There exists little human neuroscience research to explain why some individuals lose their appetite when they become depressed, while others eat more. Answering this question may reveal much about the various pathophysiologies underlying depression. The present study combined neuroimaging, salivary cortisol, and blood markers of inflammation and metabolism collected prior to scanning. We compared the relationships between peripheral endocrine, metabolic, and immune signaling and brain activity to food cues between depressed participants experiencing increased (N = 23) or decreased (N = 31) appetite and weight in their current depressive episode and healthy control participants (N = 42). The two depression subgroups were unmedicated and did not differ in depression severity, anxiety, anhedonia, or body mass index. Depressed participants experiencing decreased appetite had higher cortisol levels than subjects in the other two groups, and their cortisol values correlated inversely with the ventral striatal response to food cues. In contrast, depressed participants experiencing increased appetite exhibited marked immunometabolic dysregulation, with higher insulin, insulin resistance, leptin, CRP, IL-1RA, and IL-6, and lower ghrelin than subjects in other groups, and the magnitude of their insulin resistance correlated positively with the insula response to food cues. These findings provide novel evidence linking aberrations in homeostatic signaling pathways within depression subtypes to the activity of neural systems that respond to food cues and select when, what, and how much to eat. In conjunction with prior work, the present findings strongly support the existence of pathophysiologically distinct depression subtypes for which the direction of appetite change may be an easily measured behavioral marker.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $62.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Kraepelin E. Lectures on clinical psychiatry. New York, NY: Wood; 1904.
Li Y, Aggen S, Shi S, Gao J, Li Y, Tao M, et al. Subtypes of major depression: latent class analysis in depressed Han Chinese women. Psychol Med. 2014;44:3275–88.
Sullivan PF, Kessler RC, Kendler KS. Latent class analysis of lifetime depressive symptoms in the national comorbidity survey. Am J Psychiatry. 1998;155:1398–406.
Sullivan PF, Prescott CA, Kendler KS. The subtypes of major depression in a twin registry. J Affect Disord. 2002;68:273–84.
Ten Have M, Lamers F, Wardenaar K, Beekman A, de Jonge P, van Dorsselaer S, et al. The identification of symptom-based subtypes of depression: a nationally representative cohort study. J Affect Disord. 2016;190:395–406.
Maxwell MA, Cole DA. Weight change and appetite disturbance as symptoms of adolescent depression: Toward an integrative biopsychosocial model. Clin Psychol Rev. 2009;29:260–73.
Nierenberg AA, Pava JA, Clancy K, Rosenbaum JF, Fava M. Are neurovegetative symptoms stable in relapsing or recurrent atypical depressive episodes? Biol Psychiatry. 1996;40:691–6.
Lamers F, Rhebergen D, Merikangas KR, de Jonge P, Beekman AT, Penninx BW. Stability and transitions of depressive subtypes over a 2-year follow-up. Psychol Med. 2012;42:2083–93.
Simmons WK, Burrows K, Avery JA, Kerr KL, Bodurka J, Savage CR, et al. Depression-related increases and decreases in appetite: dissociable patterns of aberrant activity in reward and interoceptive neurocircuitry. Am J Psychiatry. 2016;173:418–28.
Craig AD. How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci. 2002;33:655–66.
Barrett LF, Simmons WK. Interoceptive predictions in the brain. Nat Rev Neurosci. 2015;16:419–29.
Simmons WK, Avery JA, Barcalow JC, Bodurka J, Drevets WC, Bellgowan P. Keeping the body in mind: insula functional organization and functional connectivity integrate interoceptive, exteroceptive, and emotional awareness. Human brain Mapp. 2013;34:2944–58.
Critchley HD, Harrison NA. Visceral influences on brain and behavior. Neuron. 2013;77:624–38.
Harrison NA, Voon V, Cercignani M, Cooper EA, Pessiglione M, Critchley HD. A neurocomputational account of how inflammation enhances sensitivity to punishments versus rewards. Biol Psychiatry. 2015;80:73–81.
Jastreboff AM, Lacadie C, Seo D, Kubat J, Van Name MA, Giannini C, et al. Leptin is associated with exaggerated brain reward and emotion responses to food images in adolescent obesity. Diabetes care. 2014;37:3061–8.
Montoya ER, Bos PA, Terburg D, Rosenberger LA, van Honk J. Cortisol administration induces global down-regulation of the brain’s reward circuitry. Psychoneuroendocrinology. 2014;47:31–42.
Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Dolan RJ, et al. Neural origins of human sickness in interoceptive responses to inflammation. Biol Psychiatry. 2009;66:415–22.
