Effects of High-Fructose Corn Syrup Intake on Glucocorticoid Metabolism in Rats During Childhood, Adolescence and Adulthood

Abstract

The consumption of high-fructose corn syrup (HFCS) has been increasing in recent decades, especially among children. Some reports suggest that children and adolescents are more sensitive to the adverse effects of fructose intake than adults. However, the underlying mechanism of the difference in vulnerability between adolescence and adulthood have not yet been elucidated. In this study, we attempted to elucidate the different effects of HFCS intake at different growth stages in rats: childhood and adolescence (postnatal day (PD) 21–60), young adulthood (PD60–100), and adulthood (PD100–140). Since alterations in hepatic glucocorticoid (GC) metabolism can cause diseases including insulin resistance, we focused on GC metabolizing enzymes such as 11 beta-hydroxysteroid dehydrogenase 1 and 2 (Hsd11b1 and Hsd11b2) and steroid 5 alpha-reductase 1 (Srd5a1). Western blotting showed an increase in Hsd11b1 expression and a decrease in Hsd11b2 expression in childhood and adolescence but not in adulthood. We also observed changes in Hsd11b1 and Hsd11b2 activities only in childhood and adolescence, consistent with the results of mRNA and protein expression analysis. The effect of high-fructose intake with regards to GC metabolism may therefore vary with developmental stage. This study provides insight into the adverse effects of fructose on GC metabolism in children in the context of increasing rates of HFCS consumption.

Key words

11 beta-hydroxysteroid dehydrogenase - steroid 5 alpha-reductase 1 - corticosterone - metabolic disorders - sugar

