Modulation of hepatic inflammation and energy-sensing pathways in the rat liver by high-fructose diet and chronic stress
High-fructose consumption and chronic stress are both associated with metabolic inflammation and insulin resistance. Recently, disturbed activity of energy sensor AMP-activated protein kinase (AMPK) was recognized as mediator between nutrient-induced stress and inflammation. Thus, we analyzed the effects of high-fructose diet, alone or in combination with chronic stress, on glucose homeostasis, inflammation and expression of energy sensing proteins in the rat liver.
In male Wistar rats exposed to 9-week 20% fructose diet and/or 4-week chronic unpredictable stress we measured plasma and hepatic corticosterone level, indicators of glucose homeostasis and lipid metabolism, hepatic inflammation (pro- and anti-inflammatory cytokine levels, Toll-like receptor 4, NLRP3, activation of NFκB, JNK and ERK pathways) and levels of energy-sensing proteins AMPK, SIRT1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α).
High-fructose diet led to glucose intolerance, activation of NFκB and JNK pathways and increased intrahepatic IL-1β, TNFα and inhibitory phosphorylation of insulin receptor substrate 1 on Ser307. It also decreased phospho-AMPK/AMPK ratio and increased SIRT1 expression. Stress alone increased plasma and hepatic corticosterone but did not influence glucose tolerance, nor hepatic inflammatory or energy-sensing proteins. After the combined treatment, hepatic corticosterone was increased, glucose tolerance remained preserved, while hepatic inflammation was partially prevented despite decreased AMPK activity.
High-fructose diet resulted in glucose intolerance, hepatic inflammation, decreased AMPK activity and reduced insulin sensitivity. Chronic stress alone did not exert such effects, but when applied together with high-fructose diet it could partially prevent fructose-induced inflammation, presumably due to increased hepatic glucocorticoids.
KeywordsInflammation AMP-activated protein kinase Dietary fructose Stress Rat liver
This work was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant III41009) and SCOPES JRP (Grant no. IZ73ZO_152331). The authors gratefully appreciate Dr. Đurđica Ignjatović for providing ERK and phospho-ERK antibodies, Dr. Desa Milanović for providing phospho-AMPK antibody and Dr. Ivana Stojanović for providing NLRP3 antibody.
Compliance with ethical standards
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
- 2.Yau YH, Potenza MN (2013) Stress and eating behaviors. Minerva Endocrinol 38:255–267Google Scholar
- 3.Kuo LE, Kitlinska JB, Tilan JU, Li L, Baker SB, Johnson MD, Lee EW, Burnett MS, Fricke ST, Kvetnansky R, Herzog H, Zukowska Z (2007) Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome. Nat Med 13:803–811. https://doi.org/10.1038/nm1611 CrossRefGoogle Scholar
- 5.Le Marchand-Brustel Y, Gual P, Gremeaux T, Gonzalez T, Barres R, Tanti JF (2003) Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling. Biochem Soc Trans 31:1152–1156. https://doi.org/10.1042/BST0311152 CrossRefGoogle Scholar
- 12.Zhao C, Zhang Y, Liu H, Li P, Zhang H, Cheng G (2017) Fortunellin protects against high fructose-induced diabetic heart injury in mice by suppressing inflammation and oxidative stress via AMPK/Nrf-2 pathway regulation. Biochem Biophys Res Commun 490:552–559. https://doi.org/10.1016/j.bbrc.2017.06.076 CrossRefGoogle Scholar
- 13.Mancini SJ, White AD, Bijland S, Rutherford C, Graham D, Richter EA, Viollet B, Touyz RM, Palmer TM, Salt IP (2017) Activation of AMP-activated protein kinase rapidly suppresses multiple pro-inflammatory pathways in adipocytes including IL-1 receptor-associated kinase-4 phosphorylation. Mol Cell Endocrinol 440:44–56. https://doi.org/10.1016/j.mce.2016.11.010 CrossRefGoogle Scholar