Page KA, Seo D, Belfort-DeAguiar R, Lacadie C, Dzuira J, Naik S, et al. Circulating glucose levels modulate neural control of desire for high-calorie foods in humans. J Clin Investig. 2011;121:4161–9.
Malik S, McGlone F, Bedrossian D, Dagher A. Ghrelin modulates brain activity in areas that control appetitive behavior. Cell Metab. 2008;7:400–9.
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;99:1319–30.
Kelley AE, Baldo BA, Pratt WE, Will MJ. Corticostriatal-hypothalamic circuitry and food motivation: Integration of energy, action and reward. Physiol Behav. 2005;86:773–95.
Domingos AI, Vaynshteyn J, Voss HU, Ren X, Gradinaru V, Zang F, et al. Leptin regulates the reward value of nutrient. Nat Neurosci. 2011;14:1562–8.
Capuron L, Pagnoni G, Drake DF, Woolwine BJ, Spivey JR, Crowe RJ, et al. Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration. Arch General Psychiatry. 2012;69:1044–53.
Andreasson A, Arborelius L, Erlanson-Albertsson C, Lekander M. A putative role for cytokines in the impaired appetite in depression. Brain, Behav, Immun. 2007;21:147–52.
Penninx BW, Milaneschi Y, Lamers F, Vogelzangs N. Understanding the somatic consequences of depression: biological mechanisms and the role of depression symptom profile. BMC Med. 2013;11:129.
Binder EB, Nemeroff CB. The CRF system, stress, depression and anxiety-insights from human genetic studies. Mol Psychiatry. 2010;15:574–88.
Gold PW. The organization of the stress system and its dysregulation in depressive illness. Mol Psychiatry. 2015;20:32–47.
van Reedt Dortland AK, Giltay EJ, van Veen T, van Pelt J, Zitman FG, Penninx BW. Associations between serum lipids and major depressive disorder: results from the Netherlands Study of Depression and Anxiety (NESDA). J Clin Psychiatry. 2010;71:729–36.
Lamers F, Vogelzangs N, Merikangas KR, de Jonge P, Beekman AT, Penninx BW. Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Mol Psychiatry. 2013;18:692–9.
Milaneschi Y, Lamers F, Bot M, Drent ML, Penninx BW. Leptin dysregulation is specifically associated with major depression with atypical features: evidence for a mechanism connecting obesity and depression. Biol Psychiatry. 2015;81:807–14.
Benjamini A, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B. 1995;57:289–300.
Pariante CM, Lightman SL. The HPA axis in major depression: classical theories and new developments. Trends Neurosci. 2008;31:464–8.
Nemeroff CB. The role of corticotropin-releasing factor in the pathogenesis of major depression. Pharmacopsychiatry. 1988;21:76–82.
Herbert J. Cortisol and depression: three questions for psychiatry. Psychol Med. 2013;43:449–69.
Carroll BJ, Cassidy F, Naftolowitz D, Tatham NE, Wilson WH, Iranmanesh A, et al. Pathophysiology of hypercortisolism in depression. Acta Psychiatr Scand Suppl. 2007;433:90–103.
Carroll BJ, Iranmanesh A, Keenan DM, Cassidy F, Wilson WH, Veldhuis JD. Pathophysiology of hypercortisolism in depression: pituitary and adrenal responses to low glucocorticoid feedback. Acta Psychiatr Scand. 2012;125:478–91.
Knorr U, Vinberg M, Kessing LV, Wetterslev J. Salivary cortisol in depressed patients versus control persons: a systematic review and meta-analysis. Psychoneuroendocrinology. 2010;35:1275–86.
Kaestner F, Hettich M, Peters M, Sibrowski W, Hetzel G, Ponath G, et al. Different activation patterns of proinflammatory cytokines in melancholic and non-melancholic major depression are associated with HPA axis activity. J Affect Disord. 2005;87:305–11.
O’Keane V, Frodl T, Dinan TG. A review of Atypical depression in relation to the course of depression and changes in HPA axis organization. Psychoneuroendocrinology. 2012;37:1589–99.
Karlovic D, Serretti A, Vrkic N, Martinac M, Marcinko D. Serum concentrations of CRP, IL-6, TNF-alpha and cortisol in major depressive disorder with melancholic or atypical features. Psychiatry Res. 2012;198:74–80.
Casper RC, Kocsis J, Dysken M, Stokes P, Croughan J, Maas J. Cortisol measures in primary major depressive disorder with hypersomnia or appetite increase. J Affect Disord. 1988;15:131–40.
