230:30310–6.

    Google Scholar 

  54. Sirohi S, Richardson BD, Lugo JM, Rossi DJ, Davis JF. Impact of Roux-en-Y gastric bypass surgery on appetite, alcohol intake behaviors, and midbrain ghrelin signaling in the rat. Obes (Silver Spring). 2017;25(7):1228–1236.

    Article  CAS  Google Scholar 

  55. King WC, Chen JY, Courcoulas AP, Dakin GF, Engel SG, Flum DR, et al. Alcohol and other substance use after bariatric surgery: prospective evidence from a U.S. multicenter cohort study. Surg Obes Relat Dis. 2017;13(8):1392–1402.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Rullmann M, Preusser S, Poppitz S, Heba S, Hoyer J, Schutz T, et al. Gastric-bypass surgery induced widespread neural plasticity of the obese human brain. Neuroimage. 2017;S1053-8119(17):30896–0.

    Google Scholar 

  57. Yousseif A, Emmanuel J, Karra E, Millet Q, Elkalaawy M, Jenkinson AD, et al. Differential effects of laparoscopic sleeve gastrectomy and laparoscopic gastric bypass on appetite, circulating acyl-ghrelin, peptide YY3-36 and active GLP-1 levels in non-diabetic humans. Obes Surg. 2014;24(2):241–252.

    Article  PubMed  Google Scholar 

  58. Filigheddu N, Gnocchi VF, Coscia M, Cappelli M, Porporato PE, Taulli R, et al. Ghrelin and des-acyl ghrelin promote differentiation and fusion of C2C12 skeletal muscle cells. Mol Biol Cell. 2007;18(3):986–994.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China under Grant Nos. 61431013, 81470816, 81601563, 81501543, and 81730016; National Clinical Research Center for Digestive Diseases, Xi’an, China under Grant No. 2015BAI13B07; and support in part from the Intramural Research Program of the United States National Institute on Alcoholism and Alcohol Abuse, Z01AA3009 (DT, CEW, NDV, GJW).

Author information

Authors and Affiliations

Authors

Contributions

The authors’ responsibilities were as follows – GJW and YN: study design; GJ and QZ: performed bariatric surgery; GC: data collection; GL, QM, JZ, YH, LL, and QJ: data analysis; YZ, GJ, and GL: drafting of the manuscript; JT, KW, KMV, PM, DT, and NDV: critical revision of the manuscript; and all authors: critically reviewed the content and approved the final version for publication.

Corresponding authors

Correspondence to Yi Zhang, Gang Ji or Gene-Jack Wang.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Ji, G., Li, G. et al. Ghrelin reductions following bariatric surgery were associated with decreased resting state activity in the hippocampus. Int J Obes 43, 842–851 (2019). https://doi.org/10.1038/s41366-018-0126-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-018-0126-x

This article is cited by

Search

Quick links