pISSN 2287-3732   eISSN 2287-3740
Open Access, Quarterly
    Clin Nutr Res. 2021 Oct;10(4):292-302. English.
    Published online Oct 20, 2021.
    https://doi.org/10.7762/cnr.2021.10.4.292
    Copyright © 2021. The Korean Society of Clinical Nutrition
    Review

    Irisin Acts via the PGC-1α and BDNF Pathway to Improve Depression-like Behavior

    Danbi Jo,1,2 and Juhyun Song1,2
      • 1BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, Hwasun 58128, Korea.
      • 2Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea.
    • Correspondence to Juhyun Song. Department of Anatomy, Chonnam National University Medical School, 264 Seoyang-ro, Hwasun-eup, Hwasun 58128, Korea. Email: juhyunsong@chonnam.ac.kr
    Received August 15, 2021; Revised September 09, 2021; Accepted September 09, 2021.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Depression is the most prevalent psychiatric disorder experienced by the world's population. Mechanisms associated with depression-like behavior have not been fully investigated. Among the therapeutic solution for depression, exercise is considered an important regulator attenuating depressive neuropathology. Exercise has been reported to boost the secretion of myokines such as irisin and myostatin in skeletal muscles. Myokines secreted during exercise are involved in various cellular responses including the endocrine and autocrine systems. Especially, irisin as a cleaved version of fibronectin domain-containing protein 5 has multiple functions such as white fat-browning, energy expenditure increase, anti-inflammatory effects, and mitochondrial function improvement in both systemic circulation and central nervous system. Furthermore, irisin activates energy metabolism-related signaling peroxisome proliferator-activated receptor-gamma coactivator-1 alpha and memory formation-related signaling brain-derived neurotrophic factor involved in depression. However, the role and mechanism of irisin in depression disorder is not obvious until now. Here, we review recent evidences regarding the therapeutic effect of irisin in depression disorder. We suggest that irisin is a key molecule that suppresses several neuropathological mechanisms involved in depression.

    Keywords
    Irisin; Depression; Energy metabolism; Brain-derived neurotrophic factor (BDNF); Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α)

    INTRODUCTION

    Depression is a common mental disorder with a lifetime prevalence of 20% in the global population [1, 2]. Considering the global report, the number of patients with depression will increase to approximately 300 million by 2021, and depression is one of the main causes of mortality worldwide [3].

    Depression is associated with damage in several regions of the brain such as the hippocampus, and linked to mood dysregulation, increased anxiety, fatigue, reduced attention, reduced self-esteem, disturbed sleep pattern, and hopeless behavior pattern [4, 5].

    Numerous studies have demonstrated that the risk factors of depression include dysregulation of energy metabolism [6, 7], chronic neuroinflammation, and neurotransmitter efficiency [8]. Studies have suggested that monoamine transmitters including serotonin (5-HT), norepinephrine, and dopamine are decreased in patients with depression [9].

    For treating depressive neuropathology, many clinical approaches such as antidepressant medication, psychotherapy, light therapy, and herbal supplements have been suggested [10, 11, 12]. Among suggestions for attenuating depressive mood, physical exercise is the easiest and most effective, and acts by promoting the secretion of endorphin and myokines [13, 14, 15]. Physical exercise has been also reported to improve appetite [16], sleep disorder [17], learning and memory function [18, 19], motor function [20], and mood [21]. Current study suggested that sarcopenia defined as decreased muscle mass is directly related with depressive behavior [22]. During exercise, skeletal muscle secretes various myokines, which exert endocrine and paracrine effects in numerous tissues and organs [23].

    Exercise upregulates the expression of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) in skeletal muscle cells and subsequently promotes the generation of fibronectin domain-containing protein 5 (FNDC5); its cleavage results in the production of irisin as one of myokines [24]. Irisin is a peptide type myokine that is cleaved from FNDC5 [25]. Irisin is expressed in skeletal muscles [25], adipose tissue, pancreas, cardiac muscle [26] and several regions of the brain [27, 28]. Several studies suggested that irisin and FNDC5 are observed in purkinje cells, neurons in cerebellum [28] and cerebrospinal fluid [29].

    Numerous studies have mentioned that exercise increases the expression of FNDC5 gene in skeletal muscle and levels of irisin in both circulating blood [30] and the hippocampus of the brain [31]. One cohort study demonstrated that FNDC5 and irisin levels are increased in skeletal muscle after exercise [32].

    Therefore, we assume that irisin secreted by exercise may influence the improvement of depressive symptoms. Hence, understanding the mechanism of irisin in the regulation of depressive symptoms is crucial for a therapeutic solution for depression. Thus, we review emerging evidences regarding related mechanisms and the role of irisin in depressive symptoms.

