No CrossRef data available.
Article contents
Maternal hyperglycemia and postnatal high-fat diet impair metabolic regulation and autophagy response in the liver of adult female rats
Published online by Cambridge University Press: 20 February 2025
Abstract
This study aimed to investigate the mechanisms by which the association between maternal hyperglycemia and postnatal high-fat diet (HFD) exposure compromises metabolic parameters and hepatic autophagy in adult female pups. For this, Sprague Dawley rats, female pups from nondiabetic (control = FC) or diabetic (FD) mothers, were fed a standard diet (SD) or HFD from weaning until adulthood (n minimum = 5 rats/group): FC/SD, FC/HFD, FD/SD, and FD/HFD. In adulthood, these rats were tested with the oral glucose tolerance test, euthanized, and serum biochemistry parameters were analyzed. Liver samples were collected to evaluate cytokines, redox status, and protein expression autophagy and apoptosis markers. Histomorphometric analyses and an assessment of lipofuscin accumulation were also performed to reflect incomplete autolysosomal digestion. The FC/HFD, FD/SD, and FD/HFD groups showed glucose intolerance and an increased number of hepatocytes. Furthermore, FD/SD and FD/HFD rats showed hyperlipidemia and insulin resistance. Adaptations in hepatic redox pathways were observed in the FD/SD group with increased antioxidant defense marker activity. The FD/SD group also exhibited increased autophagy protein expression, such as p-AMPK, LC3-II/LC3-I, and p62/SQSTM1, lipofuscin accumulation, and caspase-3 activation. After exposure to HFD, the adult female pups of diabetic rats had a reduced p-AMPK and LC3-II/LC3-I ratio, the presence of steatosis, oxidative stress, and inflammation. The reduction of autophagy, stimulated by HFD, may be of vital importance for the susceptibility to metabolic dysfunction-associated fatty liver disease induced by maternal diabetes.
Keywords
- Type
- Original Article
- Information
- Copyright
- © The Author(s), 2025. Published by Cambridge University Press in association with The International Society for Developmental Origins of Health and Disease (DOHaD)
References
Spradley, FT, Smith, JA, Alexander, BT, Anderson, CD. Developmental origins of nonalcoholic fatty liver disease as a risk factor for exaggerated metabolic and cardiovascular-renal disease. Am J Physiol Endocrinol Metab. 2018; 315(5), E795–E814. DOI: 10.1152/ajpendo.00394.2017.CrossRefGoogle ScholarPubMed
American Diabetes Association, ADA. Diagnosis and classification of diabetes: standards of care in diabetes—2024. Diabetes Care. 2024; 47(Supplement_1), S20–S44. DOI: 10.2337/dc24-S002.CrossRefGoogle Scholar
Hod, M, Kapur, A, Sacks, DA, et al. The International Federation of Gynecology and Obstetrics (FIGO) initiative on gestational diabetes mellitus: a pragmatic guide for diagnosis, management, and care. Int J Gynaecol Obstet. 2015; 131(S3), S173–211. DOI: 10.1016/S0020-7292(15)30033-3.CrossRefGoogle ScholarPubMed
Tozour, J, Hughes, F, Carrier, A, Vieau, D, Delahaye, F. Prenatal hyperglycemia exposure and cellular stress, a sugar-coated view of early programming of metabolic diseases. Biomolecules. 2020; 10(10), 1359. DOI: 10.3390/biom10101359.CrossRefGoogle Scholar
