Insulin signaling is critical for neuroplasticity, cerebral metabolism as well as for systemic energy metabolism. In rodent studies, impaired brain insulin signaling with resultant insulin resistance (IR) modulates synaptic plasticity and the corresponding behavioral functions. Despite discoveries of central actions of insulin, in vivo molecular mechanisms of brain IR until recently have proven difficult to study in the human brain. In the current study, we leveraged recent technological advances in molecular biology and herein report an increased number of exosomes enriched for L1CAM, a marker predominantly expressed in the brain, in subjects with major depressive disorder (MDD) as compared with age- and sex-matched healthy controls (HC). We also report increased concentration of the insulin receptor substrate-1 (IRS-1) in L1CAM+ exosomes in subjects with MDD as compared with age- and sex-matched HC. We found a relationship between expression of IRS-1 in L1CAM+ exosomes and systemic IR as assessed by homeostatic model assessment of IR in HC, but not in subjects with MDD. The increased IRS-1 levels in L1CAM+ exosomes were greater in subjects with MDD and were associated with suicidality and anhedonia. Finally, our data suggested sex differences in serine-312 phosphorylation of IRS-1 in L1CAM+ exosomes in subjects with MDD. These findings provide a starting point for creating mechanistic framework of brain IR in further development of personalized medicine strategies to effectively treat MDD.
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.
Arnold SE, Arvanitakis Z, Macauley-Rambach SL, Koenig AM, Wang HY, Ahima RS, et al. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nat Rev Neurol. 2018;14:168–81.
Biessels GJ, Reagan LP. Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci. 2015;16:660–71.
Grillo CA, Piroli GG, Lawrence RC, Wrighten SA, Green AJ, Wilson SP, et al. Hippocampal insulin resistance impairs spatial learning and synaptic plasticity. Diabetes. 2015;64:3927–36.
Ferrario CR, Reagan LP. Insulin-mediated synaptic plasticity in the CNS: Anatomical, functional and temporal contexts. Neuropharmacology. 2018;136:182–91.
Nasca C, Rasgon N, McEwen B. An emerging epigenetic framework of systemic and central mechanisms underlying stress-related disorders. Neuropsychopharmacology. 2019;44:235–6.
Watson K, Nasca C, Aasly L, McEwen B, Rasgon N. Insulin resistance, an unmasked culprit in depressive disorders: promises for interventions. Neuropharmacology. 2018;136(Pt B):327–34.
Reaven GM. Pathophysiology of insulin resistance in human disease. Physiol Rev. 1995;75:473–86.
Kenna H, Hoeft F, Kelley R, Wroolie T, DeMuth B, Reiss A, et al. Fasting plasma insulin and the default mode network in women at risk for Alzheimer’s disease. Neurobiol Aging. 2013;34:641–9.
Rasgon NL, Kenna HA, Wroolie TE, Kelley R, Silverman D, Brooks J, et al. Insulin resistance and hippocampal volume in women at risk for Alzheimer’s disease. Neurobiol Aging. 2011;32:1942–8.
Wroolie TE, Kenna HA, Singh MK, Rasgon NL. Association between insulin resistance and cognition in patients with depressive disorders: exploratory analyses into age-specific effects. J Psychiatr Res. 2015;60:65–72.
Nasca C, Watson-Lin K, Bigio B, Robakis TK, Myoraku A, Wroolie TE, et al. Childhood trauma and insulin resistance in patients suffering from depressive disorders. Exp Neurol. 2019;315:15–20.
Lin KW, Wroolie TE, Robakis T, Rasgon NL. Adjuvant pioglitazone for unremitted depression: clinical correlates of treatment response. Psychiatry Res. 2015;230:846–52.
Rasgon NL, Kenna HA, Williams KE, Powers B, Wroolie T, Schatzberg AF. Rosiglitazone add-on in treatment of depressed patients with insulin resistance: a pilot study. Scientific World J. 2010;10:321–8.
McIntyre RS, Powell AM, Kaidanovich-Beilin O, Soczynska JK, Alsuwaidan M, Woldeyohannes HO, et al. The neuroprotective effects of GLP-1: possible treatments for cognitive deficits in individuals with mood disorders. Behav Brain Res. 2013;237:164–71.
