Metformin Attenuates the Metabolic Disturbance and Depression-like Behaviors Induced by Corticosterone and Mediates the Glucose Metabolism Pathway

Abstract

Background Metabolism disturbances are common in patients with depression. The drug metformin has been reported to exhibit antidepressant activity. The purpose of this study was to investigate metabolism disturbances induced by corticosterone (CORT) and determine if metformin can reverse these effects and their accompanying depression-like behaviors.

Methods Rats were exposed to corticosterone with or without metformin administration. Depression-like behaviors were tested. Gene expression was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis. In addition, the metabolites were quantified by LC-MS/MS analysis.

Results Metformin attenuated the depression-like behaviors induced by CORT. Furthermore, metformin reversed disturbances in body weight, serum glucose, and triglyceride levels, as well as hepatic TG levels induced by CORT. Metformin normalized the alterations in the expression of glucose metabolism-related genes (PGC-1α, G6pc, Pepck, Gck, PYGL, Gys2, PKLR, GLUT4) and insulin resistance-related genes (AdipoR1, AdipoR2) in the muscles and livers of rats induced by CORT. Metabolomic analysis showed that metformin reversed the effects of CORT on 11 metabolites involved in the pathways of the tricarboxylic acid cycle, glycolysis, and gluconeogenesis (3-phospho-D-glycerate, β-D-fructose 6-phosphate, D-glucose 6-phosphate, and pyruvate).

Conclusion Our findings suggest that metformin can attenuate metabolism disturbances and depression-like behaviors induced by CORT mediating the glucose metabolism pathway.

Key words

metformin - glucose metabolism - LC-MS/MS - depression-like behavior - metabolomics analysis

^* Yong Hao and Yingpeng Tong contributed equally to this work.

^# Zezhi Li and Yangtai Guan are both corresponding authors.