Bugianesi, E, McCullough, AJ, Marchesini, G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology. 2005; 42(5), 987–1000. DOI: 10.1002/hep.20920.CrossRefGoogle ScholarPubMed
Yzydorczyk, C, Li, N, Chehade, H, et al. Transient postnatal overfeeding causes liver stress-induced premature senescence in adult mice. Sci Rep. 2017; 7(1), 12911. DOI: 10.1038/s41598-017-11756-2.CrossRefGoogle ScholarPubMed
González, P, Lozano, P, Ros, G, Solano, F. Hyperglycemia and oxidative stress: an integral, updated and critical overview of their metabolic interconnections. Int J Mol Sci. 2023; 24(11), 9352. DOI: 10.3390/ijms24119352.CrossRefGoogle ScholarPubMed
Eslam, M, Newsome, PN, Sarin, SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. J Hepatol. 2020; 73(1), 202–209. DOI: 10.1016/j.jhep.2020.03.039.CrossRefGoogle ScholarPubMed
Joo, HW, Song, YS, Park, IH, et al. Granulocyte colony stimulating factor ameliorates hepatic steatosis associated with improvement of autophagy in diabetic rats. Can J Gastroenterol Hepatol. 2020; 2020, 2156829. DOI: 10.1155/2020/2156829.CrossRefGoogle ScholarPubMed
Madrigal-Matute, J, Cuervo, AM. Regulation of liver metabolism by autophagy. Gastroenterology. 2016; 150(2), 328–339. DOI: 10.1053/j.gastro.2015.09.042.CrossRefGoogle ScholarPubMed
Arden, C. A role for glucagon-like peptide-1 in the regulation of β-cell autophagy. Peptides. 2018; 100, 85–93. DOI: 10.1016/j.peptides.2017.12.002.CrossRefGoogle ScholarPubMed
Yao, D, GangYi, Y, QiNan, W. Autophagic dysfunction of β cell dysfunction in type 2 diabetes, a double-edged sword. Genes Dis. 2020; 8(4), 438–447. DOI: 10.1016/j.gendis.2020.03.003.CrossRefGoogle ScholarPubMed
Qian, Q, Zhang, Z, Orwig, A, et al. S-Nitrosoglutathione reductase dysfunction contributes to obesity-associated hepatic insulin resistance via regulating autophagy. Diabetes. 2018; 67(2), 193–207. DOI: 10.2337/db17-0223.CrossRefGoogle ScholarPubMed
da Cruz, LL, Vesentini, G, Sinzato, YK, Villaverde, AISB, Volpato, GT, Damasceno, DC. Effects of high-fat diet-induced diabetes on autophagy in the murine liver: a systematic review and meta-analysis. Life Sci. 2022; 309, 121012. DOI: 10.1016/j.lfs.2022.121012.CrossRefGoogle ScholarPubMed
National Research Council US. Committee for the update of the guide for the care and use of laboratory animals, 2011; In Guide for the care and use of laboratory animals. 8 ed. National Academies Press (US), Washington. Available from: https://www.ncbi.nlm.nih.gov/books/NBK54050. DOI: 10.17226/12910
CrossRefGoogle Scholar
Sinzato, YK, Klöppel, E, Miranda, CA, et al. Comparison of streptozotocin-induced diabetes at different moments of the life of female rats for translational studies. Lab Anim. 2021; 55(4), 329–340. DOI: 10.1177/00236772211001895.CrossRefGoogle ScholarPubMed
Zambrano, E, Martínez-Samayoa, PM, Bautista, CJ, et al. Sex differences in transgenerational alterations of growth and metabolism in progeny (F2) of female offspring (F1) of rats fed a low protein diet during pregnancy and lactation. J Physiol. 2005; 566(1), 225–236. DOI: 10.1113/jphysiol.2005.086462.CrossRefGoogle ScholarPubMed
Zhou, W, Ye, S. Rapamycin improves insulin resistance and hepatic steatosis in type 2 diabetes rats through activation of autophagy. Cell Biol Int. 2018; 42(10), 1282–1291. DOI: 10.1002/cbin.11015.CrossRefGoogle ScholarPubMed
