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.

Lower synaptic density is associated with psychiatric and cognitive alterations in obesity

Abstract

Obesity is a serious medical condition that often co-occurs with stress-related psychiatric disorders. It is recognized that the brain plays a key role in the (patho)physiology of obesity and that there is a bidirectional relationship between obesity and psychopathology, yet molecular mechanisms altered in obesity have not been fully elucidated. Thus, we investigated relationships between obesity and synaptic density in vivo using the radioligand [11C]UCB-J (which binds to synaptic glycoprotein SV2A) and positron emission tomography in individuals with obesity, and with or without stress-related psychiatric disorders. Regions of interest were the dorsolateral prefrontal cortex, orbitofrontal cortex, ventromedial, amygdala, hippocampus, and cerebellum. Forty individuals with a body mass index (BMI) ≥ 25 kg/m2 (overweight/obese), with (n = 28) or without (n = 12) psychiatric diagnosis, were compared to 30 age- and sex-matched normal weight individuals (BMI < 25), with (n = 14) or without (n = 16) psychiatric diagnosis. Overall, significantly lower synaptic density was observed in overweight/obese relative to normal weight participants (ηp2 = 0.193, F = 2.35, p = 0.042). Importantly, in participants with stress-related psychiatric diagnoses, we found BMI to be negatively correlated with synaptic density in all regions of interest (p ≤ 0.03), but no such relationship observed for mentally healthy controls (p ≥ 0.68). In the stress-related psychiatric groups, dorsolateral prefrontal cortex synaptic density was negatively associated with measures of worry (r = −0.46, p = 0.01), tension/anxiety (r = −0.38, p = 0.04), fatigue (r = −0.44, p = 0.02), and attentional difficulties (r = −0.44, p = 0.02). In summary, the findings of this novel in vivo experiment suggest compounding effects of obesity and stress-related psychopathology on the brain and the associated symptomatology that may impact functioning. This offers a novel biological mechanism for the relationship between overweight/obesity and stress-related psychiatric disorders that may guide future intervention development efforts.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Effect of overweight/obesity status on synaptic density.
Fig. 2: Relationship between BMI and synaptic density and the influence of psychiatric morbidity.
Fig. 3: Relationship between synaptic density and mood symptoms in subjects with psychiatric disorders.
Fig. 4: Relationships between synaptic density, BMI, and measures of cognitive function in clinical subjects.

References

  1. 1.

    World Health Organization. Obesity and overweight. 2020. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Accessed 15 Feb 2021.

  2. 2.

    Centers for Disease Control and Prevention. Defining adult overweight and obesity. 2020. https://www.cdc.gov/obesity/adult/defining.html. Accessed 11 Nov 2020.

  3. 3.

    Ward ZJ, Bleich SN, Cradock AL, Barrett JL, Giles CM, Flax C, et al. Projected U.S. State-level prevalence of adult obesity and severe obesity. N Engl J Med. 2019;381:2440–50.

    PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Koliaki C, Liatis S, Kokkinos A. Obesity and cardiovascular disease: revisiting an old relationship. Metabolism. 2019;92:98–107.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    García-Jiménez C, Gutiérrez-Salmerón M, Chocarro-Calvo A, García-Martinez JM, Castaño A, De la Vieja A. From obesity to diabetes and cancer: epidemiological links and role of therapies. Br J Cancer. 2016;114:716–22.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6.

    Lohmann AE, Goodwin PJ, Chlebowski RT, Pan K, Stambolic V, Dowling RJO. Association of obesity-related metabolic disruptions with cancer risk and outcome. J Clin Oncol. 2016;34:4249–55.

    PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Simon GE, Von Korff M, Saunders K, Miglioretti DL, Crane PK, van Belle G, et al. Association between obesity and psychiatric disorders in the US adult population. Arch Gen Psychiatry. 2006;63:824–30.

    PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Stefanovics EA, Potenza MN, Pietrzak RH. PTSD and obesity in US military veterans: prevalence, health burden, and suicidality. Psychiatry Res. 2020;291:113242.

    PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Rajan TM, Menon V. Psychiatric disorders and obesity: a review of association studies. J Postgrad Med. 2017;63:182–90.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Zhuo C, Zhu J, Wang C, Qu H, Ma X, Qin W. Different spatial patterns of brain atrophy and global functional connectivity impairments in major depressive disorder. Brain Imaging Behav. 2017;11:1678–89.

    PubMed  Article  Google Scholar 

  11. 11.

    O’Doherty DCM, Tickell A, Ryder W, Chan C, Hermens DF, Bennett MR, et al. Frontal and subcortical grey matter reductions in PTSD. Psychiatry Res: Neuroimaging. 2017;266:1–9.

    PubMed  Article  Google Scholar 

  12. 12.

    Chen M-H, Kao Z-K, Chang W-C, Tu P-C, Hsu J-W, Huang K-L, et al. Increased proinflammatory cytokines, executive dysfunction, and reduced gray matter volumes in first-episode bipolar disorder and major depressive disorder. J Affect Disord. 2020;274:825–31.

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Moorhead TWJ, McKirdy J, Sussmann JED, Hall J, Lawrie SM, Johnstone EC, et al. Progressive gray matter loss in patients with bipolar disorder. Biol Psychiatry. 2007;62:894–900.

    PubMed  Article  Google Scholar 

  14. 14.

    Herringa R, Phillips M, Almeida J, Insana S, Germain A. Post-traumatic stress symptoms correlate with smaller subgenual cingulate, caudate, and insula volumes in unmedicated combat veterans. Psychiatry Res: Neuroimaging. 2012;203:139–45.

    PubMed  Article  Google Scholar 

  15. 15.

    Kassem MS, Lagopoulos J, Stait-Gardner T, Price WS, Chohan TW, Arnold JC, et al. Stress-induced grey matter loss determined by MRI is primarily due to loss of dendrites and their synapses. Mol Neurobiol. 2013;47:645–61.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Hare BD, Ghosal S, Duman RS. Rapid acting antidepressants in chronic stress models: molecular and cellular mechanisms. Chronic Stress 2017;1:2470547017697317.

    PubMed Central  Article  PubMed  Google Scholar 

  17. 17.

    Christoffel DJ, Golden SA, Russo SJ. Structural and synaptic plasticity in stress-related disorders. Rev Neurosci. 2011;22:535–49.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Kang HJ, Voleti B, Hajszan T, Rajkowska G, Stockmeier CA, Licznerski P, et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med. 2012;18:1413–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Young KA, Thompson PM, Cruz DA, Williamson DE, Selemon LD. BA11 FKBP5 expression levels correlate with dendritic spine density in postmortem PTSD and controls. Neurobiol Stress. 2015;2:67–72.

    PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Drevets WC, Price JL, Furey ML. Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Struct Funct. 2008;213:93–118.

    PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Herrmann MJ, Tesar AK, Beier J, Berg M, Warrings B. Grey matter alterations in obesity: a meta-analysis of whole-brain studies. Obes Rev. 2019;20:464–71.

    PubMed  Article  Google Scholar 

  22. 22.

    Hamer M, Batty GD. Association of body mass index and waist-to-hip ratio with brain structure. UK Biobank Study. 2019;92:e594–600.

    Google Scholar 

  23. 23.

    Dekkers IA, Jansen PR, Lamb HJ. Obesity, brain volume, and white matter microstructure at MRI: a cross-sectional UK Biobank study. Radiology. 2019;291:763–71.

    PubMed  Article  Google Scholar 

  24. 24.

    Bocarsly ME, Fasolino M, Kane GA, LaMarca EA, Kirschen GW, Karatsoreos IN, et al. Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function. Proc Natl Acad Sci USA. 2015;112:15731–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Dutheil S, Ota KT, Wohleb ES, Rasmussen K, Duman RS. High-fat diet induced anxiety and anhedonia: impact on brain homeostasis and inflammation. Neuropsychopharmacology. 2016;41:1874–87.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Valcarcel-Ares MN, Tucsek Z, Kiss T, Giles CB, Tarantini S, Yabluchanskiy A, et al. Obesity in aging exacerbates neuroinflammation, dysregulating synaptic function-related genes and altering eicosanoid synthesis in the mouse hippocampus: potential role in impaired synaptic plasticity and cognitive decline. J Gerontology: Ser A. 2018;74:290–98.