Bonato JM, Bassani TB, Milani H, Vital M, de Oliveira RMW. Pioglitazone reduces mortality, prevents depressive-like behavior, and impacts hippocampal neurogenesis in the 6-OHDA model of Parkinson’s disease in rats. Exp Neurol. 2018;300:188–200.
Rasgon NL, McEwen BS. Insulin resistance-a missing link no more. Mol Psychiatry. 2016;21:1648–52.
Havrankova J, Roth J, Brownstein M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature. 1978;272:827–9.
Duarte AI, Moreira PI, Oliveira CR. Insulin in central nervous system: more than just a peripheral hormone. J Aging Res. 2012;2012:384017.
Samuel VT, Shulman GI. Mechanisms for insulin resistance: common threads and missing links. Cell. 2012;148:852–71.
De Felice FG, Lourenco MV, Ferreira ST. How does brain insulin resistance develop in Alzheimer’s disease? Alzheimer’s Dement: J Alzheimer’s Assoc. 2014;10(Suppl 1):S26–32.
Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA, et al. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature. 1991;352:73–77.
Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem. 2002;277:1531–7.
Moloney AM, Griffin RJ, Timmons S, O’Connor R, Ravid R, O’Neill C. Defects in IGF-1 receptor, insulin receptor and IRS-1/2 in Alzheimer’s disease indicate possible resistance to IGF-1 and insulin signalling. Neurobiol Aging. 2010;31:224–43.
Bingham EM, Hopkins D, Smith D, Pernet A, Hallett W, Reed L, et al. The role of insulin in human brain glucose metabolism: an 18fluoro-deoxyglucose positron emission tomography study. Diabetes. 2002;51:3384–90.
Wortzel I, Dror S, Kenific CM, Lyden D. Exosome-mediated metastasis: communication from a distance. Dev cell. 2019;49:347–60.
Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527:329–35.
Saeedi S, Israel S, Nagy C, Turecki G. The emerging role of exosomes in mental disorders. Transl Psychiatry. 2019;9:122.
Fiandaca MS, Kapogiannis D, Mapstone M, Boxer A, Eitan E, Schwartz JB, et al. Identification of preclinical Alzheimer’s disease by a profile of pathogenic proteins in neurally derived blood exosomes: a case-control study. Alzheimer’s Dement: J Alzheimer’s Assoc. 2015;11:600–7.e601.
Kapogiannis D, Mustapic M, Shardell MD, Berkowitz ST, Diehl TC, Spangler RD, et al. Association of extracellular vesicle biomarkers with Alzheimer disease in the baltimore longitudinal study of aging. JAMA Neurol. 2019;76:1340–51.
Mustapic M, Eitan E, Werner JK Jr., Berkowitz ST, Lazaropoulos MP, Tran J, et al. Plasma extracellular vesicles enriched for neuronal origin: a potential window into brain pathologic processes. Front Neurosci. 2017;11:278.
Nasca C, Bigio B, Lee FS, Young SP, Kautz MM, Albright A, et al. Acetyl-l-carnitine deficiency in patients with major depressive disorder. Proc Natl Acad Sci USA. 2018;115:8627–32.
Kiraly DD, Horn SR, Van Dam NT, Costi S, Schwartz J, Kim-Schulze S, et al. Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome. Transl Psychiatry. 2017;7:e1065.
World Health Organization. WHO mean body mass index (BMI). World Health Organization; 2019. https://www.who.int/gho/ncd/risk_factors/bmi_text/en/.
The Blood Code. HOMA-IR: what it is & why you should know yours. 2019. https://www.thebloodcode.com/homa-ir-know/.
Schmid RS, Maness PF. L1 and NCAM adhesion molecules as signaling coreceptors in neuronal migration and process outgrowth. Curr Opin Neurobiol. 2008;18:245–50.
Lonsdale J, Thomas J, Salvatore M, Phillips R, Lo E, Shad S, et al. The genotype-tissue expression (GTEx) project. Nat Genet. 2013;45:580–5.
Takahashi H, Lassmann T, Murata M, Carninci P. 5′ end-centered expression profiling using cap-analysis gene expression and next-generation sequencing. Nat Protoc. 2012;7:542–61.
Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347:1260419.
Faure J, Lachenal G, Court M, Hirrlinger J, Chatellard-Causse C, Blot B, et al. Exosomes are released by cultured cortical neurones. Mol Cell Neurosci. 2006;31:642–8.
