Iranian Journal of Neurology 2017. 16(4):.

Molecular changes in obese and depressive patients are similar to neurodegenerative disorders
Laleh Habibi, Abbas Tafakhori, Rasoul Hadiani, Maryam Maserat-Mashhadi, Zeinab Kafrash, Shahla Torabi, Mohammad Azhdarzadeh, Seyed Mohammad Akrami, Morteza Mahmoudi, Rasoul Dinarvand




Obesity; Depression; Neurodegeneration; FOXO; Heavy Metals; Life Style


Sheikh S, Safia, Haque E, Mir SS. Neurodegenerative Diseases: Multifactorial Conformational Diseases and Their Therapeutic Interventions. J Neurodegener Dis 2013; 2013: 563481.

Crews L, Masliah E. Molecular mechanisms of neurodegeneration in Alzheimer's disease. Hum Mol Genet 2010; 19:R12-R20.

Nakamura T, Lipton SA. Cell death: protein misfolding and neurodegenerative diseases. Apoptosis 2009;14:455-468.

Jomova K, Vondrakova D, Lawson M, Valko M. Metals, oxidative stress and neurodegenerative disorders. Mol Cell Biochem 2010; 345:91-104.

Melo A, Monteiro L, Lima RM, Oliveira DM, Cerqueira MD, El-Bachá RS. Oxidative stress in neurodegenerative diseases: mechanisms and therapeutic perspectives. Oxid Med Cell Longev 2011;2011:467180.

Johri A, Beal MF. Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther 2012; 342:619-630.

Hroudová J, Singh N, Fišar Z. Mitochondrial dysfunctions in neurodegenerative diseases: relevanceto Alzheimer's disease. Biomed Res Int 2014; 2014:175062.

Blandini F, Braunewell KH, Manahan-Vaughan D, Orzi F, Sarti P. Neurodegeneration and energy metabolism: from chemistry to clinics. Cell Death Differ 2004; 11:479-484.

Maiese K. FoxO proteins in the nervous system. Anal Cell Pathol (Amst) 2015; 2015:569392.

Ghavami S, Shojaei S, Yeganeh B, et al. Autophagy and apoptosis dysfunction in neurodegenerative disorders. Prog Neurobiol 2014; 112:24-49.

Amor S, Peferoen LA, Vogel DY ,et al. Inflammation in neurodegenerative diseases--an update. Immunology 2014; 142:151-166.

Chin-Chan M, Navarro-Yepes J, Quintanilla-Vega B. Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases. Front Cell Neurosci 2015 ;9:124.

Kozlowski H, Janicka-Klos A, Brasun J, Gaggelli E, Valensin D, Valensin G. Copper, iron, and zinc ions homeostasis and their role in neurodegenerative disorders (metal uptake, transport, distribution and regulation). Coordination Chemistry Reviews 2012 ; 253: 2665–2685.

Brown RC., Lockwood A, Sonawane BR. Neurodegenerative Diseases: An Overview of Environmental Risk Factors. Environ Health Perspect 2005 ; 113: 1250–1256.

ManafiRad A, Farzadfar F, Habibi L, et al. Is amyloid-β an innocent bystander and marker in Alzheimer's disease? Is the liability of multivalent cation homeostasis and its influence on amyloid-β function the real mechanism? J Alzheimers Dis 2014 ;42:69-85.

Lavallard VJ, Meijer AJ, Codogno P, Gual P. Autophagy, signaling and obesity. Pharmacol Res 2012 ;66:513-525.

Muriach M, Flores-Bellver M, Romero FJ, Barcia JM. Diabetes and the brain: oxidative stress, inflammation, and autophagy. Oxid Med Cell Longev 2014 ;2014:102158.

Stuart MJ, Baune BT. Depression and type 2 diabetes: inflammatory mechanisms of a psychoneuroendocrine co-morbidity. Neurosci Biobehav Rev 2012 ;36:658-676.

Nguyen DM, El-Serag HB. The epidemiology of obesity. Gastroenterol Clin North Am 39:1-7.

Cheng D. Prevalence, predisposition and prevention of type II diabetes. Nutr Metab (Lond) 2010 ;2:29.

Hidaka BH. Depression as a disease of modernity: explanations for increasing prevalence. J Affect Disord 2012 ;140:205-214.

Dorsey ER, George BP, Leff B, Willis AW. The coming crisis: obtaining care for the growing burden of neurodegenerative conditions. Neurology 2013 ;80:1989-1996.