    IRISIN AND DEPRESSIVE BEHAVIOR

    Irisin is a polypeptide hormone stimulated by exercise, and cleaved from FNDC5 [25, 33]. It is found in various organs including the brain, heart, liver, and skeletal muscles [34], and has been reported to control glucose metabolism, lipid metabolism, and energy homeostasis in skeletal muscle and adipose tissues [35, 36, 37]. In addition, one recent study suggested that irisin has anti-inflammatory, anti-oxidative, and anti-apoptotic effects [38].

    Since irisin plays a role in biological responses, it also contributes to the pathological process in chronic kidney disease [39], obesity [40], and type 2 diabetes mellitus [41]. Additionally, irisin prevents blood vessel dysfunction [42] and ameliorates metabolic imbalance [43] by controlling the expression of other myokines and adipokines [44]. Irisin is released into the circulatory system to induce browning of white fats, oxygen consumption, and thermogenesis in adipose tissues [45, 46].

    In the central nervous system (CNS), irisin crosses the blood brain barrier [47] and its expression is found in the hippocampus and ventral tegmental area involved in the reward system and learning process [48]. Few studies have reported that irisin promotes neuronal proliferation and differentiation, and cell protection against amyloid beta peptide 42 toxicity [49, 50]. In addition, several studies suggested that irisin attenuates neuroinflammation, memory deficit [51], and ultimately improves neuropathogenesis in neurodegenerative diseases [52]. Irisin has been reported to positively influence memory-related brain regions such as the hippocampus and the dentate gyrus [53, 54].

    Recently, irisin is emerging as a therapeutic hormone for alleviating depressive behavior by affecting neuronal function in prefrontal cortex [55, 56]. Some studies suggested that irisin secreted by exercise activates the PGC-1α-FNDC5/irisin pathway in hippocampus and, ultimately ameliorates depressive symptoms [57, 58]. One study mentioned that irisin could help enhance mood by promoting the expression of brain-derived neurotrophic factor (BDNF) in various brain regions [59]. A current study suggested that irisin ameliorates depressive behavior by reducing the surface expression of epidermal growth factor receptor in mice [60]. Previous studies mentioned that irisin contributes to improvement in brain damage and depressive behavior after cerebral ischemic stroke [46, 56, 61].

    Based on previous consequences on irisin levels in CNS, depressive symptoms would be improved by increasing irisin levels. The modulation of irisin levels may influence the suppression of depressive symptoms.

    IRISIN AND ENERGY METABOLISM THROUGH PGC-1α PATHWAY

    Recently, energy metabolism is emerging as a key phenomenon in depressive symptoms [62, 63]. Current studies suggested that impaired brain energy metabolism led to severe pathogenesis in patients with depressive symptoms [64, 65, 66].

    Glycogen is the main energy supply of the brain, and it regulates neuronal activity. Its accumulation is observed in the brain of depressive patients [67, 68]. Patients with depression commonly showed abnormal glucose metabolism [69]. Tricarboxylic acid cycle which provides adenosine triphosphate (ATP) was significantly altered in patients with mild depressive disorder [70]. Some studies reported that glucose levels in blood is elevated in patients with depression than in normal subjects [71, 72] and high glucose levels in blood leads to fatigue symptoms in patients with mild depressive disorder [73].

    One study indicated that administration of irisin in the third ventricle of the brain boosts energy metabolism such as heat production and oxygen consumption [74]. Regarding depressive symptoms, energy metabolism is directly linked to progression of depression by decreasing astrocytic ATP production [75]. Astrocytes provide metabolic nutrients to neurons and produce cellular energy ATP [76]. Furthermore, abnormal mitochondrial dysfunction has been reported to trigger energy metabolism impairment in the brain of depressed individuals [77].

    One study mentioned that exercise could modulate metabolic ability, leading to improvement in depressive behaviors in the prefrontal cortex by promoting irisin secretion [78]. Exercise activates PGC-1α gene in the skeletal muscle, and subsequently increases the expression of FNDC5 [79, 80, 81].

    Considering recent studies, irisin could effectively improve depressive symptoms [55, 56] by activating PGC-1α-FNDC5/irisin pathway [57] in brain areas, involved in learning, mood, attention, and reward system (Figure 1) [82]. Irisin increases the activation of PGC-1α, and subsequently increases the expression of uncoupling protein one (UCP1) mRNA in skeletal muscle cells and adipocytes [25]. The increase in UCP1 expression means an increase in thermogenesis and energy processes in cells [83]. Previous studies demonstrated that irisin administration could activate neuroplasticity-related genes and improve depressive symptoms through improvement in energy expenditure in the prefrontal cortex and hippocampus of the brain of depressed individuals through the activation of PGC-1α [84].

