Article | Published:

Clinical Research

Sex-specific roles of cellular inflammation and cardiometabolism in obesity-associated depressive symptomatology

Abstract

Background

Obesity and depression are complex conditions with stronger comorbid relationships among women than men. Inflammation and cardiometabolic dysfunction are likely mechanistic candidates for increased depression risk, and their prevalence differs by sex. Whether these relationships extend to depressive symptoms is poorly understood. Therefore, we analyzed sex in associations between inflammation and metabolic syndrome (MetS) criteria on depressive symptomatology. Specifically, we examined whether sex positively moderates the relationship between depressive symptoms and inflammation among women, and whether MetS has parallel effects among men.

Methods

Depressive symptoms, MetS, and inflammation were assessed in 129 otherwise healthy adults. Depressive symptoms were assessed using Beck Depression Inventory (BDI-Ia). Monocyte inflammation regulation (BARIC) was quantified using flow cytometry measurement of TNF-α suppression by β-agonist. Moderation effects of sex on associations between BARIC, MetS criteria, and BDI were estimated using two-way ANOVA and linear regression, adjusting for BMI, and by sex subgroup analyses.

Results

Obese individuals reported more depressive symptoms. Sex did not formally moderate this relationship, though BDI scores tended to differ by BMI among women, but not men, in subgroup analysis. Poorer inflammation control and higher MetS criteria were correlated with somatic depressive symptoms. Sex moderated associations between MetS criteria and somatic symptoms; among men, MetS criteria predicted somatic symptoms, not among women. Subgroup analysis further indicated that poorer inflammation control tended to be associated with higher somatic symptoms in women.

Conclusions

These results indicate that obesity-related inflammation and MetS factors have sex-specific effects on depressive symptoms in a non-clinical population. Although pathophysiological mechanisms underlying sex differences remain to be elucidated, our findings suggest that distinct vulnerabilities to depressive symptoms exist between women and men, and highlight the need to consider sex as a key biological variable in obesity-depression relationships. Future clinical studies on comorbid obesity and depression should account for sex, which may optimize therapeutic strategies.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

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

References

  1. 1.

    Pratt LA, Brody DJ. Depression and obesity in the U.S. Adult household population, 2005–2010. NCHS Data Brief. 2014;167:1–8.

  2. 2.

    Luppino FS, de Wit LM, Bouvy PF, Stijnen T, Cuijpers P, Penninx BWJH, et al. Overweight, obesity, and depression. Arch Gen Psychiatry. 2010;67:220.

  3. 3.

    Woo Y, Seo H-J, McIntyre R, Bahk W-M. Obesity and Its potential effects on antidepressant treatment outcomes in patients with depressive disorders: a literature review. Int J Mol Sci. 2016;17:80.

  4. 4.

    Fabricatore AN, Wadden TA, Moore RH, Butryn ML, Heymsfield SB, Nguyen AM. Predictors of attrition and weight loss success: Results from a randomized controlled trial. Behav Res Ther. 2009;47:685–91.

  5. 5.

    de Wit L, Luppino F, van Straten A, Penninx B, Zitman F, Cuijpers P. Depression and obesity: A meta-analysis of community-based studies. Psychiatry Res. 2010;178:230–5.

  6. 6.

    Tronieri JS, Wurst CMC, Pearl RL, Allison KC. Sex Differences in obesity and mental health. Curr Psychiatry Rep. 2017;19. https://doi.org/10.1007/s11920-017-0784-8.

  7. 7.

    Bangasser DA, Valentino RJ. Sex differences in stress-related psychiatric disorders: neurobiological perspectives. Front Neuroendocrinol. 2014;35:303–19.

  8. 8.

    Shi H, Seeley RJ, Clegg DJ. Sexual differences in the control of energy homeostasis. Front. Neuroendocrinol. 2009;30:396–404.

  9. 9.

    Juster RP, Hatzenbuehler ML, Mendrek A, Pfaus JG, Smith NG, Johnson PJ, et al. Sexual orientation modulates endocrine stress reactivity. Biol Psychiatry. 2015;77:668–76.

  10. 10.

