Metabolic Brain Disease

, Volume 32, Issue 4, pp 1163–1172 | Cite as

Curcumin reverses the depressive-like behavior and insulin resistance induced by chronic mild stress

  • Ji-Duo Shen
  • Yu Wei
  • Yu-Jie Li
  • Jing-Yi Qiao
  • Yu-Cheng Li
Original Article
First Online:
Received:
Accepted:

Abstract

Increasing evidence has demonstrated that patients with depression have a higher risk of developing type 2 diabetes. Insulin resistance has been identified as the key mechanism linking depression and diabetes. The present study established a rat model of depression complicated by insulin resistance using a 12-week exposure to chronic mild stress (CMS) and investigated the therapeutic effects of curcumin. Sucrose intake tests were used to evaluate depressive-like behaviors, and oral glucose tolerance tests (OGTT) and intraperitoneal insulin tolerance tests (IPITT) were performed to evaluate insulin sensitivity. Serum parameters were detected using commercial kits. Real-time quantitative PCR was used to examine mRNA expression. CMS rats exhibited reduced sucrose consumption, increased serum glucose, insulin, triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), non-esterified fatty acid (NEFA), glucagon, leptin, and corticosterone levels, as well as impaired insulin sensitivity. Curcumin upregulated the phosphorylation of insulin receptor substrate (IRS)-1 and protein kinase B (Akt) in the liver, enhanced insulin sensitivity, and reversed the metabolic abnormalities and depressive-like behaviors mentioned above. Moreover, curcumin increased the hepatic glycogen content by inhibiting glycogen synthase kinase (GSK)-3β and prevented gluconeogenesis by inhibiting phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase). These results suggest that curcumin not only exerted antidepressant-like effects, but also reversed the insulin resistance and metabolic abnormalities induced by CMS. These data may provide evidence to support the potential use of curcumin against depression and/or metabolic disorders.

Keywords

Chronic mild stress Curcumin Depression Insulin resistance 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

The project was supported by grants from the National Natural Science Foundation of China (No.81303278, 81673629) and the Talent Project of Science and Technology Innovation of Henan University of Traditional Chinese Medicine (2015XCXRC03).

Compliance with ethical standards

Declaration of interest

None of the authors have any potential conflicts of interest associated with this research.