    Figure 1
    Schematic images showing the effects of irisin on PGC-1α and BDNF pathways. In central nervous system, irisin plays multiple roles to improve mitochondria function through PGC-1α signaling and to enhance synaptic plasticity through BDNF signaling in neurons, leading to the improvement of depressive neuropathology.
    CTF, C-terminal fragment; MD, membrane domain; FNDC5, fibronectin domain-containing protein 5; PGC-1α, proliferator-activated receptor-gamma coactivator-1 alpha; UCP1, uncoupling protein one; BDNF, brain-derived neurotrophic factor; TrkB, tropomyosin receptor kinase B.

    Given emerging findings, irisin could modulate energy metabolism in brain through the activation of PGC-1α, and subsequently could exert therapeutic effect in depressive like behavior.

    IRISIN AND SYNAPTIC PLASTICITY THROUGH BDNF PATHWAY

    BDNF is known to have anti-inflammatory effect by regulating microglia activation and polarization with binding its receptor tropomyosin receptor kinase B (TrkB) [85]. In the brain, BDNF and TrkB are also expressed in various brain regions such as the hippocampal formation and brain stem [31, 86].

    BDNF controls inflammation signaling such as extracellular-signal-regulated kinase, nuclear factor-kappa light chain enhancer of activated B cells, p38 and c-Jun N-terminal kinase [87, 88, 89] and boosts memory function-related signaling including glycogen synthase kinase 3 and cAMP-response element binding protein [90].

    Some studies indicated that BDNF is a critical marker in major depressive disorders [91], and the BDNF levels in serum shows negative correlation with the depression score [92, 93]. BDNF is secreted during exercise and protects neurons and glia against brain damage [31].

    Moreover, BDNF secretion is related with FNDC5/irisin expression in the hippocampus of the brain [28, 31]. Furthermore, elevation of FNDC5/irisin expression in brain hippocampus boosts activation of BDNF, and subsequent neuroprotective effects (Figure 1) [31]. One study demonstrated that FNDC5/irisin expressed in the wide brain region is modulated by BDNF levels and promotes hippocampal neurogenesis and memory function (Figure 1) [31]. Another study indicated that activation of irisin-BDNF signaling could effectively reduce stress-induced depression [94].

    Recent studies suggested that irisin could induce BDNF secretion in the ventral tegmental area, hippocampal area, and limbic circuit, involved in reward system, learning system, mood, and motivation [48, 82, 95, 96]. The ventral tegmental area, ventral-striatum axis, dentate gyrus, and hippocampus are important target areas in major depressive disorder and anxiety [97, 98, 99]. Regarding that irisin promotes the expression of BDNF in various brain regions such as the hippocampus, irisin may play a key role in modulating depression-like symptoms by promoting the secretion of BDNF (Figure 1).

    CONCLUSION

    Irisin is helpful in enhancing depressive neuropathology. Impairment of energy metabolism and synaptic impairment caused by a deficit of neurotrophic factors are important features in the brain of patients with depressive disorders. Irisin secreted during exercise could control energy expenditure through PGC-1α and moreover, improves the production of BDNF in depressive brain. Finally, irisin may enhance the depressive mood problem in patients with depression through the activation of PGC-1α and BDNF pathways.

    Notes

    Funding:This study was financially supported by Chonnam National University (grant number: 2020-3836).

    Conflict of Interest:The authors declare that they have no competing interests.