Ashrafian H, Harling L, Darzi A, Athanasiou T. Neurodegenerative disease and obesity: what is the role of weight loss and bariatric interventions? Metab Brain Dis 2013 ;28:341-353.

Janson J, Laedtke T, Parisi JE, O'Brien P, Petersen RC, Butler PC. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 2004 ;53:474-481.

Wuwongse S, Chang RC, Law AC. The putative neurodegenerative links between depression and Alzheimer's disease. Prog Neurobiol 2010 ;91:362-375.

Caraci F, Copani A, Nicoletti F, Drago F. Depression and Alzheimer's disease: neurobiological links and common pharmacological targets. Eur J Pharmacol 2010 ;626:64-71.

Jansen HJ, van Essen P, Koenen T, et al. Autophagy activity is up-regulated in adipose tissue of obese individuals and modulates proinflammatory cytokine expression. Endocrinology 2012 ;153:5866-5874.

Masini M, Bugliani M, Lupi R, del Guerra S, Boggi U, Filipponi F, Marselli L, Masiello P, Marchetti P. Autophagy in human type 2 diabetes pancreatic beta cells. Diabetologia 2009 ;52:1083-1086.

Das UN, Rao AA. Gene expression profile in obesity and type 2 diabetes mellitus. Lipids Health Dis 2007 ;6:35.

Mehta D, Menke A, Binder EB. Gene expression studies in major depression. Curr Psychiatry Rep 2010 ;12:135-144.

Fischer R, Maier O. Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF. Oxid Med Cell Longev 2015 ;2015:610813.

Kousteni S. FoxO1, the transcriptional chief of staff of energy metabolism. Bone 2012; 50:437-443.

Nakae J, Oki M, Cao Y. The FoxO transcription factors and metabolic regulation. FEBS Lett 2008 ;582:54-67.

Costa Cdos S, Rohden F, Hammes TO, et al. Resveratrol upregulated SIRT1, FOXO1, and adiponectin and downregulated PPARγ1-3 mRNA expression in human visceral adipocytes. Obes Surg 2011 ;21:356-361.

Qiu H, Wang F, Liu C, Xu X, Liu B. TEAD1-dependent expression of the FoxO3a gene in mouse skeletal muscle. BMC Mol Biol 2011 ;12:1.

Li J, Moran T, Swanson E, et al. Regulation of IL-8 and IL-1beta expression in Crohn's disease associated NOD2/CARD15 mutations. Hum Mol Genet 2004 ;13:1715-1725.

Oberbach A, Schlichting N, Blüher M, et al. Palmitate induced IL-6 and MCP-1 expression in human bladder smooth muscle cells provides a link between diabetes and urinary tract infections. PLoS One 2010 ;5:e10882

Habibi L, Shokrgozar MA, Tabrizi M, Modarressi MH, Akrami SM. Mercury specifically induces LINE-1 activity in a human neuroblastoma cell line. Mutat Res Genet Toxicol Environ Mutagen 2014 ;759:9-20.

Brunet A, Sweeney LB, Sturgill JF, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004 ;303:2011-2015.

Tran H, Brunet A, Grenier JM, et al.. DNA repair pathway stimulated by the forkhead transcription factor FOXO3a through the Gadd45 protein. Science 2002 ;296:530-534.

Warr MR, Binnewies M, Flach J, et al. FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 2013 ;494:323-327.

Zhao Y, Yang J, Liao W, et al. Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat Cell Biol 2010;12:665-675.

Samuel VT, Choi CS, Phillips TG, et al. Targeting foxo1 in mice using antisense oligonucleotide improves hepatic and peripheral insulin action. Diabetes 2006 ;55:2042-2050.

Relling DP, Esberg LB, Fang CX, et al. High-fat diet-induced juvenile obesity leads to cardiomyocyte dysfunction and upregulation of Foxo3a transcription factor independent of lipotoxicity and apoptosis. J Hypertens 2006 ;24:549-561.

Xiao-Feng Y, Fang P, Meng Sh, et al. The forkhead transcription factors are important in regulating vascular pathology, diabetes and regulatory t cells. Front Biosci (Schol Ed) 2009 ; 1:420–436.

Zemva J, Schilbach K, Stöhr O, et al. Central FoxO3a and FoxO6 expression is down-regulated in obesity induced diabetes but not in aging. Exp Clin Endocrinol Diabetes 2012; 120:340-350.