Lai, LL, Lu, HQ, Li, WN, et al. Protective effects of quercetin and crocin in the kidneys and liver of obese Sprague-Dawley rats with Type 2 diabetes: effects of quercetin and crocin on T2DM rats. Hum Exp Toxicol. 2021; 40(4), 661–672. DOI: 10.1177/0960327120954521.CrossRefGoogle ScholarPubMed
Paula, VG, Sinzato, YK, Gallego, FQ, et al. Intergenerational hyperglycemia impairs mitochondrial function and follicular development and causes oxidative stress in rat ovaries independent of the consumption of a high-fat diet. Nutrients. 2023; 15(20), 4407. DOI: 10.3390/nu15204407.CrossRefGoogle ScholarPubMed
Paula, VG, Sinzato, YK, de Moraes-Souza, RQ, et al. Metabolic changes in female rats exposed to intrauterine hyperglycemia and postweaning consumption of high-fat diet. Biol Reprod. 2022; 106(1), 200–212. DOI: 10.1093/biolre/ioab195.CrossRefGoogle ScholarPubMed
Lomas-Soria, C, Reyes-Castro, LA, Rodríguez-González, GL, et al. Maternal obesity has sex-dependent effects on insulin, glucose and lipid metabolism and the liver transcriptome in young adult rat offspring. J Physiol. 2018; 596(19), 4611–4628. DOI: 10.1113/JP276372.CrossRefGoogle ScholarPubMed
Tai, MM. A mathematical model for the determination of total area under glucose tolerance and other metabolic curves. Diabetes Care. 1944; 17(2), 152–154. DOI: 10.2337/diacare.17.2.152.CrossRefGoogle Scholar
Knopfholz, J, Disserol, CC, Pierin, AJ, et al. Validation of the Friedewald formula in patients with metabolic syndrome. Cholesterol. 2014; 2014, 261878. DOI: 10.1155/2014/261878.CrossRefGoogle ScholarPubMed
Guerrero-Romero, F, Simental-Mendía, LE, González-Ortiz, M, et al. The product of triglycerides and glucose, a simple measure of insulin sensitivity. Comparison with the euglycemic-hyperinsulinemic clamp. J Clin Endocrinol Metab. 2010; 95(7), 3347–3351. DOI: 10.1210/jc.2010-0288.CrossRefGoogle ScholarPubMed
De, Ritis, Coltorti, M, Giusti, G. An enzymic test for the diagnosis of viral hepatitis; the transaminase serum activities. Clin Chim Acta. 1957; 2(1), 70–74. DOI: 10.1016/0009-8981(57)90027-x.Google Scholar
da Cruz, LL, Barco, VS, Paula, VG, et al. Severe diabetes induction as a generational model for growth restriction of rat. Reprod Sci. 2023; 30(8), 2416–2428. DOI: 10.1007/s43032-023-01198-9.CrossRefGoogle ScholarPubMed
Sinzato, YK, Rodrigues, T, Cruz, LL, et al. Assessment of oxidative stress biomarkers in rat blood. Bio-protocol. 2023; 13(5), e4626. DOI: 10.21769/BioProtoc.4626.CrossRefGoogle ScholarPubMed
Bradford, MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72, 248–254. DOI: 10.1006/abio.1976.9999.CrossRefGoogle ScholarPubMed
Piao, D, Sultana, N, Holyoak, GR, et al. In vivo assessment of diet-induced rat hepatic steatosis development by percutaneous single-fiber spectroscopy detects scattering spectral changes due to fatty infiltration. J Biomed Opt. 2015; 20(11), 117002. DOI: 10.1117/1.JBO.20.11.117002.CrossRefGoogle ScholarPubMed
Bechmann, LP, Hannivoort, RA, Gerken, G, Hotamisligil, GS, Trauner, M, Canbay, A. The interaction of hepatic lipid and glucose metabolism in liver diseases. J Hepatol. 2012; 56(4), 952–964. DOI: 10.1016/j.jhep.2011.08.025.CrossRefGoogle ScholarPubMed