    References

      1. Bromet E, Andrade LH, Hwang I, Sampson NA, Alonso J, de Girolamo G, de Graaf R, Demyttenaere K, Hu C, Iwata N, Karam AN, Kaur J, Kostyuchenko S, Lépine JP, Levinson D, Matschinger H, Mora ME, Browne MO, Posada-Villa J, Viana MC, Williams DR, Kessler RC. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med 2011;9:90.
      1. Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, Mohr DC, Schatzberg AF. Major depressive disorder. Nat Rev Dis Primers 2016;2:16065.
      1. Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, Charlson FJ, Norman RE, Flaxman AD, Johns N, Burstein R, Murray CJ, Vos T. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 2013;382:1575–1586.
      1. Engin E, Treit D. The role of hippocampus in anxiety: intracerebral infusion studies. Behav Pharmacol 2007;18:365–374.
      1. Degroot A, Treit D. Anxiety is functionally segregated within the septo-hippocampal system. Brain Res 2004;1001:60–71.
      1. Mallei A, Giambelli R, Gass P, Racagni G, Mathé AA, Vollmayr B, Popoli M. Synaptoproteomics of learned helpless rats involve energy metabolism and cellular remodeling pathways in depressive-like behavior and antidepressant response. Neuropharmacology 2011;60:1243–1253.
      1. Della FP, Abelaira HM, Réus GZ, Ribeiro KF, Antunes AR, Scaini G, Jeremias IC, dos Santos LM, Jeremias GC, Streck EL, Quevedo J. Tianeptine treatment induces antidepressive-like effects and alters BDNF and energy metabolism in the brain of rats. Behav Brain Res 2012;233:526–535.
      1. Felger JC. Imaging the role of inflammation in mood and anxiety-related disorders. Curr Neuropharmacol 2018;16:533–558.
      1. Ruhé HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry 2007;12:331–359.
      1. Kim YR, Park BK, Seo CS, Kim NS, Lee MY. Antidepressant and anxiolytic-like effects of the stem bark extract of Fraxinus rhynchophylla hance and its components in a mouse model of depressive-like disorder induced by reserpine administration. Front Behav Neurosci 2021;15:650833
      1. Cosker E, Moulard M, Schmitt S, Angioi-Duprez K, Baumann C, Laprévote V, Schwan R, Schwitzer T. Portable light therapy in the treatment of unipolar non-seasonal major depressive disorder: study protocol for the LUMIDEP randomised controlled trial. BMJ Open 2021;11:e049331
      1. Wu S, Zhou Y, Xuan Z, Xiong L, Ge X, Ye J, Liu Y, Yuan L, Xu Y, Ding G, Xiao A, Guo J, Yu L. Repeated use of SSRIs potentially associated with an increase on serum CK and CK-MB in patients with major depressive disorder: a retrospective study. Sci Rep 2021;11:13365.
      1. Dinas PC, Koutedakis Y, Flouris AD. Effects of exercise and physical activity on depression. Ir J Med Sci 2011;180:319–325.
      1. Ahn JH, So SP, Kim NY, Kim HJ, Yoon SY, Kim DH. c-Jun N-terminal Kinase (JNK) induces phosphorylation of amyloid precursor protein (APP) at Thr668, in okadaic acid-induced neurodegeneration. BMB Rep 2016;49:376–381.
      1. Brüchle W, Schwarzer C, Berns C, Scho S, Schneefeld J, Koester D, Schack T, Schneider U, Rosenkranz K. Physical activity reduces clinical symptoms and restores neuroplasticity in major depression. Front Psychiatry 2021;12:660642
      1. Blundell JE, Gibbons C, Caudwell P, Finlayson G, Hopkins M. Appetite control and energy balance: impact of exercise. Obes Rev 2015;16 Suppl 1:67–76.
      1. Kelley GA, Kelley KS. Exercise and sleep: a systematic review of previous meta-analyses. J Evid Based Med 2017;10:26–36.
      1. Cotman CW, Berchtold NC. Exercise: a behavioral intervention to enhance brain health and plasticity. Trends Neurosci 2002;25:295–301.
      1. Aberg MA, Pedersen NL, Torén K, Svartengren M, Bäckstrand B, Johnsson T, Cooper-Kuhn CM, Aberg ND, Nilsson M, Kuhn HG. Cardiovascular fitness is associated with cognition in young adulthood. Proc Natl Acad Sci U S A 2009;106:20906–20911.
      1. Smith PJ, Blumenthal JA, Hoffman BM, Cooper H, Strauman TA, Welsh-Bohmer K, Browndyke JN, Sherwood A. Aerobic exercise and neurocognitive performance: a meta-analytic review of randomized controlled trials. Psychosom Med 2010;72:239–252.