Publication History

Received: 28 September 2020
Received: 11 December 2020

Accepted: 29 December 2020

Article published online:
25 February 2021

• References

• 1 Zankert S, Bellingrath S, Wust S. et al. HPA axis responses to psychological challenge linking stress and disease: What do we know on sources of intra- and interindividual variability?. Psychoneuroendocrinology 2019; 105: 86-97
• 2 Kinlein SA, Phillips DJ, Keller CR. et al. Role of corticosterone in altered neurobehavioral responses to acute stress in a model of compromised hypothalamic-pituitary-adrenal axis function. Psychoneuroendocrinology 2019; 102: 248-255
• 3 Ali SH, Madhana RM, Athira KV. et al. Resveratrol ameliorates depressive-like behavior in repeated corticosterone-induced depression in mice. Steroids 2015; 101: 37-42
• 4 Steiner MA, Marsicano G, Nestler EJ. et al. Antidepressant-like behavioral effects of impaired cannabinoid receptor type 1 signaling coincide with exaggerated corticosterone secretion in mice. Psychoneuroendocrinology 2008; 33: 54-67
• 5 Assefa Z, Akbib S, Lavens A. et al. Direct effect of glucocorticoids on glucose-activated adult rat beta-cells increases their cell number and their functional mass for transplantation. Am J Physiol Endocrinol Metab 2016; 311: E698-E705
• 6 Groenink L, Dirks A, Verdouw PM. et al. HPA axis dysregulation in mice overexpressing corticotropin releasing hormone. Biol Psychiatry 2002; 51: 875-881
• 7 Marks W, Fournier NM, Kalynchuk LE.. Repeated exposure to corticosterone increases depression-like behavior in two different versions of the forced swim test without altering nonspecific locomotor activity or muscle strength. Physiol Behav 2009; 98: 67-72
• 8 Keller J, Gomez R, Williams G. et al. HPA axis in major depression: cortisol, clinical symptomatology and genetic variation predict cognition. Mol Psychiatry 2017; 22: 527-536
• 9 Wang Q, Timberlake MA, Prall K. et al. The recent progress in animal models of depression. Prog Neuropsychopharmacol Biol Psychiatry 2017; 77: 99-109
• 10 Harvey I, Stephenson EJ, Redd JR. et al. Glucocorticoid-induced metabolic disturbances are exacerbated in obese male mice. Endocrinology 2018; 159: 2275-2287
• 11 Abad V, Chrousos GP, Reynolds JC. et al. Glucocorticoid excess during adolescence leads to a major persistent deficit in bone mass and an increase in central body fat. J Bone Miner Res 2001; 16: 1879-1885
• 12 Shpilberg Y, Beaudry JL, D’Souza A. et al. A rodent model of rapid-onset diabetes induced by glucocorticoids and high-fat feeding. Dis Model Mech 2012; 5: 671-680
• 13 Djurhuus CB, Gravholt CH, Nielsen S. et al. Additive effects of cortisol and growth hormone on regional and systemic lipolysis in humans. Am J Physiol Endocrinol Metab 2004; 286: E488-494
• 14 Wesolowski SR, Hay WW. Role of placental insufficiency and intrauterine growth restriction on the activation of fetal hepatic glucose production. Mol Cell Endocrinol 2016; 435: 61-68
• 15 Moulton CD, Hopkins CWP, Ismail K. et al. Repositioning of diabetes treatments for depressive symptoms: A systematic review and meta-analysis of clinical trials. Psychoneuroendocrinology 2018; 94: 91-103
• 16 Graham EA, Deschenes SS, Khalil MN. et al. Measures of depression and risk of type 2 diabetes: a systematic review and meta-analysis. J Affect Disord 2020; 265: 224-232
• 17 Grigolon RB, Brietzke E, Mansur RB. et al. Association between diabetes and mood disorders and the potential use of anti-hyperglycemic agents as antidepressants. Prog Neuropsychopharmacol Biol Psychiatry 2019; 95: 109720
• 18 Chen F, Wei G, Wang Y. et al. Risk factors for depression in elderly diabetic patients and the effect of metformin on the condition. BMC Public Health 2019; 19: 1063
• 19 Abdallah MS, Mosalam EM, Zidan AA. et al. The antidiabetic metformin as an adjunct to antidepressants in patients with major depressive disorder: a proof-of-concept, randomized, double-blind, placebo-controlled trial. Neurotherapeutics 2020; [Epub ahead]