Gold PW, Chrousos GP. Melancholic and atypical subtypes of depression represent distinct pathophysiological entities: CRH, neural circuits, and the diathesis for anxiety and depression. Mol Psychiatry. 2013;18:632–4.
Berridge KC. ‘Liking’ and ‘wanting’ food rewards: brain substrates and roles in eating disorders. Physiol Behav. 2009;97:537–50.
Berridge KC, Ho CY, Richard JM, DiFeliceantonio AG. The tempted brain eats: pleasure and desire circuits in obesity and eating disorders. Brain Res. 2010;1350:43–64.
Rudenga KJ, Sinha R, Small DM. Acute stress potentiates brain response to milkshake as a function of body weight and chronic stress. Int J Obes. 2013;37:309–16.
Li Y, Sescousse G, Dreher JC. Endogenous cortisol levels are associated with an imbalanced striatal sensitivity to monetary versus non-monetary cues in pathological gamblers. Front Behav Neurosci. 2014;8:83.
Licinio J, Negrao AB, Wong ML. Plasma leptin concentrations are highly correlated to emotional states throughout the day. Transl Psychiatry. 2014;4:e475.
Guo M, Huang TY, Garza JC, Chua SC, Lu XY. Selective deletion of leptin receptors in adult hippocampus induces depression-related behaviours. Int J Neuropsychopharmacol. 2013;16:857–67.
Farr OM, Fiorenza C, Papageorgiou P, Brinkoetter M, Ziemke F, Koo BB, et al. Leptin therapy alters appetite and neural responses to food stimuli in brain areas of leptin-sensitive subjects without altering brain structure. J Clin Endocrinol Metab. 2014;99:E2529–38.
Stieg MR, Sievers C, Farr O, Stalla GK, Mantzoros CS. Leptin: a hormone linking activation of neuroendocrine axes with neuropathology. Psychoneuroendocrinology. 2015;51:47–57.
Lu XY. The leptin hypothesis of depression: a potential link between mood disorders and obesity? Curr Opin Pharmacol. 2007;7:648–52.
Zupancic ML, Mahajan A. Leptin as a neuroactive agent. Psychosom Med. 2011;73:407–14.
Milaneschi Y, Lamers F, Bot M, Drent ML, Penninx BW. 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.
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.
Milaneschi Y, Sutin AR, Terracciano A, Canepa M, Gravenstein KS, Egan JM, et al. The association between leptin and depressive symptoms is modulated by abdominal adiposity. Psychoneuroendocrinology. 2014;42:1–10.
Munzberg H, Myers MG Jr. Molecular and anatomical determinants of central leptin resistance. Nat Neurosci. 2005;8:566–70.
Jung CH, Kim MS. Molecular mechanisms of central leptin resistance in obesity. Arch Pharm Res. 2013;36:201–7.
Cui H, Lopez M, Rahmouni K. The cellular and molecular bases of leptin and ghrelin resistance in obesity. Nat Rev Endocrinol. 2017;13:338–51.
Hribal ML, Fiorentino TV, Sesti G. Role of C reactive protein (CRP) in leptin resistance. Curr Pharm Des. 2014;20:609–15.
Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D. Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell. 2008;135:61–73.
Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219–46.
Chen L, Chen R, Wang H, Liang F. Mechanisms linking inflammation to insulin resistance. Int J Endocrinol. 2015;2015:508409.
Su D, Coudriet GM, Hyun Kim D, Lu Y, Perdomo G, Qu S, et al. FoxO1 links insulin resistance to proinflammatory cytokine IL-1beta production in macrophages. Diabetes. 2009;58:2624–33.
Boni-Schnetzler M, Donath MY. How biologics targeting the IL-1 system are being considered for the treatment of type 2 diabetes. Br J Clin Pharmacol. 2013;76:263–8.
Serrano-Marco L, Barroso E, El Kochairi I, Palomer X, Michalik L, Wahli W, et al. The peroxisome proliferator-activated receptor (PPAR) beta/delta agonist GW501516 inhibits IL-6-induced signal transducer and activator of transcription 3 (STAT3) activation and insulin resistance in human liver cells. Diabetologia. 2012;55:743–51.
Lukic L, Lalic NM, Rajkovic N, Jotic A, Lalic K, Milicic T, et al. Hypertension in obese type 2 diabetes patients is associated with increases in insulin resistance and IL-6 cytokine levels: potential targets for an efficient preventive intervention. Int J Environ Res Public Health. 2014;11:3586–98.
Simmons WK, Rapuano KM, Kallman SJ, Ingeholm JE, Miller B, Gotts SJ, et al. Category-specific integration of homeostatic signals in caudal but not rostral human insula. Nat Neurosci. 2013;16:1551–2.