      1. Crush EA, Frith E, Loprinzi PD. Experimental effects of acute exercise duration and exercise recovery on mood state. J Affect Disord 2018;229:282–287.
      1. Yuenyongchaiwat K, Boonsinsukh R. Sarcopenia and its relationships with depression, cognition, and physical activity in Thai community-dwelling older adults. Curr Gerontol Geriatr Res 2020;2020:8041489
      1. Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 2008;88:1379–1406.
      1. Norheim F, Langleite TM, Hjorth M, Holen T, Kielland A, Stadheim HK, Gulseth HL, Birkeland KI, Jensen J, Drevon CA. The effects of acute and chronic exercise on PGC-1α, irisin and browning of subcutaneous adipose tissue in humans. FEBS J 2014;281:739–749.
      1. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Boström EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Højlund K, Gygi SP, Spiegelman BM. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012;481:463–468.
      1. Aydin S. Three new players in energy regulation: preptin, adropin and irisin. Peptides 2014;56:94–110.
      1. Teufel A, Malik N, Mukhopadhyay M, Westphal H. Frcp1 and Frcp2, two novel fibronectin type III repeat containing genes. Gene 2002;297:79–83.
      1. Dun SL, Lyu RM, Chen YH, Chang JK, Luo JJ, Dun NJ. Irisin-immunoreactivity in neural and non-neural cells of the rodent. Neuroscience 2013;240:155–162.
      1. Piya MK, Harte AL, Sivakumar K, Tripathi G, Voyias PD, James S, Sabico S, Al-Daghri NM, Saravanan P, Barber TM, Kumar S, Vatish M, McTernan PG. The identification of irisin in human cerebrospinal fluid: influence of adiposity, metabolic markers, and gestational diabetes. Am J Physiol Endocrinol Metab 2014;306:E512–E518.
      1. Tiano JP, Springer DA, Rane SG. SMAD3 negatively regulates serum irisin and skeletal muscle FNDC5 and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) during exercise. J Biol Chem 2015;290:11431.
      1. Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, Lin JD, Greenberg ME, Spiegelman BM. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab 2013;18:649–659.
      1. Elsen M, Raschke S, Eckel J. Browning of white fat: does irisin play a role in humans? J Endocrinol 2014;222:R25–R38.
      1. Huh JY, Mougios V, Kabasakalis A, Fatouros I, Siopi A, Douroudos II, Filippaios A, Panagiotou G, Park KH, Mantzoros CS. Exercise-induced irisin secretion is independent of age or fitness level and increased irisin may directly modulate muscle metabolism through AMPK activation. J Clin Endocrinol Metab 2014;99:E2154–E2161.
      1. Ferrer-Martínez A, Ruiz-Lozano P, Chien KR. Mouse PeP: a novel peroxisomal protein linked to myoblast differentiation and development. Dev Dyn 2002;224:154–167.
      1. Xin C, Liu J, Zhang J, Zhu D, Wang H, Xiong L, Lee Y, Ye J, Lian K, Xu C, Zhang L, Wang Q, Liu Y, Tao L. Irisin improves fatty acid oxidation and glucose utilization in type 2 diabetes by regulating the AMPK signaling pathway. Int J Obes 2016;40:443–451.
      1. Crujeiras AB, Zulet MA, Lopez-Legarrea P, de la Iglesia R, Pardo M, Carreira MC, Martínez JA, Casanueva FF. Association between circulating irisin levels and the promotion of insulin resistance during the weight maintenance period after a dietary weight-lowering program in obese patients. Metabolism 2014;63:520–531.
      1. Choi YK, Kim MK, Bae KH, Seo HA, Jeong JY, Lee WK, Kim JG, Lee IK, Park KG. Serum irisin levels in new-onset type 2 diabetes. Diabetes Res Clin Pract 2013;100:96–101.
      1. Askari H, Rajani SF, Poorebrahim M, Haghi-Aminjan H, Raeis-Abdollahi E, Abdollahi M. A glance at the therapeutic potential of irisin against diseases involving inflammation, oxidative stress, and apoptosis: an introductory review. Pharmacol Res 2018;129:44–55.
      1. Rodríguez-Carmona A, Pérez Fontán M, Sangiao Alvarellos S, García Falcón T, Pena Bello ML, López Muñiz A, Cordido F. Serum levels of the adipomyokine irisin in patients with chronic kidney disease. Nefrologia 2016;36:496–502.