Lachenal G, Pernet-Gallay K, Chivet M, Hemming FJ, Belly A, Bodon G, et al. Release of exosomes from differentiated neurons and its regulation by synaptic glutamatergic activity. Mol Cell Neurosci. 2011;46:409–18.
Shi M, Liu C, Cook TJ, Bullock KM, Zhao Y, Ginghina C, et al. Plasma exosomal alpha-synuclein is likely CNS-derived and increased in Parkinson’s disease. Acta Neuropathol. 2014;128:639–50.
Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature. 2018;560:382–6.
Budnik V, Ruiz-Canada C, Wendler F. Extracellular vesicles round off communication in the nervous system. Nat Rev Neurosci. 2016;17:160–72.
Nasca C, Bigio B, Zelli D, de Angelis P, Lau T, Okamoto M, et al. Role of the astroglial glutamate exchanger xCT in ventral hippocampus in resilience to stress. Neuron. 2017;96:402–13.e405.
Lau T, Bigio B, Zelli D, McEwen BS, Nasca C. Stress-induced structural plasticity of medial amygdala stellate neurons and rapid prevention by a candidate antidepressant. Mol Psychiatry. 2017;22:227–34.
Nasca C, Xenos D, Barone Y, Caruso A, Scaccianoce S, Matrisciano F, et al. L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors. Proc Natl Acad Sci USA. 2013;110:4804–9.
Cuccurazzu B, Bortolotto V, Valente MM, Ubezio F, Koverech A, Canonico PL, et al. Upregulation of mGlu2 receptors via NF-kappaB p65 acetylation is involved in the Proneurogenic and antidepressant effects of acetyl-L-carnitine. Neuropsychopharmacology. 2013;38:2220–30.
Wang W, Lu Y, Xue Z, Li C, Wang C, Zhao X, et al. Rapid-acting antidepressant-like effects of acetyl-l-carnitine mediated by PI3K/AKT/BDNF/VGF signaling pathway in mice. Neuroscience. 2015;285:281–91.
Bigio B, Mathe AA, Sousa VC, Zelli D, Svenningsson P, McEwen BS, et al. Epigenetics and energetics in ventral hippocampus mediate rapid antidepressant action: Implications for treatment resistance. Proc Natl Acad Sci USA. 2016;113:7906–11.
Grillo CA, Piroli GG, Kaigler KF, Wilson SP, Wilson MA, Reagan LP. Downregulation of hypothalamic insulin receptor expression elicits depressive-like behaviors in rats. Behav Brain Res. 2011;222:230–5.
Grillo CA, Tamashiro KL, Piroli GG, Melhorn S, Gass JT, Newsom RJ, et al. Lentivirus-mediated downregulation of hypothalamic insulin receptor expression. Physiol Behav. 2007;92:691–701.
Draznin B. Molecular mechanisms of insulin resistance: serine phosphorylation of insulin receptor substrate-1 and increased expression of p85α. Diabetes. 2006;55:2392.
Kessler RC, Bromet EJ. The epidemiology of depression across cultures. Annu Rev Public Health. 2013;34:119–38.
Kessler RC. Epidemiology of women and depression. J Affect Disord. 2003;74:5–13.
Carvalho CR, Carvalheira JB, Lima MH, Zimmerman SF, Caperuto LC, Amanso A, et al. Novel signal transduction pathway for luteinizing hormone and its interaction with insulin: activation of Janus kinase/signal transducer and activator of transcription and phosphoinositol 3-kinase/Akt pathways. Endocrinology. 2003;144:638–47.
This work was supported by a grant from the Robertson Therapeutic Development Foundation to CN, 1R21 MH093948-01A1 (SPO #50260) to NR, a grant from the Hearst Foundation to NR and CN, and, by a grant from the Hope for Depression Foundation (HDRF) to BMC and CN. All data and code will be made available upon request to the corresponding author.
Conflict of interest
The authors declare that they have no conflict of interest.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Nasca, C., Dobbin, J., Bigio, B. et al. Insulin receptor substrate in brain-enriched exosomes in subjects with major depression: on the path of creation of biosignatures of central insulin resistance. Mol Psychiatry (2020). https://doi.org/10.1038/s41380-020-0804-7