Advertisement

Maternal betaine protects rat offspring from glucocorticoid-induced activation of lipolytic genes in adipose tissue through modification of DNA methylation

  • Nannan Zhao
  • Shu Yang
  • Bo Sun
  • Yue Feng
  • Ruqian ZhaoEmail author
Original Contribution

Abstract

Purpose

Excessive exposure of glucocorticoids activates adipose lipolysis, increases circulating free fatty acids, and contributes to ectopic lipid deposition in liver and skeletal muscle. Our previous study demonstrated that maternal betaine supplementation attenuates glucocorticoid-induced hepatic lipid accumulation in rat offspring. However, it is unclear whether maternal betaine supplementation is effective in preventing glucocorticoid-induced lipolysis in the adipose tissue of offspring.

Methods

In this study, 20 pregnant rats were fed with basal or betaine-supplemented (10 g/kg) diets throughout gestation and lactation, and the offspring rats were raised on the basal diet from weaning till 3 months of age followed by daily intraperitoneal injection of saline or 0.1 mg/kg dexamethasone (DEX) for 3 weeks.

Results

Chronic DEX treatment significantly (P < 0.05) decreased serum corticosterone level and increased proinflammatory cytokines, such as TNFα, IL-1β, and IL-6. Meanwhile, GR protein content in adipose tissue was increased in response to DEX treatment, which was associated with a significant (P < 0.05) up-regulation of ATGL and HSL expression at both mRNA and protein levels. All these DEX-induced changes were significantly (P < 0.05) attenuated in progeny rats derived from betaine-supplemented dams. Furthermore, DEX-induced hypomethylation of ATGL and HSL gene promoters was reversed by maternal betaine supplementation.

Conclusions

Taken together, these results suggest that maternal betaine supplementation is effective in alleviating glucocorticoid-induced lipolysis in adipose tissue with modification of DNA methylation on the promoter of lipolytic genes.

Keywords

Maternal Betaine Glucocorticoid Lipolysis DNA methylation 

Abbreviations

ACC

Acetyl-CoA carboxylase

AKT

Serine/threonine-specific protein kinase

AMPK

AMP-activated protein kinase

ATGL

Adipose triglyceride lipase

FAS

Fatty acid synthase

GR

Glucocorticoid receptor

HSL

Hormone sensitive lipase

IL-1β

Interleukin 1β

IL-6

Interleukin 6

NAFLD

Non-alcoholic fatty liver disease

TNFα

Tumor necrosis factor α

Notes

Acknowledgements

The present study was supported by the National Key Research and Development Program of China (2016YFD0500502), the National Basic Research Program of China (2012CB124703), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control.

Author contributions

NZ contributed to hormone and gene assays, data analysis, and drafting of the manuscript. SY was responsible for animal care, breeding and sampling. BS and YF provided technical support. RZ contributed to conception, experimental design, data interpretation, and critical revision of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest associated with this manuscript.