Publication History

Received: 22 April 2022
Received: 19 August 2022

Accepted: 25 August 2022

Article published online:
11 November 2022

• References

• 1 Yamazaki M, Munetsuna E, Yamada H. et al. Fructose consumption induces hypomethylation of hepatic mitochondrial DNA in rats. Life Sci 2016; 149: 146-152 DOI: 10.1016/j.lfs.2016.02.020.
• 2 Ohashi K, Munetsuna E, Yamada H. et al. High fructose consumption induces DNA methylation at PPARalpha and CPT1A promoter regions in the rat liver. Biochem Biophys Res Commun 2015; 468: 185-189 DOI: 10.1016/j.bbrc.2015.10.134.
• 3 Dornas WC, de Lima WG, Pedrosa ML. et al. Health implications of high-fructose intake and current research. Adv Nutr 2015; 6: 729-737 DOI: 10.3945/an.114.008144.
• 4 Hemmingsson E. Early childhood obesity risk factors: Socioeconomic adversity, family dysfunction, offspring distress, and junk food self-medication. Curr Obes Rep 2018; 7: 204-209 DOI: 10.1007/s13679-018-0310-2.
• 5 Vos MB, Kimmons JE, Gillespie C. et al. Dietary fructose consumption among US children and adults: The Third National Health and Nutrition Examination Survey. Medscape J Med 2008; 10: 160
• 6 Collaboration NCDRF. Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults. Lancet 2017; 390: 2627-2642 DOI: 10.1016/S0140-6736(17)32129-3.
• 7 Azogu I, Cossette I, Mukunzi J. et al. Sex-specific differences in adult cognition and neuroplasticity following repeated combinatory stress and TrkB receptor antagonism in adolescence. Horm Behav 2019; 113: 21-37 DOI: 10.1016/j.yhbeh.2019.04.006.
• 8 Hsu TM, Konanur VR, Taing L. et al. Effects of sucrose and high fructose corn syrup consumption on spatial memory function and hippocampal neuroinflammation in adolescent rats. Hippocampus 2015; 25: 227-239 DOI: 10.1002/hipo.22368.
• 9 Crescenzo R, Cigliano L, Mazzoli A. et al. Early effects of a low fat, fructose-rich diet on liver metabolism, insulin signaling, and oxidative stress in young and adult rats. Front Physiol 2018; 9: 411 DOI: 10.3389/fphys.2018.00411.
• 10 Macfarlane DP, Forbes S, Walker BR. Glucocorticoids and fatty acid metabolism in humans: Fuelling fat redistribution in the metabolic syndrome. J Endocrinol 2008; 197: 189-204 DOI: 10.1677/JOE-08-0054.
• 11 Moraitis AG, Block T, Nguyen D. et al. The role of glucocorticoid receptors in metabolic syndrome and psychiatric illness. J Steroid Biochem Mol Biol 2017; 165: 114-120 DOI: 10.1016/j.jsbmb.2016.03.023.
• 12 Morgan SA, Hassan-Smith ZK, Doig CL. et al. Glucocorticoids and 11beta-HSD1 are major regulators of intramyocellular protein metabolism. J Endocrinol 2016; 229: 277-286 DOI: 10.1530/JOE-16-0011.
• 13 Tomlinson JW, Walker EA, Bujalska IJ. et al. 11beta-hydroxysteroid dehydrogenase type 1: A tissue-specific regulator of glucocorticoid response. Endocr Rev 2004; 25: 831-866 DOI: 10.1210/er.2003-0031.
• 14 Livingstone DE, Barat P, Di Rollo EM. et al. 5alpha-Reductase type 1 deficiency or inhibition predisposes to insulin resistance, hepatic steatosis, and liver fibrosis in rodents. Diabetes 2015; 64: 447-458 DOI: 10.2337/db14-0249.
• 15 Romero DG, Zhou M, Gomez-Sanchez CE. Cloning and expression of the bovine 11beta-hydroxysteroid dehydrogenase type-2. J Steroid Biochem Mol Biol 2000; 72: 231-237 DOI: 10.1016/s0960-0760(00)00034-0.
• 16 Odermatt A, Kratschmar DV. Tissue-specific modulation of mineralocorticoid receptor function by 11beta-hydroxysteroid dehydrogenases: An overview. Mol Cell Endocrinol 2012; 350: 168-186 DOI: 10.1016/j.mce.2011.07.020.
• 17 Paterson JM, Morton NM, Fievet C. et al. Metabolic syndrome without obesity: Hepatic overexpression of 11beta-hydroxysteroid dehydrogenase type 1 in transgenic mice. Proc Natl Acad Sci U S A 2004; 101: 7088-7093 DOI: 10.1073/pnas.0305524101.
• 18 Ueda K, Nishimoto M, Hirohama D. et al. Renal dysfunction induced by kidney-specific gene deletion of Hsd11b2 as a primary cause of salt-dependent. hypertension. Hypertension 2017; 70: 111-118 DOI: 10.1161/HYPERTENSIONAHA.116.08966.
• 19 London E, Castonguay TW. High fructose diets increase 11beta-hydroxysteroid dehydrogenase type 1 in liver and visceral adipose in rats within 24-h exposure. Obesity (Silver Spring) 2011; 19: 925-932 DOI: 10.1038/oby.2010.284.
• 20 Vasiljevic A, Bursac B, Djordjevic A. et al. Hepatic inflammation induced by high-fructose diet is associated with altered 11betaHSD1 expression in the liver of Wistar rats. Eur J Nutr 2014; 53: 1393-1402 DOI: 10.1007/s00394-013-0641-4.
• 21 Hodges TE, Lee GY, Noh SH. et al. Sex and age differences in cognitive bias and neural activation in response to cognitive bias testing. Neurobiol Stress 2022; 18: 100458 DOI: 10.1016/j.ynstr.2022.100458.