Gallego, FQ, Barco, VS, Sinzato, YK, et al. Effect of transgenerational diabetes via maternal lineage in female rats. Heliyon. 2024; 10(10), e31049. DOI: 10.1016/j.heliyon.2024.e31049.CrossRefGoogle Scholar
Aerts, L, Van Assche, FA. Animal evidence for the transgenerational development of diabetes mellitus. Int J Biochem Cell Biol. 2006; 38(5-6), 894–903. DOI: 10.1016/j.biocel.2005.07.006.CrossRefGoogle ScholarPubMed
Vasques, AC, Novaes, FS, de Oliveira Mda, S, et al. TyG index performs better than HOMA in a Brazilian population: a hyperglycemic clamp validated study. Diabetes Res Clin Pract. 2011; 93(3), e98–e100. DOI: 10.1016/j.diabres.2011.05.030.CrossRefGoogle Scholar
Niu, H, Zhou, Y. Nonlinear relationship between AST-to-ALT ratio and the incidence of Type 2 diabetes mellitus: a follow-up study. Int J Gen Med. 2021; 14, 8373–8382. DOI: 10.2147/IJGM.S341790.CrossRefGoogle ScholarPubMed
Müllebner, A, Herminghaus, A, Miller, I, et al. Tissue damage, not infection, triggers epatic unfolded protein response in an experimental rat peritonitis model. Front Med (Lausanne). 2022; 9, 785285. DOI: 10.3389/fmed.2022.785285.CrossRefGoogle ScholarPubMed
Sorbi, D, Boynton, J, Lindor, KD. The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease. Am J Gastroenterol. 1999; 94(4), 1018–1022. DOI: 10.1111/j.1572-0241.1999.01006.x.CrossRefGoogle ScholarPubMed
Arab, JP, Arrese, M, Trauner, M. Recent insights into the pathogenesis of nonalcoholic fatty liver disease. Annu Rev Pathol. 2018; 13(1), 321–350. DOI: 10.1146/annurev-pathol-020117-043617.CrossRefGoogle ScholarPubMed
Finck, BN. Targeting metabolism, insulin resistance, and diabetes to treat nonalcoholic steatohepatitis. Diabetes. 2018; 67(12), 2485–2493. DOI: 10.2337/dbi18-0024.CrossRefGoogle ScholarPubMed
Michalopoulos, GK, Bhushan, B. Liver regeneration: biological and pathological mechanisms and implications. Nat Rev Gastroenterol Hepatol. 2021; 18(1), 40–55. DOI: 10.1038/s41575-020-0342-4.CrossRefGoogle ScholarPubMed
Quinn, R. Comparing rat’s to human’s age: how old is my rat in people years? Nutrition. 2005; 21(6), 775–777. DOI: 10.1016/j.nut.2005.04.002.CrossRefGoogle ScholarPubMed
Devarajan, A, Rajasekaran, NS, Valburg, C, Ganapathy, E, Bindra, S, Freije, WA. Maternal perinatal calorie restriction temporally regulates the hepatic autophagy and redox status in male rat. Free Radic Biol Med. 2019; 130, 592–600. DOI: 10.1016/j.freeradbiomed.2018.09.029.CrossRefGoogle ScholarPubMed
Bak, DH, Na, J, Choi, MJ, et al. Anti-apoptotic effects of human placental hydrolysate against hepatocyte toxicity in vivo and in vitro. Int J Mol Med. 2018; 42, 2569–2583. DOI: 10.3892/ijmm.2018.3830.Google ScholarPubMed
Zeng, TS, Liu, FM, Zhou, J, Pan, SX, Xia, WF, Chen, LL. Depletion of Kupffer cells attenuates systemic insulin resistance, inflammation and improves liver autophagy in high-fat diet fed mice. Endocr J. 2015; 62(7), 615–626. DOI: 10.1507/endocrj.EJ15-0046.CrossRefGoogle ScholarPubMed
Xu, F, Hua, C, Tautenhahn, HM, Dirsch, O, Dahmen, U. The role of autophagy for the regeneration of the aging liver. Int J Mol Sci. 2020; 21(10), 3606. DOI: 10.3390/ijms21103606.CrossRefGoogle ScholarPubMed
Ouyang, W, Rutz, S, Crellin, NK, Valdez, PA, Hymowitz, SG. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol. 2011; 29(1), 71–109. DOI: 10.1146/annurev-immunol-031210-101312.CrossRefGoogle Scholar