    Zagni E, Simoni L, Colombo D, Zagni E, Simoni L, Colombo D. Sex and gender differences in central nervous system-related disorders. Neurosci J. 2016;2016:1–13.

  11. 11.

    Seedat S, Scott KM, Angermeyer MC, Berglund P, Bromet EJ, Brugha TS, et al. Cross-national associations between gender and mental disorders in the World Health Organization World Mental Health Surveys. Arch Gen Psychiatry. 2009;66:785–95.

  12. 12.

    Capuron L, Lasselin J, Castanon N. Role of adiposity-driven inflammation in depressive morbidity. Neuropsychopharmacology. 2017;42:115–28.

  13. 13.

    Ahmadi-Abhari S, Luben RN, Wareham NJ, Khaw KT. Seventeen year risk of all-cause and cause-specific mortality associated with C-reactive protein, fibrinogen and leukocyte count in men and women: The EPIC-Norfolk study. Eur J Epidemiol. 2013;28:541–50.

  14. 14.

    Dalmas E, Clément K, Guerre-Millo M. Defining macrophage phenotype and function in adipose tissue. Trends Immunol. 2011;32:307–14.

  15. 15.

    Young JJ, Bruno D, Pomara N. A review of the relationship between proinflammatory cytokines and major depressive disorder. J Affect Disord. 2014;169:15–20.

  16. 16.

    Felger JC, Lotrich FE. Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications. Neuroscience. 2013;246:199–229.

  17. 17.

    Calabrese F, Rossetti AC, Racagni G, Gass P, Riva MA, Molteni R. Brain-derived neurotrophic factor: a bridge between inflammation and neuroplasticity. Front Cell Neurosci. 2014;8:1–7.

  18. 18.

    Raison CL, Miller AH. Is depression an inflammatory disorder? Curr Psychiatry Rep. 2011;13:467–75.

  19. 19.

    Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, et al. A randomized controlled trial of the Tumor Necrosis Factor-alpha antagonist infliximab in treatment resistant depression: role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70:31–41.

  20. 20.

    Derry HM, Padin AC, Kuo JL, Hughes S, Kiecolt-Glaser JK. Sex differences in depression: does inflammation play a role? Curr Psychiatry Rep. 2015;17. https://doi.org/10.1007/s11920-015-0618-5.

  21. 21.

    Moieni M, Irwin MR, Jevtic I, Olmstead R, Breen EC, Eisenberger NI. Sex Differences in Depressive and Socioemotional Responses to an Inflammatory Challenge: Implications for Sex Differences in Depression. Neuropsychopharmacology. 2015;40:1–8.

  22. 22.

    Valentine RJ, McAuley E, Vieira VJ, Baynard T, Hu L, Evans EM, et al. Sex differences in the relationship between obesity, C-reactive protein, physical activity, depression, sleep quality and fatigue in older adults. Brain Behav Immun. 2009;23:643–8.

  23. 23.

    Slavich GM, Irwin MR. From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychol Bull. 2014;140:774–815.

  24. 24.

    Goel N, Workman JL, Lee TT, Innala L, Viau V. Sex differences in the HPA axis. Compr Physiol. 2014;4:1121–55.

  25. 25.

    Prather AA, Carroll JE, Fury JM, McDade KK, Ross D, Marsland AL. Gender differences in stimulated cytokine production following acute psychological stress. Brain Behav Immun. 2009;23:622–8.

  26. 26.

    Rohleder N, Schommer NC, Hellhammer DH, Engel R, Kirschbaum C. Sex differences in glucocorticoid sensitivity of proinflammatory cytokine production after psychosocial stress. Psychosom Med. 2001;63:966–72.

  27. 27.

    McEwen BS, Milner TA. Understanding the broad influence of sex hormones and sex differences in the brain. J Neurosci Res. 2017;95:24–39.

  28. 28.

    Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther. 2011;130:226–38.

  29. 29.

    Choi J, Joseph L, Pilote L. Obesity and C-reactive protein in various populations: a systematic review and meta-analysis. Obes Rev. 2013;14:232–44.

  30. 30.

    Fuente-Martín E, Argente-Arizón P, Ros P, Argente J, Chowen JA. Sex differences in adipose tissue: It is not only a question of quantity and distribution. Adipocyte. 2013;2:128–34.