Guidotti G, Calabrese F, Anacker C, Racagni G, Pariante CM, Riva MA. Glucocorticoid receptor and FKBP5 expression is altered following exposure to chronic stress: modulation by antidepressant treatment. Neuro psycho-pharmacology 2013;38:616-627.

Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Annu Rev Immunol 2011; 29:415-445.

Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 2011; 11:98-107.

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

Ramesh G, MacLean AG, Philipp MT. Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration, and neuropathic pain. Mediators Inflamm 2013;2013:480739.

Fain JN. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm 2006; 74:443-477.

Spranger J, Kroke A, Möhlig M, et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 2003; 52:812-817.

Kozlowski H, Luczkowski M, Remelli M, Valensin D. Copper, zinc and iron in neurodegenerative diseases (Alzheimer’s, Parkinson’s and prion diseases). Coordination Chemistry Reviews 2012; 256: 2129–2141.

Thomas B, Gautam A, Prasad BR, Kumari S. Evaluation of micronutrient (zinc, copper and iron) levels in periodontitis patients with and without diabetes mellitus type 2: a biochemical study. Indian J Dent Res 2013; 24:468-473.

Forte G, Bocca B, Peruzzu A, et al. Blood metals concentration in type 1 and type 2 diabetics. Biol Trace Elem Res 2013; 156:79-90.

Islam MR, Ahmed MU, Mitu SA, et al. Comparative analysis of serum zinc, copper, manganese, iron, calcium, and magnesium level and complexity of interelement relations in generalized anxiety disorder patients. Biol Trace Elem Res 2013; 154:21-27.

Dexter DT, Carayon A, Javoy-Agid F, et al. Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia. Brain 1991; 114:1953-1975.

Varela-Silva MI, Frisancho AR, Bogin B, et al. Behavioral, environmental, metabolic and intergenerational components of early life undernutrition leading to later obesity in developing nations and in minority groups in the U.S.A. Coll Antropol 2007; 31:39-46.

Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH. The disease burden associated with overweight and obesity. JAMA 1999; 282:1523-1529.

Petrov D, Pedrós I, Artiach G, et al. High-fat diet-induced deregulation of hippocampal insulin signaling and mitochondrial homeostasis deficiences contribute to Alzheimer disease pathology in rodents. Biochim Biophys Acta 2015; 1852:1687-1699.

Hao S, Dey A, Yu X, Stranahan AM. Dietary obesity reversibly induces synaptic stripping by microglia and impairs hippocampal plasticity. Brain Behav Immun 2016; 51:230-239.

de la Monte SM, Longato L, Tong M, Wands JR. Insulin resistance and neurodegeneration: roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis. Curr Opin Investig Drugs 2009 ;10:1049-1060.

Pickup JC, Crook MA. Is type II diabetes mellitus a disease of the innate immune system? Diabetologia 1998 ;41:1241-1248.

Stegenga ME, van der Crabben SN, Dessing MC, et al. Effect of acute hyperglycaemia and/or hyperinsulinaemia on proinflammatory gene expression, cytokine production and neutrophil function in humans. Diabet Med 2008 ;25:157-164.

Allan SM. The role of pro- and antiinflammatory cytokines in neurodegeneration. Ann N Y Acad Sci 2000 ;917:84-93.

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.

Dowlati Y, Herrmann N, Swardfager W, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010 ;2010 67:446-457.

Smith JA, Das A, Ray SK, Banik NL. Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases. Brain Res Bull 2012 ; 87:10-20.

Jia JP, Meng R, Sun YX, Sun WJ, Ji XM, Jia LF. Cerebrospinal fluid tau, Abeta1-42 and inflammatory cytokines in patients with Alzheimer's disease and vascular dementia. Neurosci Lett 2005 ;383:12-16.

Carlson NG, Wieggel WA, Chen J, Bacchi A, Rogers SW, Gahring LC. Inflammatory cytokines IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha impart neuroprotection to an excitotoxin through distinct pathways. J Immunol 1999 ;163:3963-3968.

Ali C, Nicole O, Docagne F, Lesne S, MacKenzie ET, Nouvelot A, Buisson A, Vivien D. Ischemia-induced interleukin-6 as a potential endogenous neuroprotective cytokine against NMDA receptor-mediated excitotoxicity in the brain. J Cereb Blood Flow Metab 2000 ;20:956-966.


  • There are currently no refbacks.

Creative Commons Attribution-NonCommercial 3.0

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.