- 14.Bess E, Fisslthaler B, Fromel T, Fleming I (2011) Nitric oxide-induced activation of the AMP-activated protein kinase alpha2 subunit attenuates IkappaB kinase activity and inflammatory responses in endothelial cells. PLoS One 6:e20848. https://doi.org/10.1371/journal.pone.0020848 CrossRefGoogle Scholar
- 18.Kim HJ, Park KG, Yoo EK, Kim YH, Kim YN, Kim HS, Kim HT, Park JY, Lee KU, Jang WG, Kim JG, Kim BW, Lee IK (2007) Effects of PGC-1alpha on TNF-alpha-induced MCP-1 and VCAM-1 expression and NF-kappaB activation in human aortic smooth muscle and endothelial cells. Antioxid Redox Signal 9:301–307. https://doi.org/10.1089/ars.2006.1456 CrossRefGoogle Scholar
- 19.Pereira CD, Severo M, Neves D, Ascensao A, Magalhaes J, Guimaraes JT, Monteiro R, Martins MJ (2015) Natural mineral-rich water ingestion improves hepatic and fat glucocorticoid-signaling and increases sirtuin 1 in an animal model of metabolic syndrome. Horm Mol Biol Clin Investig 21:149–157. https://doi.org/10.1515/hmbci-2014-0032 Google Scholar
- 22.de Sousa Rodrigues ME, Bekhbat M, Houser MC, Chang J, Walker DI, Jones DP, Oller do Nascimento CM, Barnum CJ, Tansey MG (2017) 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 59:158–172. https://doi.org/10.1016/j.bbi.2016.08.021 CrossRefGoogle Scholar
- 26.Velickovic N, Djordjevic A, Vasiljevic A, Bursac B, Milutinovic DV, Matic G (2013) Tissue-specific regulation of inflammation by macrophage migration inhibitory factor and glucocorticoids in fructose-fed Wistar rats. Br J Nutr 110:456–465. https://doi.org/10.1017/S0007114512005193 CrossRefGoogle Scholar
- 27.Vasiljevic A, Velickovic N, Bursac B, Djordjevic A, Milutinovic DV, Nestorovic N, Matic G (2013) Enhanced prereceptor glucocorticoid metabolism and lipogenesis impair insulin signaling in the liver of fructose-fed rats. J Nutr Biochem 24:1790–1797. https://doi.org/10.1016/j.jnutbio.2013.04.001 CrossRefGoogle Scholar
- 28.Folch J, Lees M, Sloane Stanley GH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226:497–509Google Scholar
- 30.Petrovic S, Arsic A, Glibetic M, Cikiriz N, Jakovljevic V, Vucic V (2016) The effects of polyphenol-rich chokeberry juice on fatty acid profiles and lipid peroxidation of active handball players: results from a randomized, double-blind, placebo-controlled study. Can J Physiol Pharmacol 94:1058–1063. https://doi.org/10.1139/cjpp-2015-0575 CrossRefGoogle Scholar
- 36.Axelsen LN, Lademann JB, Petersen JS, Holstein-Rathlou NH, Ploug T, Prats C, Pedersen HD, Kjolbye AL (2010) Cardiac and metabolic changes in long-term high fructose-fat fed rats with severe obesity and extensive intramyocardial lipid accumulation. Am J Physiol Regul Integr Comp Physiol 298:R1560–R1570. https://doi.org/10.1152/ajpregu.00392.2009 CrossRefGoogle Scholar
- 39.Tranchida F, Rakotoniaina Z, Shintu L, Tchiakpe L, Deyris V, Yemloul M, Stocker P, Vidal N, Rimet O, Hiol A, Caldarelli S (2017) Hepatic metabolic effects of Curcuma longa extract supplement in high-fructose and saturated fat fed rats. Sci Rep 7:5880. https://doi.org/10.1038/s41598-017-06220-0 CrossRefGoogle Scholar
- 41.Softic S, Gupta MK, Wang GX, Fujisaka S, O’Neill BT, Rao TN, Willoughby J, Harbison C, Fitzgerald K, Ilkayeva O, Newgard CB, Cohen DE, Kahn CR (2017) Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling. J Clin Invest 127:4059–4074. https://doi.org/10.1172/JCI94585 CrossRefGoogle Scholar