• 20 Fang W, Zhang J, Hong L. et al. Metformin ameliorates stress-induced depression-like behaviors via enhancing the expression of BDNF by activating AMPK/CREB-mediated histone acetylation. J Affect Disord 2020; 260: 302-313
• 21 Ai H, Fang W, Hu H. et al. Antidiabetic drug metformin ameliorates depressive-like behavior in mice with chronic restraint stress via activation of amp-activated protein kinase. Aging Dis 2020; 11: 31-43
• 22 Zemdegs J, Martin H, Pintana H. et al. metformin promotes anxiolytic and antidepressant-like responses in insulin-resistant mice by decreasing circulating branched-chain amino acids. J Neurosci 2019; 39: 5935-5948
• 23 Madiraju AK, Erion DM, Rahimi Y. et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 2014; 510: 542-546
• 24 He L, Chang E, Peng J. et al. Activation of the cAMP-PKA pathway antagonizes metformin suppression of hepatic glucose production. J Biol Chem 2016; 291: 10562-10570
• 25 Xie X, Shen Q, Ma L. et al. Chronic corticosterone-induced depression mediates premature aging in rats. J Affect Disord 2018; 229: 254-261
• 26 Xiao Q, Xiong Z, Yu C. et al. Antidepressant activity of crocin-I is associated with amelioration of neuroinflammation and attenuates oxidative damage induced by corticosterone in mice. Physiol Behav 2019; 212: 112699
• 27 Wang Y, Liu B, Yang Y. et al. Metformin exerts antidepressant effects by regulated DNA hydroxymethylation. Epigenomics 2019; 11: 655-667
• 28 Li GF, Zhao M, Zhao T. et al. [Effects of metformin on depressive behavior in chronic stress rats]. Zhongguo Ying Yong Sheng Li Xue Za Zhi 2019; 35: 245-249
• 29 Yang S, Chen X, Xu Y. et al. Effects of metformin on lipopolysaccharide-induced depressive-like behavior in mice and its mechanisms. Neuroreport 2020; 31: 305-310
• 30 Wang C, Liu C, Gao K. et al. Metformin preconditioning provide neuroprotection through enhancement of autophagy and suppression of inflammation and apoptosis after spinal cord injury. Biochem Biophys Res Commun 2016; 477: 534-540
• 31 Petersen MC, Vatner DF, Shulman GI.. Regulation of hepatic glucose metabolism in health and disease. Nat Rev Endocrinol 2017; 13: 572-587
• 32 Hundal RS, Krssak M, Dufour S. et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 2000; 49: 2063
• 33 Shaw RJ, Lamia KA, Vasquez D. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005; 310: 1642-1646
• 34 Thiebaud D, Jacot E, DeFronzo RA. et al. The effect of graded doses of insulin on total glucose uptake, glucose oxidation, and glucose storage in man. Diabetes 1982; 31: 957-963
• 35 Krook A, Bjornholm M, Galuska D. et al. Characterization of signal transduction and glucose transport in skeletal muscle from type 2 diabetic patients. Diabetes 2000; 49: 284-292
• 36 Ryder JW, Yang J, Galuska D. et al. Use of a novel impermeable biotinylated photolabeling reagent to assess insulin- and hypoxia-stimulated cell surface GLUT4 content in skeletal muscle from type 2 diabetic patients. Diabetes 2000; 49: 647
• 37 Gurley JM, Ilkayeva O, Jackson RM. et al. Enhanced GLUT4-dependent glucose transport relieves nutrient stress in obese mice through changes in lipid and amino acid metabolism. Diabetes 2016; 65: 3585-3597
• 38 Hirata BK, Banin RM, Dornellas AP. et al. Ginkgo biloba extract improves insulin signaling and attenuates inflammation in retroperitoneal adipose tissue depot of obese rats. Mediators Inflamm 2015; 2015: 419106
• 39 He L, Sabet A, Djedjos S. et al. Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 2009; 137: 635-646
• 40 Yoon JC, Puigserver P, Chen G. et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 2001; 413: 131-138
• 41 Michael LF, Wu Z, Cheatham RB. et al. Restoration of insulin-sensitive glucose transporter (GLUT4) gene expression in muscle cells by the transcriptional coactivator PGC-1. Proc Natl Acad Sci USA 2001; 98: 3820-3825
• 42 Heibel AB, da Cunha MSB, Ferraz CTS. et al. Tucum-do-cerrado (Bactris setosa Mart.) may enhance hepatic glucose response by suppressing gluconeogenesis and upregulating Slc2a2 via AMPK pathway, even in a moderate iron supplementation condition. Food Res Int 2018; 113: 433-442