References

  1. Accili D (2004) Lilly lecture 2003: the struggle for mastery in insulin action: from triumvirate to republic. Diabetes 53:1633–1642CrossRefPubMedGoogle Scholar
  2. Ding XQ et al (2015) Curcumin protects against fructose-induced podocyte insulin signaling impairment through upregulation of miR-206. Mol Nutr Food Res 59:2355–2370. doi: 10.1002/mnfr.201500370 CrossRefPubMedGoogle Scholar
  3. Duda W et al (2016) The effect of chronic mild stress and imipramine on the markers of oxidative stress and antioxidant system in rat liver. Neurotox Res 30:173–184. doi: 10.1007/s12640-016-9614-8 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Hill MN, Hellemans KG, Verma P, Gorzalka BB, Weinberg J (2012) Neurobiology of chronic mild stress: parallels to major depression. Neurosci Biobehav Rev 36:2085–2117. doi: 10.1016/j.neubiorev.2012.07.001 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Hummel J et al (2011) Serum lipoproteins improve after successful pharmacologic antidepressant treatment: a randomized open-label prospective trial. J Clin Psychiatry 72:885–891. doi: 10.4088/JCP.09m05853blu CrossRefPubMedGoogle Scholar
  6. Jia HM et al (2016) Chronic unpredictive mild stress leads to altered hepatic metabolic profile and gene expression. Sci Rep 6:Artn 23441. doi: 10.1038/Srep23441 CrossRefGoogle Scholar
  7. Kahl KG, Schweiger U, Correll C, Muller C, Busch ML, Bauer M, Schwarz P (2015) Depression, anxiety disorders, and metabolic syndrome in a population at risk for type 2 diabetes mellitus. Brain Behav 5:e00306. doi: 10.1002/brb3.306 CrossRefPubMedCentralGoogle Scholar
  8. Katon W, Pedersen HS, Ribe AR, Fenger-Gron M, Davydow D, Waldorff FB, Vestergaard M (2015) Effect of depression and diabetes mellitus on the risk for dementia: a national population-based cohort study. JAMA Psychiat 72:612–619. doi: 10.1001/jamapsychiatry.2015.0082 CrossRefGoogle Scholar
  9. Knychala MA, Jorge ML, Muniz CK, Faria PN, Jorge PT (2015) High-risk alcohol use and anxiety and depression symptoms in adolescents and adults with type 1 diabetes mellitus: a cross-sectional study. Diabetol Metab Syndr 7:24. doi: 10.1186/s13098-015-0020-9 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Li YC, Wang FM, Pan Y, Qiang LQ, Cheng G, Zhang WY, Kong LD (2009) Antidepressant-like effects of curcumin on serotonergic receptor-coupled AC-cAMP pathway in chronic unpredictable mild stress of rats. Prog Neuro-Psychopharmacol Biol Psychiatry 33:435–449. doi: 10.1016/j.pnpbp.2009.01.006 CrossRefGoogle Scholar
  11. Li JM, Li YC, Kong LD, Hu QH (2010) Curcumin inhibits hepatic protein-tyrosine phosphatase 1B and prevents hypertriglyceridemia and hepatic steatosis in fructose-fed rats. Hepatology (Baltimore, Md) 51:1555–1566. doi: 10.1002/hep.23524 CrossRefGoogle Scholar
  12. Li YC, Shen JD, Li J, Wang R, Jiao S, Yi LT (2013) Chronic treatment with baicalin prevents the chronic mild stress-induced depressive-like behavior: involving the inhibition of cyclooxygenase-2 in rat brain. Prog Neuro-Psychopharmacol Biol Psychiatry 40:138–143. doi: 10.1016/j.pnpbp.2012.09.007 CrossRefGoogle Scholar
  13. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods (San Diego, Calif) 25:402–408. doi: 10.1006/meth.2001.1262 CrossRefGoogle Scholar
  14. Pan A et al (2008) Insulin resistance and depressive symptoms in middle-aged and elderly Chinese: findings from the nutrition and health of aging population in China study. J Affect Disord 109:75–82. doi: 10.1016/j.jad.2007.11.002 CrossRefPubMedGoogle Scholar
  15. Scharnholz B et al (2014) Do depressed patients without activation of the hypothalamus-pituitary-adrenal (HPA) system have metabolic disturbances? Psychoneuroendocrinology 39:104–110. doi: 10.1016/j.psyneuen.2013.09.030 CrossRefPubMedGoogle Scholar
  16. Segerstrom SC, Miller GE (2004) Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull 130:601–630. doi: 10.1037/0033-2909.130.4.601 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Shao W et al (2012) Curcumin prevents high fat diet induced insulin resistance and obesity via attenuating lipogenesis in liver and inflammatory pathway in adipocytes. PLoS One 7:e28784. doi: 10.1371/journal.pone.0028784 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Tang M et al (2015) Fish oil supplementation alleviates depressant-like behaviors and modulates lipid profiles in rats exposed to chronic unpredictable mild stress. BMC Complement Altern Med 15:239. doi: 10.1186/s12906-015-0778-1 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Thompson AK, Fourman S, Packard AE, Egan AE, Ryan KK, Ulrich-Lai YM (2015) Metabolic consequences of chronic intermittent mild stress exposure. Physiol Behav 150:24–30. doi: 10.1016/j.physbeh.2015.02.038 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Timonen M, Rajala U, Jokelainen J, Keinanen-Kiukaanniemi S, Meyer-Rochow VB, Rasanen P (2006) Depressive symptoms and insulin resistance in young adult males: results from the northern Finland 1966 birth cohort. Mol Psychiatry 11:929–933. doi: 10.1038/sj.mp.4001838 CrossRefPubMedGoogle Scholar
  21. Ulrich-Lai YM, Herman JP (2009) Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci 10:397–409. doi: 10.1038/nrn2647 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Vareka T, Vecka M, Jirak R, Tvrzicka E, Macasek J, Zak A, Zeman M (2012) Plasma fatty acid profile in depressive disorder resembles insulin resistance state. Neuro Endocrinol Lett 33(Suppl 2):83–86PubMedGoogle Scholar
  23. Weisberg S, Leibel R, Tortoriello DV (2016) Proteasome inhibitors, including curcumin, improve pancreatic beta-cell function and insulin sensitivity in diabetic mice. Nutrition & diabetes 6:e205. doi: 10.1038/nutd.2016.13 CrossRefGoogle Scholar
  24. Willner P (2017) The chronic mild stress (CMS) model of depression: history, evaluation and usage. Neurobiology of stress 6:78–93. doi: 10.1016/j.ynstr.2016.08.002 CrossRefPubMedGoogle Scholar
  25. Willner P, Towell A, Sampson D, Sophokleous S, Muscat R (1987) Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacology 93:358–364CrossRefPubMedGoogle Scholar
  26. Zhang L, Luo J, Zhang M, Yao W, Ma X, Yu SY (2014) Effects of curcumin on chronic, unpredictable, mild, stress-induced depressive-like behaviour and structural plasticity in the lateral amygdala of rats. The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum 17:793–806. doi: 10.1017/s1461145713001661 CrossRefGoogle Scholar
  27. Zheng T et al (2015) Salidroside ameliorates insulin resistance through activation of a mitochondria-associated AMPK/PI3K/Akt/GSK3beta pathway. Br J Pharmacol 172:3284–3301. doi: 10.1111/bph.13120 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Ji-Duo Shen
    • 1
  • Yu Wei
    • 1
  • Yu-Jie Li
    • 2
  • Jing-Yi Qiao
    • 3
  • Yu-Cheng Li
    • 1
  1. 1.College of PharmacyHenan University of Chinese MedicineZhengzhouPeople’s Republic of China
  2. 2.College of Basic MedicineHenan University of Chinese MedicineZhengzhouPeople’s Republic of China
  3. 3.Experiment center of Pharmacology and Toxicology, Department of Science and TechnologyHenan University of Chinese MedicineZhengzhouPeople’s Republic of China

Personalised recommendations