Fluctuations in depression and anxiety predict dysregulated leptin among obese breast cancer survivors

Abstract

Purpose

Leptin influences inflammation and tumor growth and leptin signaling is often dysregulated among obese breast cancer survivors. This leads to a lack of satiety and, ultimately, risk for further weight gain. Breast cancer survivors also experience high rates of depression and anxiety, which are linked to leptin production. This study examined how a woman’s anxiety and depressive symptoms, in combination with their obesity status, were associated with leptin.

Methods

Breast cancer survivors (n = 200, stages 0–IIIa) completed a baseline visit before treatment and two follow-up visits, 6 and 18 months after treatment ended. Women completed anxiety and depression measures, and blood samples provided leptin data at each visit. This study related fluctuations in a survivor’s own depression and anxiety (i.e., within-person effects), as well as average effects of depression and anxiety (i.e., between-person effects) to changes in leptin depending on BMI.

Results

Obese survivors’ leptin was significantly higher at visits when they had higher anxiety and depression symptoms than their own average level of symptoms. In contrast, within-person fluctuations in depression and anxiety were not related to leptin levels among non-obese survivors. No significant between-person effects of depression or anxiety on leptin emerged.

Conclusions

Leptin is a critical risk factor for recurrence and further health consequences. Our findings highlight how psychological health influences leptin production among breast cancer survivors.

Implications for Cancer Survivors

These results highlight a biological pathway that may facilitate further weight gain and health risks among distressed, obese breast cancer survivors.

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

Fig. 1
Fig. 2

References

  1. 1.

    Carreira H, et al. Associations between breast cancer survivorship and adverse mental health outcomes: a systematic review. J Nat Cancer Inst. 2018;110(12):1311–27.

    PubMed  Article  Google Scholar 

  2. 2.

    Di Angelantonio E, et al. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet. 2016;388(10046):776–86.

    PubMed  Article  Google Scholar 

  3. 3.

    Protani M, Coory M, Martin JH. Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis. Breast Cancer Res Treat. 2010;123(3):627–35.

    PubMed  Article  Google Scholar 

  4. 4.

    Chan D, et al. Body mass index and survival in women with breast cancer—systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol. 2014;25(10):1901–14.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007;8(1):21–34.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Allison MB, Myers M. Connecting leptin signaling to biological function. J Endocrinol. 2014;223(1):T25–35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000;404(6778):661–71.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334(5):292–5.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Dallner OS, Marinis JM, Lu YH, Birsoy K, Werner E, Fayzikhodjaeva G, et al. Dysregulation of a long noncoding RNA reduces leptin leading to a leptin-responsive form of obesity. Nat Med. 2019;25(3):507–16.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Jung CH, Kim M-S. Molecular mechanisms of central leptin resistance in obesity. Arch Pharm Res. 2013;36(2):201–7.

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Myers MG Jr, Heymsfield SB, Haft C, Kahn BB, Laughlin M, Leibel RL, et al. Defining clinical leptin resistance-challenges and opportunities. Cell Metab. 2012;15(2):150–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Toh YL, Tan CJ, Yeo AHL, Shwe M, Ho HK, Gan YX, et al. Association of plasma leptin, pro-inflammatory adipokines and cancer-related fatigue in early-stage breast cancer patients: a prospective cohort study. J Cell Mol Med. 2019;23(6):4281–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Blair CK, et al. Obesity and survival among a cohort of breast cancer patients is partially mediated by tumor characteristics. NPJ Breast Cancer. 2019;5(1):1–7.

    Article  Google Scholar 

  14. 14.

    Dieudonne M-N, Machinal-Quelin F, Serazin-Leroy V, Leneveu MC, Pecquery R, Giudicelli Y. Leptin mediates a proliferative response in human MCF7 breast cancer cells. Biochem Biophys Res Commun. 2002;293(1):622–8.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Hu X, et al. Leptin—a growth factor in normal and malignant breast cells and for normal mammary gland development. J Natl Cancer Inst. 2002;94(22):1704–11.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Andò S, et al. Obesity, leptin and breast cancer: epidemiological evidence and proposed mechanisms. Cancers. 2019;11(1):1–27.