      1. Moreno-Navarrete JM, Ortega F, Serrano M, Guerra E, Pardo G, Tinahones F, Ricart W, Fernández-Real JM. Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance. J Clin Endocrinol Metab 2013;98:E769–E778.
      1. Zhu D, Wang H, Zhang J, Zhang X, Xin C, Zhang F, Lee Y, Zhang L, Lian K, Yan W, Ma X, Liu Y, Tao L. Irisin improves endothelial function in type 2 diabetes through reducing oxidative/nitrative stresses. J Mol Cell Cardiol 2015;87:138–147.
      1. Lu J, Xiang G, Liu M, Mei W, Xiang L, Dong J. Irisin protects against endothelial injury and ameliorates atherosclerosis in apolipoprotein E-Null diabetic mice. Atherosclerosis 2015;243:438–448.
      1. Chen JQ, Huang YY, Gusdon AM, Qu S. Irisin: a new molecular marker and target in metabolic disorder. Lipids Health Dis 2015;14:2.
      1. Roca-Rivada A, Castelao C, Senin LL, Landrove MO, Baltar J, Belén Crujeiras A, Seoane LM, Casanueva FF, Pardo M. FNDC5/irisin is not only a myokine but also an adipokine. PLoS One 2013;8:e60563
      1. Kristóf E, Doan-Xuan QM, Bai P, Bacso Z, Fésüs L. Laser-scanning cytometry can quantify human adipocyte browning and proves effectiveness of irisin. Sci Rep 2015;5:12540.
      1. Li DJ, Li YH, Yuan HB, Qu LF, Wang P. The novel exercise-induced hormone irisin protects against neuronal injury via activation of the Akt and ERK1/2 signaling pathways and contributes to the neuroprotection of physical exercise in cerebral ischemia. Metabolism 2017;68:31–42.
      1. Phillips C, Baktir MA, Srivatsan M, Salehi A. Neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling. Front Cell Neurosci 2014;8:170.
      1. Zsuga J, Biro K, Papp C, Tajti G, Gesztelyi R. The “proactive” model of learning: integrative framework for model-free and model-based reinforcement learning utilizing the associative learning-based proactive brain concept. Behav Neurosci 2016;130:6–18.
      1. Xia DY, Huang X, Bi CF, Mao LL, Peng LJ, Qian HR. PGC-1α or FNDC5 is involved in modulating the effects of Aβ1-42 oligomers on suppressing the expression of BDNF, a beneficial factor for inhibiting neuronal apoptosis, Aβ deposition and cognitive decline of APP/PS1 Tg mice. Front Aging Neurosci 2017;9:65.
      1. Wang K, Li H, Wang H, Wang JH, Song F, Sun Y. Irisin exerts neuroprotective effects on cultured neurons by regulating astrocytes. Mediators Inflamm 2018;2018:9070341
      1. Wang K, Song F, Xu K, Liu Z, Han S, Li F, Sun Y. Irisin attenuates neuroinflammation and prevents the memory and cognitive deterioration in streptozotocin-induced diabetic mice. Mediators Inflamm 2019;2019:1567179
      1. Kempuraj D, Thangavel R, Natteru PA, Selvakumar GP, Saeed D, Zahoor H, Zaheer S, Iyer SS, Zaheer A. Neuroinflammation induces neurodegeneration. J Neurol Neurosurg Spine 2016;1:1003.
      1. Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci 2007;30:464–472.
      1. Mattson MP. Energy intake and exercise as determinants of brain health and vulnerability to injury and disease. Cell Metab 2012;16:706–722.
      1. Carvalho AF, Rocha DQ, McIntyre RS, Mesquita LM, Köhler CA, Hyphantis TN, Sales PM, Machado-Vieira R, Berk M. Adipokines as emerging depression biomarkers: a systematic review and meta-analysis. J Psychiatr Res 2014;59:28–37.
      1. Wang S, Pan J. Irisin ameliorates depressive-like behaviors in rats by regulating energy metabolism. Biochem Biophys Res Commun 2016;474:22–28.
      1. Schuch FB, Vancampfort D, Richards J, Rosenbaum S, Ward PB, Stubbs B. Exercise as a treatment for depression: a meta-analysis adjusting for publication bias. J Psychiatr Res 2016;77:42–51.
      1. Wrann CD. FNDC5/irisin - their role in the nervous system and as a mediator for beneficial effects of exercise on the brain. Br Plast 2015;1:55–61.
      1. Papp C, Pak K, Erdei T, Juhasz B, Seres I, Szentpéteri A, Kardos L, Szilasi M, Gesztelyi R, Zsuga J. Alteration of the irisin-brain-derived neurotrophic factor axis contributes to disturbance of mood in COPD patients. Int J Chron Obstruct Pulmon Dis 2017;12:2023–2033.
      1. Hou Z, Zhang J, Yu K, Song F. Irisin ameliorates the postoperative depressive-like behavior by reducing the surface expression of epidermal growth factor receptor in mice. Neurochem Int 2020;135:104705