References

  1. 1.
    Baschant U, Tuckermann J (2010) The role of the glucocorticoid receptor in inflammation and immunity. J Steroid Biochem Mol Biol 120(2–3):69–75.  https://doi.org/10.1016/j.jsbmb.2010.03.058 CrossRefGoogle Scholar
  2. 2.
    Geer EB, Islam J, Buettner C (2014) Mechanisms of glucocorticoid-induced insulin resistance: focus on adipose tissue function and lipid metabolism. Endocrinol Metab Clin N Am 43(1):75–102.  https://doi.org/10.1016/j.ecl.2013.10.005 CrossRefGoogle Scholar
  3. 3.
    Do TTH, Marie G, Heloise D, Guillaume D, Marthe M, Bruno F, Marion B (2018) Glucocorticoid-induced insulin resistance is related to macrophage visceral adipose tissue infiltration. J Steroid Biochem Mol Biol.  https://doi.org/10.1016/j.jsbmb.2018.08.010 Google Scholar
  4. 4.
    Wang JC, Gray NE, Kuo T, Harris CA (2012) Regulation of triglyceride metabolism by glucocorticoid receptor. Cell Biosci 2(1):19.  https://doi.org/10.1186/2045-3701-2-19 CrossRefGoogle Scholar
  5. 5.
    Campbell JE, Peckett AJ, D’Souza AM, Hawke TJ, Riddell MC (2011) Adipogenic and lipolytic effects of chronic glucocorticoid exposure. Am J Physiol Cell Physiol 300(1):C198–C209.  https://doi.org/10.1152/ajpcell.00045.2010 CrossRefGoogle Scholar
  6. 6.
    Day CR, Kempson SA (2016) Betaine chemistry, roles, and potential use in liver disease. Biochem Biophys Acta 6:1098–1106.  https://doi.org/10.1016/j.bbagen.2016.02.001 CrossRefGoogle Scholar
  7. 7.
    Bingul I, Aydin AF, Basaran-Kucukgergin C, Dogan-Ekici I, Coban J, Dogru-Abbasoglu S, Uysal M (2016) High-fat diet plus carbon tetrachloride-induced liver fibrosis is alleviated by betaine treatment in rats. Int Immunopharmacol 39:199–207.  https://doi.org/10.1016/j.intimp.2016.07.028 CrossRefGoogle Scholar
  8. 8.
    Ge CX, Yu R, Xu MX, Li PQ, Fan CY, Li JM, Kong LD (2016) Betaine prevented fructose-induced NAFLD by regulating LXRalpha/PPARalpha pathway and alleviating ER stress in rats. Eur J Pharmacol 770:154–164.  https://doi.org/10.1016/j.ejphar.2015.11.043 CrossRefGoogle Scholar
  9. 9.
    Kitagawa E, Yamamoto T, Fujishita M, Ota Y, Yamamoto K, Nakagawa T, Hayakawa T (2017) Choline and betaine ameliorate liver lipid accumulation induced by vitamin B6 deficiency in rats. Biosci Biotechnol Biochem 81(2):316–322.  https://doi.org/10.1080/09168451.2016.1240604 CrossRefGoogle Scholar
  10. 10.
    Kovacevic S, Nestorov J, Matic G, Elakovic I (2017) Fructose and stress induce opposite effects on lipid metabolism in the visceral adipose tissue of adult female rats through glucocorticoid action. Eur J Nutr 56(6):2115–2128.  https://doi.org/10.1007/s00394-016-1251-8 CrossRefGoogle Scholar
  11. 11.
    Dou X, Xia Y, Chen J, Qian Y, Li S, Zhang X, Song Z (2014) Rectification of impaired adipose tissue methylation status and lipolytic response contributes to hepatoprotective effect of betaine in a mouse model of alcoholic liver disease. Br J Pharmacol 171(17):4073–4086.  https://doi.org/10.1111/bph.12765 CrossRefGoogle Scholar
  12. 12.
    Wang Z, Yao T, Pini M, Zhou Z, Fantuzzi G, Song Z (2010) Betaine improved adipose tissue function in mice fed a high-fat diet: a mechanism for hepatoprotective effect of betaine in nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol 298(5):G634–G642.  https://doi.org/10.1152/ajpgi.00249.2009 CrossRefGoogle Scholar
  13. 13.
    Xu M, Che L, Yang Z, Zhang P, Shi J, Li J, Lin Y, Fang Z, Che L, Feng B, Wu D, Xu S (2016) Effect of high fat dietary intake during maternal gestation on offspring ovarian health in a pig model. Nutrients 8(8):E498.  https://doi.org/10.3390/nu8080498 CrossRefGoogle Scholar