    Article  CAS  Google Scholar 

  17. 17.

    Lorincz A, Sukumar S. Molecular links between obesity and breast cancer. Endocr Relat Cancer. 2006;13(2):279–92.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Garofalo C, Surmacz E. Leptin and cancer. J Cell Physiol. 2006;207(1):12–22.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  19. 19.

    Wu M, et al. Circulating levels of leptin, adiposity and breast cancer risk. Br J Cancer. 2009;100(4):578–82.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Jim HS, Andrykowski MA, Munster PN, Jacobsen PB. Physical symptoms/side effects during breast cancer treatment predict posttreatment distress. Ann Behav Med. 2007;34(2):200–8.

    PubMed  Article  Google Scholar 

  21. 21.

    Ng CG, Mohamed S, Kaur K, Sulaiman AH, Zainal NZ, Taib NA, et al. Perceived distress and its association with depression and anxiety in breast cancer patients. PLoS One. 2017;12(3):e0172975.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. 22.

    Walker J, Hansen CH, Martin P, Symeonides S, Ramessur R, Murray G, et al. Prevalence, associations, and adequacy of treatment of major depression in patients with cancer: a cross-sectional analysis of routinely collected clinical data. Lancet Psychiatry. 2014;1(5):343–50.

    PubMed  Article  Google Scholar 

  23. 23.

    Pitman A, et al. Depression and anxiety in patients with cancer. Bmj. 2018;361:1–6.

    Google Scholar 

  24. 24.

    Finger BC, Dinan TG, Cryan JF. Leptin-deficient mice retain normal appetitive spatial learning yet exhibit marked increases in anxiety-related behaviours. Psychopharmacology. 2010;210(4):559–68.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Lawson EA, Miller KK, Blum JI, Meenaghan E, Misra M, Eddy KT, et al. Leptin levels are associated with decreased depressive symptoms in women across the weight spectrum, independent of body fat. Clin Endocrinol. 2012;76(4):520–5.

    CAS  Article  Google Scholar 

  26. 26.

    Yoshida-Komiya H, Takano K, Fujimori K, Niwa SI. Plasma levels of leptin in reproductive-aged women with mild depressive and anxious states. Psychiatry Clin Neurosci. 2014;68(7):574–81.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Masdrakis VG, Papageorgiou C, Markianos M. Associations of plasma leptin to clinical manifestations in reproductive aged female patients with panic disorder. Psychiatry Res. 2017;255:161–6.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Haleem DJ, Sheikh S, Fawad A, Haleem MA. Fasting leptin and glucose in normal weight, over weight and obese men and women diabetes patients with and without clinical depression. Metab Brain Dis. 2017;32(3):757–64.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol. 1988;56(6):893.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Radloff LS. The CES-D scale: a self-report depression scale for research in the general population. Appl Psychol Meas. 1977;1(3):385–401.

    Article  Google Scholar 

  31. 31.

    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(7):824–30.

    PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Andrykowski MA, Donovan KA, Laronga C, Jacobsen PB. Prevalence, predictors, and characteristics of off-treatment fatigue in breast cancer survivors. Cancer. 2010;116(24):5740–8.

    PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994;47(11):1245–51.

    CAS  Article  Google Scholar 

  34. 34.

    Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med. 2001;2(4):297–307.

    PubMed  Article  Google Scholar 

  35. 35.

    Brauer M, Curtin JJ. Linear mixed-effects models and the analysis of nonindependent data: a unified framework to analyze categorical and continuous independent variables that vary within-subjects and/or within-items. Psychol Methods. 2018;23(3):389–411.

    PubMed  Article  Google Scholar 

  36. 36.

