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Sex-dependent metabolic effects of pregestational exercise on prenatally stressed mice

Published online by Cambridge University Press:  14 May 2020

Carolina Luft
Laboratory of Pediatric Physical Activity, Infant Center, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil Laboratory of Cellular Biophysics and Inflammation, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul CEP 90619-900, Brazil
Isadora Perez Levices
Laboratory of Pediatric Physical Activity, Infant Center, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
Leonardo Pedrazza
Laboratory of Ubiquitination and Cellular Signalization, IDIBELL, Campus de Bellvitge, Universitat de Barcelona, L’Hospitalet de Llobregat, ES-08907 Barcelona, Spain
Jarbas Rodrigues de Oliveira
Laboratory of Cellular Biophysics and Inflammation, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul CEP 90619-900, Brazil
Márcio Vinícius Fagundes Donadio*
Laboratory of Pediatric Physical Activity, Infant Center, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil Laboratory of Cellular Biophysics and Inflammation, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Rio Grande do Sul CEP 90619-900, Brazil
Address for correspondence: Professor Márcio V. F. Donadio, Centro Infant, Pontifícia Universidade Católica do Rio Grande do Sul – Av. Ipiranga, 6690, 2º andar, Porto Alegre, Rio Grande do Sul CEP 90610-000, Brazil. Email:


Stressful events during the prenatal period have been related to hyperactive hypothalamic–pituitary–adrenal (HPA) axis responses as well as metabolic changes in adult life. Moreover, regular exercise may contribute to the improvement of the symptoms associated with stress and stress-related chronic diseases. Therefore, this study aims to investigate the effects of exercise, before the gestation period, on the metabolic changes induced by prenatal stress in adult mice. Female Balb/c mice were divided into three groups: control (CON), prenatal restraint stress (PNS) and exercise before the gestational period plus PNS (EX + PNS). When adults, the plasmatic biochemical analysis, oxidative stress, gene expression of metabolic-related receptors and sex differences were assessed in the offspring. Prenatal stress decreased neonatal and adult body weight when compared to the pregestational exercise group. Moreover, prenatal stress was associated with reduced body weight in adult males. PNS and EX + PNS females showed decreased hepatic catalase. Pregestational exercise prevented the stress-induced cholesterol increase in females but did not prevent the liver mRNA expression reduction on the peroxisome proliferator-activated receptors (PPARs) α and γ in PNS females. Conversely, PNS and EX + PNS males showed an increased PPARα mRNA expression. In conclusion, pregestational exercise prevented some effects of prenatal stress on metabolic markers in a sex-specific manner.

Original Article
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2020

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Woods, SM, Melville, JL, Guo, Y, Fan, MY, Gavin, A. Psychosocial stress during pregnancy. Am J Obstet Gynecol. 2010; 202, 61.e161.e7.CrossRefGoogle ScholarPubMed
Kapoor, A, Dunn, E, Kostaki, A, Andrews, MH, Matthews, SG. Fetal programming of hypothalamo-pituitary-adrenal function: prenatal stress and glucocorticoids. J Physiol. 2006; 572, 3144.CrossRefGoogle ScholarPubMed
Harris, A, Seckl, J. Glucocorticoids, prenatal stress and the programming of disease. Horm Behav. 2011; 59, 279289.CrossRefGoogle ScholarPubMed
Tamashiro, KL, Moran, TH. Perinatal environment and its influences on metabolic programming of offspring. Phys Behav. 2010; 100(5), 560566.CrossRefGoogle ScholarPubMed
Peckett, AJ, Wright, DC, Riddell, MC. The effects of glucocorticoids on adipose tissue lipid metabolism. Metab Clin Exp. 2011; 60, 15001510.CrossRefGoogle ScholarPubMed