Yu, X, Zhang, L, Lu, H, et al. Rapamycin protects against hepatic injury in streptozotocin-induced diabetic rats by enhancing autophagy. Int J Clin Exp Med. 2019; 12, 11383–11393.Google Scholar
Singh, R, Kaushik, S, Wang, Y, et al. Autophagy regulates lipid metabolism. Nature. 2009; 458(7242), 1131–1135. DOI: 10.1038/nature07976.CrossRefGoogle ScholarPubMed
Martinez-Lopez, N, Singh, R. Autophagy and lipid droplets in the liver. Annu Rev Nutr. 2015; 35(1), 215–237. DOI: 10.1146/annurev-nutr-071813-105336.CrossRefGoogle ScholarPubMed
Maiuri, MC, Zalckvar, E, Kimchi, A, Kroemer, G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007; 8(9), 741–752. DOI: 10.1038/nrm2239.CrossRefGoogle ScholarPubMed
Alers, S, Löffler, AS, Wesselborg, S, Stork, B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol. 2012; 32(1), 2–11. DOI: 10.1128/MCB.06159-11.CrossRefGoogle ScholarPubMed
Petrović, A, Bogojević, D, Korać, A, et al. Oxidative stress-dependent contribution of HMGB1 to the interplay between apoptosis and autophagy in diabetic rat liver. J Physiol Biochem. 2017; 73(4), 511–521. DOI: 10.1007/s13105-017-0574-0.CrossRefGoogle Scholar
Klionsky, DJ, Abdel-Aziz, AK, Abdelfatah, S, et al. Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy. 2021; 17(1), 1–382. DOI: 10.1080/15548627.2020.1797280.CrossRefGoogle ScholarPubMed
Avagliano, L, Massa, V, Terraneo, L, et al. Gestational diabetes affects fetal autophagy. Placenta. 2017; 55, 90–93. DOI: 10.1016/j.placenta.2017.05.002.CrossRefGoogle ScholarPubMed
Mariño, G, Pietrocola, F, Eisenberg, T, et al. Regulation of autophagy by cytosolic acetyl-coenzyme A. Mol Cell. 2014; 53(5), 710–725. DOI: 10.1016/j.molcel.2014.01.016.CrossRefGoogle ScholarPubMed
Czaja, MJ. Function of autophagy in nonalcoholic fatty liver disease. Dig Dis Sci. 2016; 61(5), 1304–1313. DOI: 10.1007/s10620-015-4025-x.CrossRefGoogle ScholarPubMed
Tanaka, S, Hikita, H, Tatsumi, T, et al. Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease in mice. Hepatology. 2016; 64(6), 1994–2014. DOI: 10.1002/hep.28820.CrossRefGoogle ScholarPubMed
Zhang, D, Liu, K, Hu, W, et al. Prenatal dexamethasone exposure caused fetal rats liver dysplasia by inhibiting autophagy-mediated cell proliferation. Toxicology. 2021; 449, 152664. DOI: 10.1016/j.tox.2020.152664.CrossRefGoogle ScholarPubMed
Hoefel, AL, Hansen, F, Rosa, PD, et al. The effects of hypercaloric diets on glucose homeostasis in the rat: influence of saturated and monounsaturated dietary lipids. Cell Biochem Funct. 2011; 29(7), 569–576. DOI: 10.1002/cbf.1789.CrossRefGoogle ScholarPubMed
Jung, T, Höhn, A, Grune, T. Lipofuscin: detection and quantification by microscopic techniques. Methods Mol Biol. 2010; 594, 173–193. DOI: 10.1007/978-1-60761-411-1_13.CrossRefGoogle ScholarPubMed
Ajoolabady, A, Aslkhodapasandhokmabad, H, Libby, P, et al. Ferritinophagy and ferroptosis in the management of metabolic diseases. Trends Endocrinol Metab. 2021; 32(7), 444–462. DOI: 10.1016/j.tem.2021.04.010.CrossRefGoogle ScholarPubMed
Mahdavi, S, Khodarahmi, P, Roodbari, NH. Effects of cadmium on Bcl-2/ Bax expression ratio in rat cortex brain and hippocampus. Hum Exp Toxicol. 2018; 37(3), 321–328. DOI: 10.1177/0960327117703687.CrossRefGoogle ScholarPubMed
Cruz et al. supplementary material
Cruz et al. supplementary material
File
14 KB