• 22 Kageyama I, Yamada H, Munetsuna E. et al. Differential effects of excess high-fructose corn syrup on the DNA methylation of hippocampal neurotrophic factor in childhood and adolescence. PLoS One 2022; 17: e0270144 DOI: 10.1371/journal.pone.0270144.
• 23 Ando Y, Yamada H, Munetsuna E. et al. Maternal high-fructose corn syrup consumption causes insulin resistance and hyperlipidemia in offspring via DNA methylation of the Pparα promoter region. J Nutr Biochem 2022; 103: 108951 DOI: 10.1016/j.jnutbio.2022.108951.
• 24 Munetsuna E, Yamada H, Yamazaki M. et al. Maternal high-fructose intake increases circulating corticosterone levels via decreased adrenal corticosterone clearance in adult offspring. J Nutr Biochem 2019; 67: 44-50 DOI: 10.1016/j.jnutbio.2019.01.016.
• 25 Mizuno G, Munetsuna E, Yamada H. et al. Maternal fructose consumption downregulates hippocampal catalase expression via DNA methylation in rat offspring. Nutr Res 2021; 92: 40-48 DOI: 10.1016/j.nutres.2021.06.002.
• 26 Yamada H, Munetsuna E, Yamazaki M. et al. Maternal fructose-induced oxidative stress occurs via Tfam and Ucp5 epigenetic regulation in offspring hippocampi. FASEB J 2019; 33: 11431-11442 DOI: 10.1096/fj.201901072R.
• 27 Prince PD, Santander YA, Gerez EM. et al. Fructose increases corticosterone production in association with NADPH metabolism alterations in rat epididymal white adipose tissue. J Nutr Biochem 2017; 46: 109-116 DOI: 10.1016/j.jnutbio.2017.02.021.
• 28 Balazs Z, Schweizer RA, Frey FJ. et al. DHEA induces 11 -HSD2 by acting on CCAAT/enhancer-binding proteins. J Am Soc Nephrol 2008; 19: 92-101 DOI: 10.1681/ASN.2007030263.
• 29 Jamieson PM, Walker BR, Chapman KE. et al. 11 beta-hydroxysteroid dehydrogenase type 1 is a predominant 11 beta-reductase in the intact perfused rat liver. J Endocrinol 2000; 165: 685-692 DOI: 10.1677/joe.0.1650685.
• 30 Yamazaki M, Yamada H, Munetsuna E. et al. Excess maternal fructose consumption impairs hippocampal function in offspring via epigenetic modification of BDNF promoter. FASEB J 2018; 32: 2549-2562 DOI: 10.1096/fj.201700783RR.
• 31 Kinlein SA, Shahanoor Z, Romeo RD. et al. Chronic corticosterone treatment during adolescence has significant effects on metabolism and skeletal development in male C57BL6/N mice. Endocrinology 2017; 158: 2239-2254 DOI: 10.1210/en.2017-00208.
• 32 Kotelevtsev Y, Holmes MC, Burchell A. et al. 11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress. Proc Natl Acad Sci U S A 1997; 94: 14924-14929 DOI: 10.1073/pnas.94.26.14924.
• 33 Chia YY, Ton SH, Kadir KB. Effects of glycyrrhizic acid on 11 beta-hydroxysteroid dehydrogenase (11 betaHSD1 and 2) activities and HOMA-IR in rats at different treatment periods. Exp Clin Endocrinol Diabetes 2010; 118: 617-624 DOI: 10.1055/s-0029-1237703.
• 34 Kuhlmann K, Buhler H, Ragosch V. et al. Kinetic studies on rabbit liver glucocorticoid 5alpha-reductase. Horm Metab Res 2000; 32: 20-25 DOI: 10.1055/s-2007-978580.
• 35 Naray-Fejes-Toth A, Fejes-Toth G. Subcellular localization of the type 2 11beta-hydroxysteroid dehydrogenase. A green fluorescent protein study. J Biol Chem 1996; 271: 15436-15442 DOI: 10.1074/jbc.271.26.15436.
• 36 Huang D, Dhawan T, Young S. et al. Fructose impairs glucose-induced hepatic triglyceride synthesis. Lipids Health Dis 2011; 10: 20 DOI: 10.1186/1476-511X-10-20.
• 37 Kawasaki T, Igarashi K, Koeda T. et al. Rats fed fructose-enriched diets have characteristics of nonalcoholic hepatic steatosis. J Nutr 2009; 139: 2067-2071 DOI: 10.3945/jn.109.105858.
• 38 Ibrahim SM, El-Denshary ES, Abdallah DM. Geraniol, alone and in combination with pioglitazone, ameliorates fructose-induced metabolic syndrome in rats via the modulation of both inflammatory and oxidative stress status. PLoS One 2015; 10: e0117516 DOI: 10.1371/journal.pone.0117516.
• 39 Mahmoud AA, Elshazly SM. Ursodeoxycholic acid ameliorates fructose-induced metabolic syndrome in rats. PLoS One 2014; 9: e106993 DOI: 10.1371/journal.pone.0106993.
• 40 Munetsuna E, Yamada H, Yamazaki M. et al. Maternal fructose intake predisposes rat offspring to metabolic disorders via abnormal hepatic programming. FASEB J 2021; 35: e22030 DOI: 10.1096/fj.202101276R.
• 41 Cooper MS, Bujalska I, Rabbitt E. et al. Modulation of 11beta-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from glucocorticoid inactivation to activation. J Bone Miner Res 2001; 16: 1037-1044 DOI: 10.1359/jbmr.2001.16.6.1037.
• 42 Elakovic I, Kovacevic S, Vojnovic Milutinovic D. et al. Fructose consumption affects glucocorticoid signaling in the liver of young female rats. Nutrients 2020; 12 DOI: 10.3390/nu12113470.