Geer, EB, Islam, J, Buettner, C. Mechanisms of glucocorticoid-induced insulin resistance: focus on adipose tissue function and lipid metabolism. Endocrin Metab Clin North Am. 2014; 43, 75102.CrossRefGoogle ScholarPubMed
Grygiel-Gorniak, B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications – a review. Nutr J. 2014; 13, 17.CrossRefGoogle ScholarPubMed
Maeyama, H, Hirasawa, T, Tahara, Y, et al. Maternal restraint stress during pregnancy in mice induces 11beta-HSD1-associated metabolic changes in the livers of the offspring. J Dev Orig Health Dis. 2015; 6, 105114.CrossRefGoogle ScholarPubMed
Brunton, PJ, Sullivan, KM, Kerrigan, D, Russell, JA, Seckl, JR, Drake, AJ. Sex-specific effects of prenatal stress on glucose homoeostasis and peripheral metabolism in rats. J Endocrinol. 2013; 217, 161173.CrossRefGoogle ScholarPubMed
Zanuso, S, Jimenez, A, Pugliese, G, Corigliano, G, Balducci, S. Exercise for the management of type 2 diabetes: a review of the evidence. Acta Diabetol. 2010; 47, 1522.CrossRefGoogle Scholar
Pi, H, Liu, M, Xi, Y, et al. Long-term exercise prevents hepatic steatosis: a novel role of FABP1 in regulation of autophagy-lysosomal machinery. FASEB J. 2019; 33(11), 1187011883.CrossRefGoogle ScholarPubMed
Harris, JE, Baer, LA, Stanford, KI. Maternal exercise improves the metabolic health of adult offspring. Trends Endocrinol Metab. 2018; 29(3), 164177.CrossRefGoogle ScholarPubMed
Luft, C, Levices, IP, Costa, MSD, et al. Exercise before pregnancy attenuates the effects of prenatal stress in adult mice in a sex-dependent manner. Int J Dev Neurosci. 2020; 80, 8695.CrossRefGoogle Scholar
Rezaee, Z, Marandi, SM, Alaei, H, Esfarjani, F. The effect of preventive exercise on the neuroprotection in 6-hydroxydopamine-lesioned rat brain. Appl Physiol Nutr Metab. 2019; 44, 12671275.CrossRefGoogle ScholarPubMed
Pitts, BL, Whealin, JM, Harpaz-Rotem, I, et al. BDNF Val66Met polymorphism and posttraumatic stress symptoms in U.S. military veterans: protective effect of physical exercise. Psychoneuroendocrinology. 2019; 100, 198202.CrossRefGoogle ScholarPubMed
Stranahan, AM, Lee, K, Mattson, MP. Central mechanisms of HPA axis regulation by voluntary exercise. Neuromolecular Med. 2008; 10, 118127.CrossRefGoogle ScholarPubMed
Herzig, KH, Ahola, R, Leppaluoto, J, Jokelainen, J, Jamsa, T, Keinanen-Kiukaanniemi, S. Light physical activity determined by a motion sensor decreases insulin resistance, improves lipid homeostasis and reduces visceral fat in high-risk subjects: PreDiabEx study RCT. Int J Obes (Lond). 2014; 38, 10891096.CrossRefGoogle ScholarPubMed
Sze, Y, Brunton, PJ. Sex, stress and steroids. Eur J Neurosci. 2019; doi: 10.1111/ejn.14615.CrossRefGoogle Scholar
Weinstock, M. Gender differences in the effects of prenatal stress on brain development and behaviour. Neurochem Res. 2007; 32, 17301740.CrossRefGoogle ScholarPubMed
Viau, V, Meaney, MJ. Variations in the hypothalamic-pituitary-adrenal response to stress during the estrous cycle in the rat. Endocrinology. 1991; 129, 25032511.CrossRefGoogle ScholarPubMed
Mauvais-Jarvis, F. Sex differences in metabolic homeostasis, diabetes, and obesity. Biol Sex Differ. 2015; 6, 14.CrossRefGoogle ScholarPubMed
Wearick-Silva, LE, Marshall, P, Viola, TW, et al. Running during adolescence rescues a maternal separation-induced memory impairment in female mice: potential role of differential exon-specific BDNF expression. Dev Psychobiol. 2017; 59, 268274.CrossRefGoogle ScholarPubMed
Vargas, MH, Campos, NE, de Souza, RG, et al. Protective effect of early prenatal stress on the induction of asthma in adult mice: sex-specific differences. Physiol Behav. 2016; 165, 358364.CrossRefGoogle ScholarPubMed
Zagron, G, Weinstock, M. Maternal adrenal hormone secretion mediates behavioural alterations induced by prenatal stress in male and female rats. Behav Brain Res. 2006; 175, 323328.CrossRefGoogle ScholarPubMed