    Shrout MR, Renna ME, Madison AA, Alfano CM, Povoski SP, Lipari AM, et al. Relationship satisfaction predicts lower stress and inflammation in breast cancer survivors: a longitudinal study of within-person and between-person effects. Psychoneuroendocrinology. 2020;118:104708.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Rose DP, Gilhooly EM, Nixon DW. Adverse effects of obesity on breast cancer prognosis, and the biological actions of leptin. Int J Oncol. 2002;21(6):1285–92.

    CAS  PubMed  Google Scholar 

  38. 38.

    Naylor C, Petri WA Jr. Leptin regulation of immune responses. Trends Mol Med. 2016;22(2):88–98.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G. Inflammation and cancer: how hot is the link? Biochem Pharmacol. 2006;72(11):1605–21.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Smyth MJ, Cretney E, Kershaw MH, Hayakawa Y. Cytokines in cancer immunity and immunotherapy. Immunol Rev. 2004;202(1):275–93.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Thaker PH, Han LY, Kamat AA, Arevalo JM, Takahashi R, Lu C, et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat Med. 2006;12(8):939–44.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Kiecolt-Glaser JK, Derry HM, Fagundes CP. Inflammation: depression fans the flames and feasts on the heat. Am J Psychiatr. 2015;172(11):1075–91.

    PubMed  Article  Google Scholar 

  43. 43.

    Renna ME, O'Toole MS, Spaeth PE, Lekander M, Mennin DS. The association between anxiety, traumatic stress, and obsessive–compulsive disorders and chronic inflammation: a systematic review and meta-analysis. Depress Anxiety. 2018;35(11):1081–94.

    PubMed  Article  Google Scholar 

  44. 44.

    Sáinz N, Barrenetxe J, Moreno-Aliaga MJ, Martínez JA. Leptin resistance and diet-induced obesity: central and peripheral actions of leptin. Metabolism. 2015;64(1):35–46.

    PubMed  Article  CAS  Google Scholar 

  45. 45.

    Leon-Cabrera S, et al. Hyperleptinemia is associated with parameters of low-grade systemic inflammation and metabolic dysfunction in obese human beings. Front Integr Neurosci. 2013;7:62.

    PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Jaremka, L.M., et al., Interpersonal stressors predict ghrelin and leptin levels in women. 2014. 48: p. 178–188.

  47. 47.

    CoC. Optimal Resources for Cancer Care (2020 Standards). 2019 [cited 2020 04/24/2020]; Available from: https://www.facs.org/-/media/files/quality-programs/cancer/coc/optimal_resources_for_cancer_care_2020_standards.ashx. Accessed 15 July 2020.

  48. 48.

    Andersen BL, DeRubeis R, Berman BS, Gruman J, Champion VL, Massie MJ, et al. Screening, assessment, and care of anxiety and depressive symptoms in adults with cancer: an American Society of Clinical Oncology guideline adaptation. J Clin Oncol. 2014;32(15):1605–19.

    PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Coskun U, et al. Serum leptin, prolactin and vascular endothelial growth factor (VEGF) levels in patients with breast cancer. Neoplasma. 2003;50(1):41–6.

    CAS  PubMed  Google Scholar 

  50. 50.

    Stattin P, Söderberg S, Olsson T, Hallmans G, Lenner P, Biessy C, et al. Plasma leptin and breast cancer risk: a prospective study in northern Sweden. Breast Cancer Res Treat. 2004;86(3):191–6.

    CAS  PubMed  Article  Google Scholar 

Download references

Funding

This work was supported in part by National Institute of Health grants CA131029, UL1TR0000090, CA016058, K05 CA172296, and T32 CA229114.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Megan E. Renna.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of The Ohio State University’s institutional research committee, and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher’s note

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Renna, M.E., Shrout, M.R., Madison, A.A. et al. Fluctuations in depression and anxiety predict dysregulated leptin among obese breast cancer survivors. J Cancer Surviv (2021). https://doi.org/10.1007/s11764-020-00977-6

Download citation

Keywords

  • Breast cancer survivors
  • Leptin
  • Anxiety
  • Depression
  • Obesity