  31. 31.

    Cartier A, Cote M, Lemieux I, Perusse L, Tremblay A, Bouchard C, et al. Sex differences in inflammatory markers: what is the contribution of. Am J Clin Nutr. 2009;89:1307–14.

  32. 32.

    Yang Y, Kozloski M. Sex differences in age trajectories of physiological dysregulation: Inflammation, metabolic syndrome, and allostatic load. Journals Gerontol - Ser A Biol Sci Med Sci. 2011;66 A:493–500.

  33. 33.

    Pan A, Keum N, Okereke OI, Sun Q, Kivimaki M, Rubin RR, et al. Bidirectional association between depression and metabolic syndrome: A systematic review and meta-analysis of epidemiological studies. Diabetes Care. 2012;35:1171–80.

  34. 34.

    Wildman RP, Muntner P, Reynolds K, McGinn AP, Rajpathak S, Wylie-Rosett J, et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering. Arch Intern Med. 2008;168:1617–24.

  35. 35.

    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.

  36. 36.

    Jokela M, Hamer M, Singh-Manoux A, Batty GD, Kivimaki M. Association of metabolically healthy obesity with depressive symptoms: pooled analysis of eight studies. Mol Psychiatry. 2014;19:910–4.

  37. 37.

    Marijnissen RM, JEMP Smits, Schoevers RA, Van Den Brink RHS, Holewijn S, Franke B, et al. Association between metabolic syndrome and depressive symptom profiles - Sex-specific? J Affect Disord. 2013;151:1138–42.

  38. 38.

    Rhee SJ, Kim EY, Kim SH, Lee HJ, Kim B, Ha K, et al. Subjective depressive symptoms and metabolic syndrome among the general population. Prog Neuro-Psychopharmacology Biol Psychiatry. 2014;54:223–30.

  39. 39.

    Delisle VC, Beck AT, Dobson KS, Dozois DJA, Thombs BD. Revisiting gender differences in somatic symptoms of depression: much ado about nothing? PLoS ONE. 2012;7:5–9.

  40. 40.

    Hong S, Dimitrov S, Cheng T, Redwine L, Pruitt C, Mills PJ, et al. Beta-adrenergic receptor mediated inflammation control by monocytes is associated with blood pressure and risk factors for cardiovascular disease. Brain Behav Immun. 2015;50:31–8.

  41. 41.

    Mulvahill JS, Nicol GE, Dixon D, Lenze EJ, Karp JF, Reynolds CF, et al. Effect of metabolic syndrome on late-life depression: associations with disease severity and treatment resistance. J Am Geriatr Soc. 2017;65:2651–8.

  42. 42.

    Brookes ST, Whitely E, Egger M, Smith GD, Mulheran PA, Peters TJ. Subgroup analyses in randomized trials: risks of subgroup-specific analyses; power and sample size for the interaction test. J Clin Epidemiol. 2004;57:229–36.

  43. 43.

    Beck AT, Steer RA. Manual for the Beck Depression inventory. Psychological Corporation, San Antonio, TX, USA 1993.

  44. 44.

    Cheng T, Dimitrov S, Pruitt C, Hong S. Glucocorticoid mediated regulation of inflammation in human monocytes is associated with depressive mood and obesity. Psychoneuroendocrinology. 2016;66:195–204.

  45. 45.

    Preiss K, Brennan L, Clarke D. A systematic review of variables associated with the relationship between obesity and depression. Obes Rev. 2013;14:906–18.

  46. 46.

    Cavanagh A, Wilson CJ, Kavanagh DJ, Caputi P. Differences in the expression of symptoms in men versus women with depression. Harv Rev Psychiatry. 2017;25:29–38.

  47. 47.

    Lasserre AM, Strippoli M-PF, Glaus J, Gholam-Rezaee M, Vandeleur CL, Castelao E, et al. Prospective associations of depression subtypes with cardio-metabolic risk factors in the general population. Mol Psychiatry. 2017;22:1026–34.

  48. 48.

    Milaneschi Y, Lamers F, Bot M.Drent ML, Penninx BWJH. Leptin dysregulation is specifically associated with major depression with atypical features: evidence for a mechanism connecting obesity and depression. Biol Psychiatry. 2017;81:807–14.