• 43 von Holstein-Rathlou S, BonDurant LD, Peltekian L. et al. FGF21 mediates endocrine control of simple sugar intake and sweet taste preference by the liver. Cell Metab 2016; 23: 335-343
• 44 Zhang X, Yang S, Chen J. et al. Unraveling the regulation of hepatic gluconeogenesis. Front Endocrinol (Lausanne) 2018; 9: 802
• 45 Jimeno B, Hau M, Verhulst S.. Corticosterone levels reflect variation in metabolic rate, independent of “stress”. Sci Rep 2018; 8: 13020
• 46 Tsoi B, He RR, Yang DH. et al. Carnosine ameliorates stress-induced glucose metabolism disorder in restrained mice. Journal of Pharmacological Sciences 2011; 117: 223-229
• 47 Franko KL, Forhead AJ, Fowden AL.. Effects of stress during pregnancy on hepatic glucogenic capacity in rat dams and their fetuses. Physiol Rep 2017; 5 (05) e13293
• 48 Greulich F, Hemmer MC, Rollins DA. et al. There goes the neighborhood: assembly of transcriptional complexes during the regulation of metabolism and inflammation by the glucocorticoid receptor. Steroids 2016; 114: 7-15
• 49 Momoda TS, Schwindt AR, Feist GW. et al. Gene expression in the liver of rainbow trout, Oncorhynchus mykiss, during the stress response. Comp Biochem Physiol Part D Genomics Proteomics 2007; 2: 303-315
• 50 Udoh US, Swain TM, Filiano AN. et al. Chronic ethanol consumption disrupts diurnal rhythms of hepatic glycogen metabolism in mice. Am J Physiol Gastrointest Liver Physiol 2015; 308: G964-974
• 51 Xie X, Shen Q, Cao L. et al. Depression caused by long-term stress regulates premature aging and is possibly associated with disruption of circadian rhythms in mice. Physiol Behav 2019; 199: 100-110
• 52 Mayerson AB, Hundal RS, Dufour S. et al. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 2002; 51: 797-802
• 53 Kim M-S, Kim S-H, Park S-J. et al. Ginseng berry improves hyperglycemia by downregulating hepatic gluconeogenesis and steatosis in mice with diet-induced type 2 diabetes. J Funct Foods 2017; 35: 295-302
• 54 Adina-Zada A, Zeczycki TN, Maurice M. et al. Allosteric regulation of the biotin-dependent enzyme pyruvate carboxylase by acetyl-CoA. Biochem Soc Trans 2012; 40: 567-572
• 55 Wang Z, Xu D, She L. et al. Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice. Mol Cell Endocrinol 2018; 474: 127-136
• 56 Guan M, Xie L, Diao C. et al. Systemic perturbations of key metabolites in diabetic rats during the evolution of diabetes studied by urine metabonomics. PLoS One 2013; 8: e60409
• 57 Nie Q, Chen H, Hu J. et al. Arabinoxylan attenuates type 2 diabetes by improvement of carbohydrate, lipid, and amino acid metabolism. Mol Nutr Food Res 2018; 62: e1800222
• 58 Cui H, Zhang C, Li C. et al. Antimicrobial mechanism of clove oil on Listeria monocytogenes. Food Control 2018; 94: 140-146
• 59 Araujo AM, Bastos ML, Fernandes E. et al. GC-MS metabolomics reveals disturbed metabolic pathways in primary mouse hepatocytes exposed to subtoxic levels of 3,4-methylenedioxymethamphetamine (MDMA). Arch Toxicol 2018; 92: 3307-3323
• 60 Pedersen BK, Febbraio M.. Muscle-derived interleukin-6—a possible link between skeletal muscle, adipose tissue, liver, and brain. Brain Behav Immun 2005; 19: 371-376
• 61 Paraiso IL, Revel JS, Choi J. et al. Targeting the liver-brain axis with hop-derived flavonoids improves lipid metabolism and cognitive performance in mice. Mol Nutr Food Res 2020; 64: e2000341
• 62 Yao Y, Zhang W, Ming R. et al. Noninvasive 40-Hz light flicker rescues circadian behavior and abnormal lipid metabolism induced by acute ethanol exposure via improving sirt1 and the circadian clock in the liver-brain axis. Front Pharmacol 2020; 11: 355
• 63 de Sousa Rodrigues ME, Bekhbat M, Houser MC. et al. Chronic psychological stress and high-fat high-fructose diet disrupt metabolic and inflammatory gene networks in the brain, liver, and gut and promote behavioral deficits in mice. Brain Behav Immun 2017; 59: 158-172