Zanatta, A, Viegas, CM, Tonin, AM, et al. Disturbance of redox homeostasis by ornithine and homocitrulline in rat cerebellum: a possible mechanism of cerebellar dysfunction in HHH syndrome. Life Sci. 2013; 93, 161168.CrossRefGoogle ScholarPubMed
Lima, KG, Krause, GC, da Silva, EFG, et al. Octyl gallate reduces ATP levels and Ki67 expression leading HepG2 cells to cell cycle arrest and mitochondria-mediated apoptosis. Toxicol In Vitro. 2018; 48, 1125.CrossRefGoogle ScholarPubMed
Kinnunen, AK, Koenig, JI, Bilbe, G. Repeated variable prenatal stress alters pre- and postsynaptic gene expression in the rat frontal pole. J Neurochem. 2003; 86, 736748.CrossRefGoogle ScholarPubMed
Markham, JA, Mullins, SE, Koenig, JI. Periadolescent maturation of the prefrontal cortex is sex-specific and is disrupted by prenatal stress. J Comp Neurol. 2013; 521, 18281843.CrossRefGoogle ScholarPubMed
Su, Q, Zhang, H, Dang, S, et al. Hippocampal protein kinase c gamma signaling mediates the impairment of spatial learning and memory in prenatally stressed offspring rats. Neuroscience. 2019; 414, 186199.CrossRefGoogle ScholarPubMed
Palacios-Garcia, I, Lara-Vasquez, A, Montiel, JF, et al. Prenatal stress down-regulates Reelin expression by methylation of its promoter and induces adult behavioral impairments in rats. PLoS One. 2015; 10, e0117680.CrossRefGoogle ScholarPubMed
Pankevich, DE, Mueller, BR, Brockel, B, Bale, TL. Prenatal stress programming of offspring feeding behavior and energy balance begins early in pregnancy. Physiol Behav. 2009; 98, 94102.CrossRefGoogle ScholarPubMed
Iturra-Mena, AM, Arriagada-Solimano, M, Luttecke-Anders, A, Dagnino-Subiabre, A. Effects of prenatal stress on anxiety- and depressive-like behaviours are sex-specific in prepubertal rats. J Neuroendocrinol. 2018; 30, e12609.CrossRefGoogle ScholarPubMed
Mueller, BR, Bale, TL. Impact of prenatal stress on long term body weight is dependent on timing and maternal sensitivity. Physiol Behav. 2006; 88, 605614.CrossRefGoogle ScholarPubMed
Klein, CP, Dos Santos Rodrigues, K, Hozer, RM, et al. Swimming exercise before and during pregnancy: promising preventive approach to impact offspring’s health. Int J Dev Neurosci. 2018; 71, 8393.CrossRefGoogle Scholar
Sickmann, HM, Skoven, C, Bastlund, JF, et al. Sleep patterning changes in a prenatal stress model of depression. J Dev Orig Health Dis. 2018; 9, 102111.CrossRefGoogle Scholar
Sickmann, HM, Arentzen, TS, Dyrby, TB, Plath, N, Kristensen, MP. Prenatal stress produces sex-specific changes in depression-like behavior in rats: implications for increased vulnerability in females. J Dev Orig Health Dis. 2015; 6, 462474.CrossRefGoogle ScholarPubMed
Liu, W, Xu, Y, Lu, J, Zhang, Y, Sheng, H, Ni, X. Swimming exercise ameliorates depression-like behaviors induced by prenatal exposure to glucocorticoids in rats. Neurosci Lett. 2012; 524(2), 119123.CrossRefGoogle ScholarPubMed
Song, MK, Kim, EJ, Kim, JK, Park, HK, Lee, SG. Effect of regular swimming exercise to duration-intensity on neurocognitive function in cerebral infarction rat model. Neurol Res. 2019; 41, 3744.CrossRefGoogle ScholarPubMed
Finken, MJ, van der Voorn, B, Heijboer, AC, de Waard, M, van Goudoever, JB, Rotteveel, J. Glucocorticoid programming in very preterm birth. Horm Res Paediatr. 2016; 85, 221231.CrossRefGoogle ScholarPubMed
Mifune, H, Tajiri, Y, Nishi, Y, et al. Voluntary exercise contributed to an amelioration of abnormal feeding behavior, locomotor activity and ghrelin production concomitantly with a weight reduction in high fat diet-induced obese rats. Peptides. 2015; 71, 4955.CrossRefGoogle Scholar
Quiclet, C, Dubouchaud, H, Berthon, P, et al. Maternal exercise modifies body composition and energy substrates handling in male offspring fed a high-fat/high-sucrose diet. J Physiol. 2017; 595, 70497062.CrossRefGoogle ScholarPubMed