  14. 14.
    Burdge GC, Slater-Jefferies J, Torrens C, Phillips ES, Hanson MA, Lillycrop KA (2007) Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations. Br J Nutr 97(3):435–439.  https://doi.org/10.1017/S0007114507352392 CrossRefGoogle Scholar
  15. 15.
    Vanselow J, Kucia M, Langhammer M, Koczan D, Metges CC (2016) Maternal high-protein diet during pregnancy, but not during suckling, induced altered expression of an increasing number of hepatic genes in adult mouse offspring. Eur J Nutr 55(3):917–930.  https://doi.org/10.1007/s00394-015-0906-1 CrossRefGoogle Scholar
  16. 16.
    Cheng Z, Zheng L, Almeida FA (2017) Epigenetic reprogramming in metabolic disorders: nutritional factors and beyond. J Nutr Biochem 54:1–10.  https://doi.org/10.1016/j.jnutbio.2017.10.004 CrossRefGoogle Scholar
  17. 17.
    Cai D, Jia Y, Lu J, Yuan M, Sui S, Song H, Zhao R (2014) Maternal dietary betaine supplementation modifies hepatic expression of cholesterol metabolic genes via epigenetic mechanisms in newborn piglets. Br J Nutr 112(9):1459–1468.  https://doi.org/10.1017/S0007114514002402 CrossRefGoogle Scholar
  18. 18.
    Cai D, Wang J, Jia Y, Liu H, Yuan M, Dong H, Zhao R (2016) Gestational dietary betaine supplementation suppresses hepatic expression of lipogenic genes in neonatal piglets through epigenetic and glucocorticoid receptor-dependent mechanisms. Biochem Biophys Acta 1:41–50.  https://doi.org/10.1016/j.bbalip.2015.10.002 Google Scholar
  19. 19.
    Zhao N, Yang S, Jia Y, Sun B, He B, Zhao R (2018) Maternal betaine supplementation attenuates glucocorticoid-induced hepatic lipid accumulation through epigenetic modification in adult offspring rats. J Nutr Biochem 54:105–112.  https://doi.org/10.1016/j.jnutbio.2017.12.003 CrossRefGoogle Scholar
  20. 20.
    Liu X, Wang J, Li R, Yang X, Sun Q, Albrecht E, Zhao R (2011) Maternal dietary protein affects transcriptional regulation of myostatin gene distinctively at weaning and finishing stages in skeletal muscle of Meishan pigs. Epigenetics 6(7):899–907CrossRefGoogle Scholar
  21. 21.
    Kiefer H (2015) Genome-wide analysis of methylation in bovine clones by methylated DNA immunoprecipitation (MeDIP). Methods Mol Biol 1222:267–280.  https://doi.org/10.1007/978-1-4939-1594-1_20 CrossRefGoogle Scholar
  22. 22.
    Sookoian S, Puri P, Castano GO, Scian R, Mirshahi F, Sanyal AJ, Pirola CJ (2017) Nonalcoholic steatohepatitis is associated with a state of betaine-insufficiency. Liver Int 37(4):611–619.  https://doi.org/10.1111/liv.13249 CrossRefGoogle Scholar
  23. 23.
    Kharbanda KK, Todero SL, King AL, Osna NA, McVicker BL, Tuma DJ, Wisecarver JL, Bailey SM (2012) Betaine treatment attenuates chronic ethanol-induced hepatic steatosis and alterations to the mitochondrial respiratory chain proteome. Int J Hepatol 2012:962183.  https://doi.org/10.1155/2012/962183 CrossRefGoogle Scholar
  24. 24.
    Kuo T, Chen TC, Lee RA, Nguyen NHT, Broughton AE, Zhang D, Wang JC (2017) Pik3r1 is required for glucocorticoid-induced perilipin 1 phosphorylation in lipid droplet for adipocyte lipolysis. Diabetes 66(6):1601–1610.  https://doi.org/10.2337/db16-0831 CrossRefGoogle Scholar
  25. 25.
    Olli K, Lahtinen S, Rautonen N, Tiihonen K (2013) Betaine reduces the expression of inflammatory adipokines caused by hypoxia in human adipocytes. Br J Nutr 109(1):43–49.  https://doi.org/10.1017/S0007114512000888 CrossRefGoogle Scholar
  26. 26.