    Google Scholar 

  27. 27.

    Park HR, Park M, Choi J, Park K-Y, Chung HY, Lee J. A high-fat diet impairs neurogenesis: involvement of lipid peroxidation and brain-derived neurotrophic factor. Neurosci Lett. 2010;482:235–39.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Wohleb ES, Franklin T, Iwata M, Duman RS. Integrating neuroimmune systems in the neurobiology of depression. Nat Rev Neurosci. 2016;17:497.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Wohleb ES. Neuron–Microglia interactions in mental health disorders: “for better, and for worse”. Front Immunol. 2016;7:544.

  30. 30.

    Karczewski J, Śledzińska E, Baturo A, Jończyk I, Maleszko A, Samborski P, et al. Obesity and inflammation. Eur Cytokine Netw. 2018;29:83–94.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Yeomans MR. Adverse effects of consuming high fat–sugar diets on cognition: implications for understanding obesity. Proc Nutr Soc. 2017;76:455–65.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Stout KA, Dunn AR, Hoffman C, Miller GW. The synaptic vesicle glycoprotein 2: structure, function, and disease relevance. ACS Chem Neurosci. 2019;10:3927–38.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  33. 33.

    Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin S-F, Chen M-K, et al. Imaging synaptic density in the living human brain. Sci Transl Med. 2016;8:348ra96–48ra96.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  34. 34.

    Holmes SE, Scheinost D, Finnema SJ, Naganawa M, Davis MT, DellaGioia N, et al. Lower synaptic density is associated with depression severity and network alterations. Nat Commun. 2019;10:1529.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  35. 35.

    Pannacciulli N, Del Parigi A, Chen K, Le DSN, Reiman EM, Tataranni PA. Brain abnormalities in human obesity: a voxel-based morphometric study. Neuroimage. 2006;31:1419–25.

    PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Raji CA, Ho AJ, Parikshak NN, Becker JT, Lopez OL, Kuller LH, et al. Brain structure and obesity. Hum Brain Mapp. 2010;31:353–64.

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    American Psychiatric Association. Diagnostic and statistical manual of mental disorders (DSM-5®). Washington, DC, USA: American Psychiatric Publication; 2013.

  38. 38.

    Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Clin Psychol. 1967;6:278–96.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Gustavson DE, du Pont A, Whisman MA, Miyake A. Evidence for transdiagnostic repetitive negative thinking and its association with rumination, worry, and depression and anxiety symptoms: a commonality analysis. Collabra Psychology. 2018;4:13.

    PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Pollock V, Cho DW, Reker D, Volavka J. Profile of Mood States: the factors and their physiological correlates. J Nerv Ment Dis. 1979;167:612–14.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Nabulsi NB, Mercier J, Holden D, Carré S, Najafzadeh S, Vandergeten M-C, et al. Synthesis and preclinical evaluation of 11C-UCB-J as a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the brain. J Nucl Med. 2016;57:777–84.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Finnema SJ, Nabulsi NB, Mercier J, Lin S-F, Chen M-K, Matuskey D, et al. Kinetic evaluation and test–retest reproducibility of [11C] UCB-J, a novel radioligand for positron emission tomography imaging of synaptic vesicle glycoprotein 2A in humans. J Cereb Blood Flow Metab. 2018;38:2041–52.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Park B-Y, Seo J, Yi J, Park H. Structural and functional brain connectivity of people with obesity and prediction of body mass index using connectivity. PloS One. 2015;10:e0141376.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. 44.

    Müller-Gärtner HW, Links JM, Prince JL, Bryan RN, McVeigh E, Leal JP, et al. Measurement of radiotracer concentration in brain gray matter using positron emission tomography: MRI-based correction for partial volume effects. J Cereb Blood Flow Metab. 1992;12:571–83.

    PubMed  Article  Google Scholar 

  45. 45.

    Carson R, Naganawa M, Matuskey D, Mecca A, Pittman B, Toyonaga T, et al. Age and sex effects on synaptic density in healthy humans as assessed with SV2A PET. J Nucl Med. 2018;59:541–41.