Kroemer NB, Krebs L, Kobiella A, Grimm O, Vollstadt-Klein S, Wolfensteller U, et al. Still) longing for food: insulin reactivity modulates response to food pictures. Human brain Mapp. 2013;34:2367–80.
Musselman DL, Miller AH, Porter MR, Manatunga A, Gao F, Penna S, et al. Higher than normal plasma interleukin-6 concentrations in cancer patients with depression: preliminary findings. Am J Psychiatry. 2001;158:1252–7.
Nikkheslat N, Zunszain PA, Horowitz MA, Barbosa IG, Parker JA, Myint AM, et al. Insufficient glucocorticoid signaling and elevated inflammation in coronary heart disease patients with comorbid depression. Brain, Behav, Immun. 2015;48:8–18.
Menard C, Pfau ML, Hodes GE, Kana V, Wang VX, Bouchard S, et al. Social stress induces neurovascular pathology promoting depression. Nat Neurosci. 2017;20:1752–60.
Muller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, et al. Ghrelin. Mol Metab. 2015;4:437–60.
Otero M, Nogueiras R, Lago F, Dieguez C, Gomez-Reino JJ, Gualillo O. Chronic inflammation modulates ghrelin levels in humans and rats. Rheumatol (Oxf). 2004;43:306–10.
Lutter M, Sakata I, Osborne-Lawrence S, Rovinsky SA, Anderson JG, Jung S, et al. The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress. Nat Neurosci. 2008;11:752–3.
Wittekind DA, Kluge M. Ghrelin in psychiatric disorders–a review. Psychoneuroendocrinology. 2015;52:176–94.
Holsen LM, Lawson EA, Christensen K, Klibanski A, Goldstein JM. Abnormal relationships between the neural response to high- and low-calorie foods and endogenous acylated ghrelin in women with active and weight-recovered anorexia nervosa. Psychiatry Res. 2014;223:94–103.
Kluge M, Schussler P, Schmid D, Uhr M, Kleyer S, Yassouridis A, et al. Ghrelin plasma levels are not altered in major depression. Neuropsychobiology. 2009;59:199–204.
Akter S, Pham NM, Nanri A, Kurotani K, Kuwahara K, Jacka FN, et al. Association of serum leptin and ghrelin with depressive symptoms in a Japanese working population: a cross-sectional study. BMC Psychiatry. 2014;14:203.
Ozsoy S, Besirli A, Abdulrezzak U, Basturk M. Serum ghrelin and leptin levels in patients with depression and the effects of treatment. Psychiatry Investig. 2014;11:167–72.
Alonso-Alonso M, Ziemke F, Magkos F, Barrios FA, Brinkoetter M, Boyd I, et al. Brain responses to food images during the early and late follicular phase of the menstrual cycle in healthy young women: relation to fasting and feeding. Am J Clin Nutr. 2011;94:377–84.
Jacobs EG, Holsen LM, Lancaster K, Makris N, Whitfield-Gabrieli S, Remington A, et al. 17beta-Estradiol differentially regulates stress circuitry activity in healthy and depressed women. Neuropsychopharmacology. 2014;40:566–76.
Milaneschi Y, Lamers F, Peyrot WJ, Abdellaoui A, Willemsen G, Hottenga JJ, et al. Polygenic dissection of major depression clinical heterogeneity. Mol Psychiatry. 2015;21:516–22.
This research was supported by the National Institute of Mental Health (K01MH096175-01) grant to WKS, and NARSAD Young Investigator Award to WKS. WKS also receives funding from a National Institute of General Medical Sciences Center Grant (1P20GM121312). We also wish to thank the University of Oklahoma Integrative Immunology Center for assistance with running immunoassays.
Conflict of interest
WKS and WCD are employees of Janssen Research and Development, LLC., of Johnson and Johnson, and WCD holds equity in Johnson and Johnson. WCD and WKS are co-inventors on a patent regarding appetite change in depression. The remaining authors declare that they have no conflict of interest.
Electronic supplementary material
About this article
Glucocorticoid Resistance: Is It a Requisite for Increased Cytokine Production in Depression? A Systematic Review and Meta-Analysis
Frontiers in Psychiatry (2019)
Ghrelin Fights Against Titanium Particle-Induced Inflammatory Osteolysis Through Activation of β-Catenin Signaling Pathway
Translational Psychiatry (2019)
Anhedonia in depression symptomatology: Appetite dysregulation and defective brain reward processing
Behavioural Brain Research (2019)
Frontiers in Psychiatry (2018)