Carter, LG, Lewis, KN, Wilkerson, DC, et al. Perinatal exercise improves glucose homeostasis in adult offspring. Am J Physiol Endocrinol Metab. 2012; 303, E1061E1068.CrossRefGoogle ScholarPubMed
Rosa, BV, Blair, HT, Vickers, MH, et al. Moderate exercise during pregnancy in Wistar rats alters bone and body composition of the adult offspring in a sex-dependent manner. PLoS One. 2013; 8, e82378.CrossRefGoogle Scholar
van der Windt, DJ, Sud, V, Zhang, H, Tsung, A, Huang, H. The effects of physical exercise on fatty liver disease. Gene Expr. 2018; 18, 89101.CrossRefGoogle ScholarPubMed
Cho, J, Kim, D, Jang, J, Kim, J, Kang, H. Treadmill running suppresses the vulnerability of dopamine D2 receptor deficiency to obesity and metabolic complications: a pilot study. J Exerc Nutr Biochem. 2018; 22, 4250.CrossRefGoogle ScholarPubMed
Ferreira, GS, Pinto, PR, Iborra, RT, et al. Aerobic exercise training selectively changes oxysterol levels and metabolism reducing cholesterol accumulation in the aorta of dyslipidemic mice. Front Physiol. 2017; 8, 644.CrossRefGoogle ScholarPubMed
Palmisano, BT, Zhu, L, Eckel, RH, Stafford, JM. Sex differences in lipid and lipoprotein metabolism. Mol Metab. 2018; 15, 4555.CrossRefGoogle ScholarPubMed
Zhang, XL, Zhao, N, Xu, B, Chen, XH, Li, TJ. Treadmill exercise inhibits amyloid-beta generation in the hippocampus of APP/PS1 transgenic mice by reducing cholesterol-mediated lipid raft formation. Neuroreport. 2019; 30, 498503.CrossRefGoogle ScholarPubMed
Tarevnic, R, Ornellas, F, Mandarim-de-Lacerda, CA, Aguila, MB. Beneficial effects of maternal swimming during pregnancy on offspring metabolism when the father is obese. J Dev Orig Health Dis. 2018; 15. doi: 10.1017/S2040174418001046 CrossRefGoogle Scholar
Wen, S, Jadhav, KS, Williamson, DL, Rideout, TC. Treadmill exercise training modulates hepatic cholesterol metabolism and circulating PCSK9 concentration in high-fat-fed mice. J Lipids. 2013; 2013, 908048.CrossRefGoogle ScholarPubMed
Jones, DP, Eklow, L, Thor, H, Orrenius, S. Metabolism of hydrogen peroxide in isolated hepatocytes: relative contributions of catalase and glutathione peroxidase in decomposition of endogenously generated H2O2 . Arch Biochem Biophys. 1981; 210, 505516.CrossRefGoogle ScholarPubMed
Jia, N, Sun, Q, Su, Q, Dang, S, Chen, G. Taurine promotes cognitive function in prenatally stressed juvenile rats via activating the Akt-CREB-PGC1alpha pathway. Redox Biol. 2016; 10, 179190.CrossRefGoogle ScholarPubMed
da Silva, LA, Pinho, CA, Rocha, LG, Tuon, T, Silveira, PC, Pinho, RA. Effect of different models of physical exercise on oxidative stress markers in mouse liver. Appl Physiol Nutr Metab. 2009; 34, 6065.CrossRefGoogle ScholarPubMed
Bustamante, C, Henriquez, R, Medina, F, Reinoso, C, Vargas, R, Pascual, R. Maternal exercise during pregnancy ameliorates the postnatal neuronal impairments induced by prenatal restraint stress in mice. Int J Dev Neurosci. 2013; 31, 267273.CrossRefGoogle ScholarPubMed
Marcelino, TB, de Lemos Rodrigues, PI, Miguel, PM, Netto, CA, Pereira Silva, LO, Matte, C. Effect of maternal exercise on biochemical parameters in rats submitted to neonatal hypoxia-ischemia. Brain Res. 2015; 1622, 91101.CrossRefGoogle ScholarPubMed
Sato, H, Takahashi, T, Sumitani, K, Takatsu, H, Urano, S. Glucocorticoid generates ros to induce oxidative injury in the hippocampus, leading to impairment of cognitive function of rats. J Clin Biochem Nutr. 2010; 47, 224232.CrossRefGoogle ScholarPubMed
Lemke, U, Krones-Herzig, A, Berriel Diaz, M, et al. The glucocorticoid receptor controls hepatic dyslipidemia through Hes1. Cell Metab. 2008; 8, 212223.CrossRefGoogle ScholarPubMed
Zollner, G, Trauner, M. Nuclear receptors as therapeutic targets in cholestatic liver diseases. Br J Pharmacol. 2009; 156, 727.CrossRefGoogle ScholarPubMed