- 43.Macedo IC, Medeiros LF, Oliveira C, Oliveira CM, Rozisky JR, Scarabelot VL, Souza A, Silva FR, Santos VS, Cioato SG, Caumo W, Torres IL (2012) Cafeteria diet-induced obesity plus chronic stress alter serum leptin levels. Peptides 38:189–196. https://doi.org/10.1016/j.peptides.2012.08.007 CrossRefGoogle Scholar
- 46.Lozano I, Van der Werf R, Bietiger W, Seyfritz E, Peronet C, Pinget M, Jeandidier N, Maillard E, Marchioni E, Sigrist S, Dal S (2016) High-fructose and high-fat diet-induced disorders in rats: impact on diabetes risk, hepatic and vascular complications. Nutr Metab (Lond) 13:15. https://doi.org/10.1186/s12986-016-0074-1 CrossRefGoogle Scholar
- 49.Sanguesa G, Baena M, Hutter N, Montanes JC, Sanchez RM, Roglans N, Laguna JC, Alegret M (2017) The addition of liquid fructose to a western-type diet in LDL-R−/− mice induces liver inflammation and fibrogenesis markers without disrupting insulin receptor signalling after an insulin challenge. Nutrients. https://doi.org/10.3390/nu9030278 Google Scholar
- 50.Vasiljevic A, Bursac B, Djordjevic A, Milutinovic DV, Nikolic M, Matic G, Velickovic N (2014) Hepatic inflammation induced by high-fructose diet is associated with altered 11betaHSD1 expression in the liver of Wistar rats. Eur J Nutr 53:1393–1402. https://doi.org/10.1007/s00394-013-0641-4 CrossRefGoogle Scholar
- 54.Gauthier MS, O’Brien EL, Bigornia S, Mott M, Cacicedo JM, Xu XJ, Gokce N, Apovian C, Ruderman N (2011) Decreased AMP-activated protein kinase activity is associated with increased inflammation in visceral adipose tissue and with whole-body insulin resistance in morbidly obese humans. Biochem Biophys Res Commun 404:382–387. https://doi.org/10.1016/j.bbrc.2010.11.127 CrossRefGoogle Scholar
- 55.Liu Q, Gauthier MS, Sun L, Ruderman N, Lodish H (2010) Activation of AMP-activated protein kinase signaling pathway by adiponectin and insulin in mouse adipocytes: requirement of acyl-CoA synthetases FATP1 and Acsl1 and association with an elevation in AMP/ATP ratio. FASEB J 24:4229–4239. https://doi.org/10.1096/fj.10-159723 CrossRefGoogle Scholar
- 56.Chen HL, Tsai TC, Tsai YC, Liao JW, Yen CC, Chen CM (2016) Kefir peptides prevent high-fructose corn syrup-induced non-alcoholic fatty liver disease in a murine model by modulation of inflammation and the JAK2 signaling pathway. Nutr Diabetes 6:e237. https://doi.org/10.1038/nutd.2016.49 CrossRefGoogle Scholar
- 60.Cao X, Miner JN, Terkeltaub R, Liu-Bryan R (2016) Fructose amplifies inflammatory potential in human monocytic cells via reduction of AMP-activated protein kinase activity. Arthritis Rheumatol 68(suppl 10):Abstract 2268Google Scholar
- 63.Zhang X, Zhang JH, Chen XY, Hu QH, Wang MX, Jin R, Zhang QY, Wang W, Wang R, Kang LL, Li JS, Li M, Pan Y, Huang JJ, Kong LD (2015) Reactive oxygen species-induced TXNIP drives fructose-mediated hepatic inflammation and lipid accumulation through NLRP3 inflammasome activation. Antioxid Redox Signal 22:848–870. https://doi.org/10.1089/ars.2014.5868 CrossRefGoogle Scholar
- 64.Bursać B, Djordjevic A, Veličković N, Milutinović D, Petrović S, Teofilović A, Gligorovska L, Preitner F, Tappy L, Matić G (2018) Involvement of glucocorticoid prereceptor metabolism and signaling in rat visceral adipose tissue lipid metabolism after chronic stress combined with high-fructose diet. Mol Cell Endocrinol. https://doi.org/10.1016/j.mce.2018.04.015 Google Scholar
- 67.Dittrich A, Khouri C, Sackett SD, Ehlting C, Bohmer O, Albrecht U, Bode JG, Trautwein C, Schaper F (2012) Glucocorticoids increase interleukin-6-dependent gene induction by interfering with the expression of the suppressor of cytokine signaling 3 feedback inhibitor. Hepatology 55:256–266. https://doi.org/10.1002/hep.24655 CrossRefGoogle Scholar