      1. Tu WJ, Qiu HC, Liu Q, Li X, Zhao JZ, Zeng X. Decreased level of irisin, a skeletal muscle cell-derived myokine, is associated with post-stroke depression in the ischemic stroke population. J Neuroinflammation 2018;15:133.
      1. Park DI, Novak B, Yan Y, Kaya ME, Turck CW. Paroxetine binding and activation of phosphofructokinase implicates energy metabolism in antidepressant mode of action. J Psychiatr Res 2020;129:8–14.
      1. Jiang H, Niu F, Zheng Y, Xu Y. CART mitigates oxidative stress and DNA damage in memory deficits of APP/PS1 mice via upregulating β-amyloid metabolism-associated enzymes. Mol Med Rep 2021;23:280.
      1. Chan SY, Probert F, Radford-Smith DE, Hebert JC, Claridge TD, Anthony DC, Burnet PW. Post-inflammatory behavioural despair in male mice is associated with reduced cortical glutamate-glutamine ratios, and circulating lipid and energy metabolites. Sci Rep 2020;10:16857.
      1. Nasca C, Dobbin J, Bigio B, Watson K, de Angelis P, Kautz M, Cochran A, Mathé AA, Kocsis JH, Lee FS, Murrough JW, McEwen BS, Rasgon N. 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
        Forthcoming.
      1. Rezin GT, Amboni G, Zugno AI, Quevedo J, Streck EL. Mitochondrial dysfunction and psychiatric disorders. Neurochem Res 2009;34:1021–1029.
      1. Obel LF, Müller MS, Walls AB, Sickmann HM, Bak LK, Waagepetersen HS, Schousboe A. Brain glycogen-new perspectives on its metabolic function and regulation at the subcellular level. Front Neuroenergetics 2012;4:3.
      1. Bélanger M, Allaman I, Magistretti PJ. Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab 2011;14:724–738.
      1. Videbech P. PET measurements of brain glucose metabolism and blood flow in major depressive disorder: a critical review. Acta Psychiatr Scand 2000;101:11–20.
      1. Chen JJ, Xie J, Li WW, Bai SJ, Wang W, Zheng P, Xie P. Age-specific urinary metabolite signatures and functions in patients with major depressive disorder. Aging (Albany NY) 2019;11:6626–6637.
      1. Bekhbat M, Treadway MT, Goldsmith DR, Woolwine BJ, Haroon E, Miller AH, Felger JC. Gene signatures in peripheral blood immune cells related to insulin resistance and low tyrosine metabolism define a sub-type of depression with high CRP and anhedonia. Brain Behav Immun 2020;88:161–165.
      1. Roy T, Lloyd CE. Epidemiology of depression and diabetes: a systematic review. J Affect Disord 2012;142 Suppl:S8–21.
      1. Demyttenaere K, De Fruyt J, Stahl SM. The many faces of fatigue in major depressive disorder. Int J Neuropsychopharmacol 2005;8:93–105.
      1. Zhang W, Chang L, Zhang C, Zhang R, Li Z, Chai B, Li J, Chen E, Mulholland M. Irisin: a myokine with locomotor activity. Neurosci Lett 2015;595:7–11.
      1. Cao X, Li LP, Wang Q, Wu Q, Hu HH, Zhang M, Fang YY, Zhang J, Li SJ, Xiong WC, Yan HC, Gao YB, Liu JH, Li XW, Sun LR, Zeng YN, Zhu XH, Gao TM. Astrocyte-derived ATP modulates depressive-like behaviors. Nat Med 2013;19:773–777.
      1. Allaman I, Bélanger M, Magistretti PJ. Astrocyte-neuron metabolic relationships: for better and for worse. Trends Neurosci 2011;34:76–87.
      1. Madrigal JL, Olivenza R, Moro MA, Lizasoain I, Lorenzo P, Rodrigo J, Leza JC. Glutathione depletion, lipid peroxidation and mitochondrial dysfunction are induced by chronic stress in rat brain. Neuropsychopharmacology 2001;24:420–429.
      1. Wang L, Song J, Wang C, Lin P, Liang K, Sun Y, He T, Li W, Zhao R, Qin J, Lu Y, Liu J, Liu F, Hou X, Chen L. Circulating levels of betatrophin and irisin are not associated with pancreatic β-cell function in previously diagnosed type 2 diabetes mellitus patients. J Diabetes Res 2016;2016:2616539
      1. Spiegelman BM. Transcriptional control of mitochondrial energy metabolism through the PGC1 coactivators. Novartis Found Symp 2007;287:60–63.
      1. Leick L, Wojtaszewski JF, Johansen ST, Kiilerich K, Comes G, Hellsten Y, Hidalgo J, Pilegaard H. PGC-1alpha is not mandatory for exercise- and training-induced adaptive gene responses in mouse skeletal muscle. Am J Physiol Endocrinol Metab 2008;294:E463–E474.