  49. 49.

    Kennedy A, Gettys TW, Watson P, Wallace P, Ganaway E, Pan Q, et al. The metabolic significance of leptin in humans: gender based differences in relationship to adiposity, insulin sensitivity, and energy expenditure. J Clin Endocrinol Metab. 1997;82:1293–1300.

  50. 50.

    Milaneschi Y, Simonsick EM, Vogelzangs N, Strotmeyer ES, Yaffe K, Harris TB, et al. Leptin, abdominal obesity, and onset of depression in older men and women. J Clin Psychiatry. 2012;73:1205–11.

  51. 51.

    Tabák AG, Akbaraly TN, Batty GD, Kivimäki M. Depression and type 2 diabetes: a causal association? Lancet Diabetes Endocrinol. 2014;2:236–2452.

  52. 52.

    Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat Rev Immunol. 2011;11:85–97.

  53. 53.

    Wohleb ES, McKim DB, Sheridan JF, Godbout JP. Monocyte trafficking to the brain with stress and inflammation: a novel axis of immune-to-brain communication that influences mood and behavior. Front Neurosci. 2015;9:1–17.

  54. 54.

    Alvares GA, Quintana DS, Hickie IB, Guastella AJ. Autonomic nervous system dysfunction in psychiatric disorders and the impact of psychotropic medications: A systematic review and meta-analysis. J Psychiatry Neurosci. 2016;41:89–104.

  55. 55.

    Powell ND, Sloan EK, Bailey MT, Arevalo JMG, Miller GE, Chen E, et al. Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis. Proc Natl Acad Sci USA. 2013;110:16574–9.

  56. 56.

    Taylor LE, Sullivan JC. Sex differences in obesity-induced hypertension and vascular dysfunction: a protective role for estrogen in adipose tissue inflammation? Am J Physiol Regul Integr Comp Physiol. 2016;2016: ajpregu.00202.

  57. 57.

    Miller AH, Raison CL. The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nat Rev Immunol. 2016;16:22–34.

  58. 58.

    Baumeister H, Hutter N, Bengel J. Psychological and pharmacological interventions for depression in patients with diabetes mellitus: an abridged Cochrane review. Diabet Med. 2014;31:773–86.

  59. 59.

    García-Toro M, Vicens-Pons E, Gili M, Roca M, Serrano-Ripoll MJ, Vives M, et al. Obesity, metabolic syndrome and Mediterranean diet: impact on depression outcome. J Affect Disord. 2016;194:105–8.

  60. 60.

    Lin KW, Wroolie TE, Robakis T, Rasgon NL. Adjuvant pioglitazone for unremitted depression: clinical correlates of treatment response. Psychiatry Res. 2015;230:846–52.

  61. 61.

    Psaltopoulou T, Sergentanis TN, Panagiotakos DB, Sergentanis IN, Kosti R, Scarmeas N. Mediterranean diet, stroke, cognitive impairment, and depression: a meta-analysis. Ann Neurol. 2013;74:580–91.

  62. 62.

    Schachter J, Martel J, Lin C-S, Chang C-J, Wu T-R, Lu C-C, et al. Effects of obesity on depression: a role for inflammation and the gut microbiota. Brain Behav Immun. 2017. https://doi.org/10.1016/j.bbi.2017.08.026

  63. 63.

    Pietrzak RH, Kinley J, Afifi TO, Enns MW, Fawcett J, Sareen J. Subsyndromal depression in the United States: prevalence, course, and risk for incident psychiatric outcomes. Psychol Med. 2013;43:1401–14.

Download references

Acknowledgements

This work was partially supported by the research grants R01HL090975 (SH) and HL090975S1 (American Recovery and Reinvestment Act grant; SH), UL1RR031980 for the UCSD Clinical and Translational Science Awards, and TL1TR001443 (JNK) from the National Institutes of Health.

Author information

Conflict of interest

The authors declare that they have no conflict of interest.

Correspondence to Suzi Hong.

Supplementary information

Supplementary Figure Legends

Supplementary Figure 1

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1
Fig. 2