    Google Scholar 

  46. 46.

    Willeumier KC, Taylor DV, Amen DG. Elevated BMI is associated with decreased blood flow in the prefrontal cortex using SPECT imaging in healthy adults. Obesity (Silver Spring). 2011;19:1095–7.

    Article  Google Scholar 

  47. 47.

    Smart K, Liu H, Matuskey D, Chen M-K, Torres K, Nabulsi N, et al. Binding of the synaptic vesicle radiotracer [11C] UCB-J is unchanged during functional brain activation using a visual stimulation task. J Cereb Blood Flow Metab. 2021;41:1067–79.

  48. 48.

    Meyer TJ, Miller ML, Metzger RL, Borkovec TD. Development and validation of the Penn State Worry Questionnaire. Behav Res Ther. 1990;28:487–95.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Mansur RB, Brietzke E, McIntyre RS. Is there a “metabolic-mood syndrome”? A review of the relationship between obesity and mood disorders. Neurosci Biobehav Rev. 2015;52:89–104.

    PubMed  Article  Google Scholar 

  50. 50.

    Cope EC, LaMarca EA, Monari PK, Olson LB, Martinez S, Zych AD, et al. Microglia play an active role in obesity-associated cognitive decline. J Neurosci. 2018;38:8889–904.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Beyer F, Kharabian Masouleh S, Kratzsch J, Schroeter ML, Röhr S, Riedel-Heller SG, et al. A metabolic obesity profile is associated with decreased gray matter volume in cognitively healthy older adults. Front Aging Neurosci. 2019;11:202.

  52. 52.

    Zonneveld MH, Noordam R, van der Grond J, van Heemst D, Mooijaart SP, Sabayan B, et al. Interplay of circulating leptin and obesity in cognition and cerebral volumes in older adults. Peptides. 2021;135:170424.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Khazen T, Hatoum OA, Ferreira G, Maroun M. Acute exposure to a high-fat diet in juvenile male rats disrupts hippocampal-dependent memory and plasticity through glucocorticoids. Sci Rep. 2019;9:12270.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  54. 54.

    Karanian T, Campbell C, Sloan A, Dupree L, Walker B, Andersen C. Variability in salivary cortisol is associated with body mass index and diet quality. Curr Dev Nutr. 2020;4:532–32.

    PubMed Central  Article  PubMed  Google Scholar 

  55. 55.

    Motamedi S, Karimi I, Jafari F. The interrelationship of metabolic syndrome and neurodegenerative diseases with focus on brain-derived neurotrophic factor (BDNF): kill two birds with one stone. Metab Brain Dis. 2017;32:651–65.

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Cota D, Matter EK, Woods SC, Seeley RJ. The role of hypothalamic mammalian target of rapamycin complex 1 signaling in diet-induced obesity. J Neurosci. 2008;28:7202–08.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Wosiski-Kuhn M, Erion JR, Gomez-Sanchez EP, Gomez-Sanchez CE, Stranahan AM. Glucocorticoid receptor activation impairs hippocampal plasticity by suppressing BDNF expression in obese mice. Psychoneuroendocrinology. 2014;42:165–77.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Gubbi S, Muniyappa R, Sharma ST, Grewal S, McGlotten R, Nieman LK. Mifepristone improves adipose tissue insulin sensitivity in insulin resistant individuals. J Clin Endocrinol Metab. 2021;106:1501–15.

  59. 59.

    Almeida C, Monteiro C, Silvestre S. Inhibitors of 11β-hydroxysteroid dehydrogenase type 1 as potential drugs for type 2 diabetes mellitus—a systematic review of clinical and in vivo preclinical studies. Scientia Pharmaceutica. 2021;89:5.

    CAS  Article  Google Scholar 

  60. 60.

    Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22:238–49.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Agrimi J, Spalletti C, Baroni C, Keceli G, Zhu G, Caragnano A, et al. Obese mice exposed to psychosocial stress display cardiac and hippocampal dysfunction associated with local brain-derived neurotrophic factor depletion. EBioMedicine. 2019;47:384–401.

    PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Santana JMS, Vega-Torres JD, Ontiveros-Angel P, Lee JB, Torres YA, Gonzalez AYC, et al. Oxidative stress and neuroinflammation in a rat model of co-morbid obesity and psychogenic stress. Behav Brain Res. 2021;400:112995.

  63. 63.

    Vanhaute H, Ceccarini J, Michiels L, Koole M, Sunaert S, Lemmens R, et al. In vivo synaptic density loss is related to tau deposition in amnestic mild cognitive impairment. Neurology. 2020;95:e545.

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Fang XT, Mecca AP, Naganawa M, O’Dell RS, Chen M-K, van Dyck CH, et al. ICA-derived sources of synaptic density PET ([11C]UCB-J) relate to cognitive impairment severity in Alzheimer’s disease. Alzheimer’s Dement. 2020;16:e041197.

    Google Scholar 

  65. 65.

    Bae JR, Lee W, Jo YO, Han S, Koh S, Song WK, et al. Distinct synaptic vesicle recycling in inhibitory nerve terminals is coordinated by SV2A. Prog Neurobiol. 2020;194:101879.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Rothman KJ. BMI-related errors in the measurement of obesity. Int J Obes. 2008;32:S56–9.

    Article  Google Scholar 

  67. 67.

    Gutin I. In BMI we trust: reframing the body mass index as a measure of health. Soc Theory Health. 2018;16:256–71.

    PubMed  Article  Google Scholar 

  68. 68.

    Hiura M, Sakata M, Ishii K, Toyohara J, Oda K, Nariai T, et al. Central μ-opioidergic system activation evoked by heavy and severe-intensity cycling exercise in humans: a pilot study using positron emission tomography with 11C-carfentanil. Int J Sports Med. 2017;38:19–26.

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Sleiman SF, Henry J, Al-Haddad R, El Hayek L, Abou Haidar E, Stringer T, et al. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. eLife. 2016;5:e15092.

    PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Lloyd BA, Hake HS, Ishiwata T, Farmer CE, Loetz EC, Fleshner M, et al. Exercise increases mTOR signaling in brain regions involved in cognition and emotional behavior. Behavioural Brain Res. 2017;323:56–67.

    CAS  Article  Google Scholar 

  71. 71.

    Beserra AHN, Kameda P, Deslandes AC, Schuch FB, Laks J, Moraes HSD. Can physical exercise modulate cortisol level in subjects with depression? A systematic review and meta-analysis. Trends Psychiatry Psychother. 2018;40:360–68.

    PubMed  Article  PubMed Central  Google Scholar 

  72. 72.

    Shefer G, Marcus Y, Stern N. Is obesity a brain disease? Neurosci Biobehav Rev. 2013;37:2489–503.

    PubMed  Article  PubMed Central  Google Scholar 

  73. 73.

    Volkow ND, O’Brien CP. Issues for DSM-V: should obesity be included as a brain disorder? Am J Psychiatry. 2007;164:708–10.

    PubMed  Article  PubMed Central  Google Scholar 

Download references

Funding

This work was funded in part by the National Institute of Mental Health, the U.S. Department of Veterans Affairs National Center for PTSD, and the Nancy Taylor Foundation. RHA receives support from the NIMH (T32 MH014276). AMJ is consultant for Novo Nordisk, Eli Lilly, Boehringer Ingelheim, and receives research support from the American Diabetes Association, Eli Lilly, Novo Nordisk, and NIH/NIDDK. SEH, MNP, SRB, REC, RHP, and IE have no further conflicts of interest to disclose.

Author information

Affiliations

Authors

Contributions

RHA was responsible for data analysis and interpretation, in addition to drafting and revising the manuscript. SEH made substantial contributions to data acquisition and analysis, as well as manuscript revisions. AMJ, MNP, and SRB provided critically important intellectual content and manuscript revisions. REC and RHP advised data analysis and interpretation. IE was responsible for the study conception and design and oversaw all aspects of the work.

Corresponding author

Correspondence to Irina Esterlis.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Asch, R.H., Holmes, S.E., Jastreboff, A.M. et al. Lower synaptic density is associated with psychiatric and cognitive alterations in obesity. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-01111-5

Download citation

Search

Quick links