John, K, Marino, JS, Sanchez, ER, Hinds, TD Jr. The glucocorticoid receptor: cause of or cure for obesity? Am J Physiol Endocrinol Metab. 2016; 310, E249E257.CrossRefGoogle ScholarPubMed
Campbell, JE, Fediuc, S, Hawke, TJ, Riddell, MC. Endurance exercise training increases adipose tissue glucocorticoid exposure: adaptations that facilitate lipolysis. Metab Clin Exp. 2009; 58, 651660.CrossRefGoogle ScholarPubMed
Li, H, Liang, A, Guan, F, Fan, R, Chi, L, Yang, B. Regular treadmill running improves spatial learning and memory performance in young mice through increased hippocampal neurogenesis and decreased stress. Brain Res. 2013; 1531, 18.CrossRefGoogle ScholarPubMed
Paternain, L, de la Garza, AL, Batlle, MA, Milagro, FI, Martinez, JA, Campion, J. Prenatal stress increases the obesogenic effects of a high-fat-sucrose diet in adult rats in a sex-specific manner. Stress. 2013; 16, 220232.CrossRefGoogle Scholar
Monsalve, FA, Pyarasani, RD, Delgado-Lopez, F, Moore-Carrasco, R. Peroxisome proliferator-activated receptor targets for the treatment of metabolic diseases. Mediat. Inflamm. 2013; 2013, 549627.CrossRefGoogle ScholarPubMed
Gavrilova, O, Haluzik, M, Matsusue, K, et al. Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem. 2003; 278, 3426834276.CrossRefGoogle ScholarPubMed
Kersten, S, Seydoux, J, Peters, JM, Gonzalez, FJ, Desvergne, B, Wahli, W. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest. 1999; 103, 14891498.CrossRefGoogle Scholar
Zhang, S, Liu, Y, Li, Q, et al. Exercise improved rat metabolism by raising PPAR-alpha. Int J Sports Med. 2011; 32, 568573.CrossRefGoogle ScholarPubMed
Bougarne, N, Paumelle, R, Caron, S, et al. PPARalpha blocks glucocorticoid receptor alpha-mediated transactivation but cooperates with the activated glucocorticoid receptor alpha for transrepression on NF-kappaB. Proc Natl Acad Sci USA. 2009; 106, 73977402.CrossRefGoogle ScholarPubMed
Rando, G, Wahli, W. Sex differences in nuclear receptor-regulated liver metabolic pathways. BBA. 2011; 1812, 964973.Google ScholarPubMed
Park, HJ, Park, HS, Lee, JU, Bothwell, AL, Choi, JM. Gender-specific differences in PPARgamma regulation of follicular helper T cell responses with estrogen. Sci Rep. 2016; 6, 28495.CrossRefGoogle ScholarPubMed
Jalouli, M, Carlsson, L, Ameen, C, et al. Sex difference in hepatic peroxisome proliferator-activated receptor alpha expression: influence of pituitary and gonadal hormones. Endocrinology. 2003; 144, 101109.CrossRefGoogle ScholarPubMed
Maghsoudi, N, Ghasemi, R, Ghaempanah, Z, Ardekani, AM, Nooshinfar, E, Tahzibi, A. Effect of chronic restraint stress on HPA axis activity and expression of BDNF and Trkb in the hippocampus of pregnant rats: possible contribution in depression during pregnancy and postpartum period. Basic Clin Neurosci. 2014; 5, 131137.Google ScholarPubMed
Lim, R, Fedulov, AV, Kobzik, L. Maternal stress during pregnancy increases neonatal allergy susceptibility: role of glucocorticoids. Am J Physiol Lung Cell Mol Physiol. 2014; 307, L141L148.CrossRefGoogle ScholarPubMed
Inoue, K, Okamoto, M, Shibato, J, et al. Long-term mild, rather than intense, exercise enhances adult hippocampal neurogenesis and greatly changes the transcriptomic profile of the hippocampus. PLoS One. 2015; 10, e0128720.CrossRefGoogle ScholarPubMed
Patki, G, Li, L, Allam, F, et al. Moderate treadmill exercise rescues anxiety and depression-like behavior as well as memory impairment in a rat model of posttraumatic stress disorder. Physiol Behav. 2014; 130, 4753.CrossRefGoogle Scholar
Schwanhausser, B, Busse, D, Li, N, et al. Global quantification of mammalian gene expression control. Nature. 2011; 473, 337342.CrossRefGoogle ScholarPubMed
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Sex-dependent metabolic effects of pregestational exercise on prenatally stressed mice
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