    Airaksinen K, Jokkala J, Ahonen I, Auriola S, Kolehmainen M, Hanhineva K, Tiihonen K (2018) High-fat diet, betaine, and polydextrose induce changes in adipose tissue inflammation and metabolism in C57BL/6J mice. Mol Nutr Food Res.  https://doi.org/10.1002/mnfr.201800455 Google Scholar
  27. 27.
    Li T, Guo K, Qu W, Han Y, Wang S, Lin M, An S, Li X, Ma S, Wang T, Ji S, Hanson C, Fu J (2016) Important role of 5-hydroxytryptamine in glucocorticoid-induced insulin resistance in liver and intra-abdominal adipose tissue of rats. J Diabetes Investig 7(1):32–41.  https://doi.org/10.1111/jdi.12406 CrossRefGoogle Scholar
  28. 28.
    Chimin P, Farias Tda S, Torres-Leal FL, Bolsoni-Lopes A, Campana AB, Andreotti S, Lima FB (2014) Chronic glucocorticoid treatment enhances lipogenic activity in visceral adipocytes of male Wistar rats. Acta Physiol 211(2):409–420.  https://doi.org/10.1111/apha.12226 CrossRefGoogle Scholar
  29. 29.
    Lee J, Kim Y, Friso S, Choi SW (2017) Epigenetics in non-alcoholic fatty liver disease. Mol Aspects Med 54:78–88.  https://doi.org/10.1016/j.mam.2016.11.008 CrossRefGoogle Scholar
  30. 30.
    Keating ST, El-Osta A (2015) Epigenetics and metabolism. Circ Res 116(4):715–736.  https://doi.org/10.1161/CIRCRESAHA.116.303936 CrossRefGoogle Scholar
  31. 31.
    Cai D, Jia Y, Song H, Sui S, Lu J, Jiang Z, Zhao R (2014) Betaine supplementation in maternal diet modulates the epigenetic regulation of hepatic gluconeogenic genes in neonatal piglets. PLoS One 9(8):e105504.  https://doi.org/10.1371/journal.pone.0105504 CrossRefGoogle Scholar
  32. 32.
    Wang LJ, Zhang HW, Zhou JY, Liu Y, Yang Y, Chen XL, Zhu CH, Zheng RD, Ling WH, Zhu HL (2014) Betaine attenuates hepatic steatosis by reducing methylation of the MTTP promoter and elevating genomic methylation in mice fed a high-fat diet. J Nutr Biochem 25(3):329–336.  https://doi.org/10.1016/j.jnutbio.2013.11.007 CrossRefGoogle Scholar
  33. 33.
    Wang L, Chen L, Tan Y, Wei J, Chang Y, Jin T, Zhu H (2013) Betaine supplement alleviates hepatic triglyceride accumulation of apolipoprotein E deficient mice via reducing methylation of peroxisomal proliferator-activated receptor alpha promoter. Lipids Health Dis 12:34.  https://doi.org/10.1186/1476-511X-12-34 CrossRefGoogle Scholar
  34. 34.
    Motta K, Barbosa AM, Bobinski F, Boschero AC, Rafacho A (2015) JNK and IKKbeta phosphorylation is reduced by glucocorticoids in adipose tissue from insulin-resistant rats. J Steroid Biochem Mol Biol 145:1–12.  https://doi.org/10.1016/j.jsbmb.2014.09.024 CrossRefGoogle Scholar
  35. 35.
    He J, Xu C, Kuang J, Liu Q, Jiang H, Mo L, Geng B, Xu G (2015) Thiazolidinediones attenuate lipolysis and ameliorate dexamethasone-induced insulin resistance. Metab Clin Exp 64(7):826–836.  https://doi.org/10.1016/j.metabol.2015.02.005 CrossRefGoogle Scholar
  36. 36.
    Troncoso R, Paredes F, Parra V, Gatica D, Vasquez-Trincado C, Quiroga C, Bravo-Sagua R, Lopez-Crisosto C, Rodriguez AE, Oyarzun AP, Kroemer G, Lavandero S (2014) Dexamethasone-induced autophagy mediates muscle atrophy through mitochondrial clearance. Cell Cycle 13(14):2281–2295.  https://doi.org/10.4161/cc.29272 CrossRefGoogle Scholar
  37. 37.
    Xu C, He J, Jiang H, Zu L, Zhai W, Pu S, Xu G (2009) Direct effect of glucocorticoids on lipolysis in adipocytes. Mol Endocrinol 23(8):1161–1170.  https://doi.org/10.1210/me.2008-0464 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.MOE Joint International Research Laboratory of Animal Health and Food SafetyNanjing Agricultural UniversityNanjingPeople’s Republic of China
  2. 2.Key Laboratory of Animal Physiology and BiochemistryNanjing Agricultural UniversityNanjingPeople’s Republic of China

Personalised recommendations