      1. Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. J Biol Chem 2010;285:7153–7164.
      1. Zsuga J, Tajti G, Papp C, Juhasz B, Gesztelyi R. FNDC5/irisin, a molecular target for boosting reward-related learning and motivation. Med Hypotheses 2016;90:23–28.
      1. Feldmann HM, Golozoubova V, Cannon B, Nedergaard J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab 2009;9:203–209.
      1. Siteneski A, Cunha MP, Lieberknecht V, Pazini FL, Gruhn K, Brocardo PS, Rodrigues AL. Central irisin administration affords antidepressant-like effect and modulates neuroplasticity-related genes in the hippocampus and prefrontal cortex of mice. Prog Neuropsychopharmacol Biol Psychiatry 2018;84:294–303.
      1. Qin L, Bouchard R, Pugazhenthi S. Regulation of cyclic AMP response element-binding protein during neuroglial interactions. J Neurochem 2016;136:918–930.
      1. Guillin O, Griffon N, Bezard E, Leriche L, Diaz J, Gross C, Sokoloff P. Brain-derived neurotrophic factor controls dopamine D3 receptor expression: therapeutic implications in Parkinson's disease. Eur J Pharmacol 2003;480:89–95.
      1. Suri D, Vaidya VA. Glucocorticoid regulation of brain-derived neurotrophic factor: relevance to hippocampal structural and functional plasticity. Neuroscience 2013;239:196–213.
      1. Jeanneteau F, Deinhardt K, Miyoshi G, Bennett AM, Chao MV. The MAP kinase phosphatase MKP-1 regulates BDNF-induced axon branching. Nat Neurosci 2010;13:1373–1379.
      1. Dong Y, Pu K, Duan W, Chen H, Chen L, Wang Y. Involvement of Akt/CREB signaling pathways in the protective effect of EPA against interleukin-1β-induced cytotoxicity and BDNF down-regulation in cultured rat hippocampal neurons. BMC Neurosci 2018;19:52.
      1. Li X, Jope RS. Is glycogen synthase kinase-3 a central modulator in mood regulation? Neuropsychopharmacology 2010;35:2143–2154.
      1. Ihara K, Yoshida H, Jones PB, Hashizume M, Suzuki Y, Ishijima H, Kim HK, Suzuki T, Hachisu M. Serum BDNF levels before and after the development of mood disorders: a case-control study in a population cohort. Transl Psychiatry 2016;6:e782
      1. Brunoni AR, Lopes M, Fregni F. A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol 2008;11:1169–1180.
      1. Kheirouri S, Noorazar SG, Alizadeh M, Dana-Alamdari L. Elevated brain-derived neurotrophic factor correlates negatively with severity and duration of major depressive episodes. Cogn Behav Neurol 2016;29:24–31.
      1. Szilasi ME, Pak K, Kardos L, Varga VE, Seres I, Mikaczo A, Fodor A, Szilasi M, Tajti G, Papp C, Gesztelyi R, Zsuga J. The alteration of irisin-brain-derived neurotrophic factor axis parallels severity of distress disorder in bronchial asthma patients. Front Neurosci 2017;11:653.
      1. Yan QS, Feng MJ, Yan SE. Different expression of brain-derived neurotrophic factor in the nucleus accumbens of alcohol-preferring (P) and -nonpreferring (NP) rats. Brain Res 2005;1035:215–218.
      1. Maia TV. Reinforcement learning, conditioning, and the brain: successes and challenges. Cogn Affect Behav Neurosci 2009;9:343–364.
      1. Huys QJ, Pizzagalli DA, Bogdan R, Dayan P. Mapping anhedonia onto reinforcement learning: a behavioural meta-analysis. Biol Mood Anxiety Disord 2013;3:12.
      1. Nestler EJ, Carlezon WA Jr. The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 2006;59:1151–1159.
      1. Ieraci A, Madaio AI, Mallei A, Lee FS, Popoli M. Brain-derived neurotrophic factor Val66Met human polymorphism impairs the beneficial exercise-induced neurobiological changes in mice. Neuropsychopharmacology 2016;41:3070–3079.
    Cited by
    Crossref 17
    Google Scholar 
    PubMed Central 8
    MeSH Terms
    Brain-Derived Neurotrophic Factor*
    Central Nervous System
    Depression
    Energy Metabolism
    Fibronectins
    Memory
    Mental Disorders
    Muscle, Skeletal
    Myostatin
    Neuropathology
    Peroxisomes
    Proteins
    Solutions
    Therapeutic Uses
    Metrics
    Share
    Links to
    Figures
    slide

    1 / 1

    ORCID IDs
    Funding Information
    PERMALINK