No CrossRef data available.
Article contents
Dietary stress triggers autophagy and apoptotic signalling pathways in the rat ovary
Published online by Cambridge University Press: 17 November 2025
Abstract
Dieting is a global emerging trend in recent years as more people strive to adhere to food restriction plans for weight management in obese people and to achieve desired slim body. This strategy may have unforeseen repercussions in females that may affect reproductive potential. Therefore, we aimed to investigate the impact of dietary stress on reproductive hormone levels, histoarchitecture of the ovary, autophagy and apoptosis markers in the rat ovary. Data suggest that dietary stress caused due to food deprivation decreased body weight and ovary weight, luteinising hormone, follicular-stimulating hormone and estradiol-17β levels. The dietary stress reduced the number of primary follicles, altered the histoarchitecture of the ovary, increased number of fragmented and irregularly shaped oocytes. Dietary stress induced autophagy signalling by inhibiting mammalian target of rapamycin and increasing Lamp-1, LC-3 and Beclin-1 in the ovarian follicles. In addition, dietary stress induced proapoptotic signalling pathway by decreasing Bcl-2 and increasing Bax as well as cytochrome-c expressions in the ovary. Taken together, these findings suggest that dietary stress caused due to food deprivation reduced reproductive hormones levels, induced autophagy and apoptotic signalling pathways that affected histoarchitecture of the ovary, ovarian function, oocyte quality and thereby reproductive potential.
Information
- Type
- Research Article
- Information
- Copyright
- © The Author(s), 2025. Published by Cambridge University Press on behalf of The Nutrition Society
References
Habib, A, Ali, T, Nazir, Z, et al. (2023) Unintended consequences of dieting: how restrictive eating habits can harm your health. Int J Surg Open 60, 100703.Google Scholar
Mao, L, Liu, A & Zhang, X (2024) Effects of intermittent fasting on female reproductive function: a review of animal and human studies. Curr Nutr Rep 13, 786–799.Google Scholar
Holesh, JE, Bass, AN & Lord, M (2023) Physiology, Ovulation. StatPearls. Treasure Island, FL: StatPearls Publishing.Google Scholar
Hułas-Stasiak, M & Gawron, A (2011) Follicular atresia in the prepubertal spiny mouse (Acomys cahirinus) ovary. Apoptosis 16, 967–975.Google Scholar
Manabe, N, Goto, Y, Matsuda-Minehata, F, et al. (2004) Regulation mechanism of selective atresia in porcine follicles: regulation of granulosa cell apoptosis during atresia. J Reprod Dev 50, 493–514.Google Scholar
Matsuda, F, Inoue, N, Manabe, N, et al. (2012) Follicular growth and atresia in mammalian ovaries: regulation by survival and death of granulosa cells. J Reprod Dev 58, 44–50.Google Scholar
Yadav, AK, Yadav, PK, Chaudhary, GR, et al. (2019) Autophagy in hypoxic ovary. Cell Mol Life Sci 76, 3311–3322.Google Scholar
Yadav, PK, Tiwari, M, Gupta, A, et al. (2018) Germ cell depletion from mammalian ovary: possible involvement of apoptosis and autophagy. J Biomed Sci 25, 36.Google Scholar
Edinger, AL & Thompson, CB (2004) Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol 16, 663–669.Google Scholar
Rodrigues, P, Limback, D, McGinnis, LK, et al. (2009) Multiple mechanisms of germ cell loss in the perinatal mouse ovary. Reproduction 137, 709–720.Google Scholar
Tiwari, M, Prasad, S, Tripathi, A, et al. (2015) Apoptosis in mammalian oocytes: a review. Apoptosis 20, 1019–1025.Google Scholar
Pandey, AN, Yadav, PK, Premkumar, KV, et al. (2024) Reactive oxygen species signalling in the deterioration of quality of mammalian oocytes cultured in vitro: protective effect of antioxidants. Cell Signal 117, 111103.Google Scholar
Yadav, PK, Pandey, AN, Premkumar, KV, et al. (2024) Follicular oocyte as a potential target for severe acute respiratory syndrome coronavirus 2 infection. Rev Med Virol 34, e2568.Google Scholar
Hutt, KJ (2015) The role of BH3-only proteins in apoptosis within the ovary. Reproduction 149, R81–89.Google Scholar
Tilly, JL (2001) Commuting the death sentence: how oocytes strive to survive. Nat Rev Mol Cell Biol 2, 838–848.Google Scholar
Mork, L, Tang, H, Batchvarov, I, et al. (2012) Mouse germ cell clusters form by aggregation as well as clonal divisions. Mech Dev 128, 591–596.Google Scholar
Chaube, SK, Prasad, S, Tiwari, M, et al. (2016) Rat: an interesting model to study oocyte meiosis in mammals. Res Rev: J Zoological Sci 4, 26–27.Google Scholar
Lobascio, AM, Klinger, FG, Scaldaferri, ML, et al. (2007) Analysis of programmed cell death in mouse fetal oocytes. Reproduction 134, 241–252.Google Scholar
Aitken, RJ, Findlay, JK, Hutt, KJ, et al. (2011) Apoptosis in the germ line. Reproduction 141, 139–150.Google Scholar
Galluzzi, L, Kepp, O, Trojel-Hansen, C, et al. (2012) Mitochondrial control of cellular life, stress, and death. Circ Res 111, 1198–1207.Google Scholar
Schwartz, MW, Seeley, RJ, Zeltser, LM, et al. (2017) Obesity pathogenesis: an endocrine society scientific statement. Endocr Rev 38, 267–296.Google Scholar
Liu, L, Tang, Y, Zhou, Z, et al. (2023) Membrane curvature: the inseparable companion of autophagy. Cells 12, 1132.Google Scholar
Kroemer, G, Galluzzi, L, Vandenabeele, P, et al. (2009) Classification of cell death: recommendations of the nomenclature committee on cell death 2009. Cell Death Differ 16, 3–11.Google Scholar
Pandey, AN, Yadav, PK, Premkumar, KV, et al. (2024) Damage mechanisms of bisphenols on the quality of mammalian oocytes. Hum Reprod 40, 186–198.Google Scholar
Chaube, S (2001) Role of meiotic maturation regulatory factors in developmental competence of mammalian oocytes. HPPI 24, 218–231.Google Scholar
Prasad, S, Tiwari, M, Koch, B, et al. (2015) Morphological, cellular and molecular changes during postovulatory egg aging in mammals. J Biomed Sci 22, 36.Google Scholar
Khaled, K, Hundley, V & Tsofliou, F (2021) Poor dietary quality and patterns are associated with higher perceived stress among women of reproductive age in the UK. Nutrients 13, 2588.Google Scholar
Ma, X, Wu, L, Wang, Y, et al. (2022) Diet and human reproductive system: insight of omics approaches. Food Sci Nutr 10, 1368–1384.Google Scholar
Sun, J, Shen, X, Liu, H, et al. (2021) Caloric restriction in female reproduction: is it beneficial or detrimental? Reprod Biol Endocrinol 19, 1.Google Scholar
Claassen, V (editor) (1994) 12 – Food and water intake. In Techniques in the Behavioral and Neural Sciences, pp. 267–287. Amsterdam: Elsevier.Google Scholar
Seki, M, Yamaguchi, K, Marumo, H, et al. (1998) Effects of food restriction on reproductive and toxicological parameters in rats – in search of suitable feeding regimen in long-term tests. J Toxicol Sci 22, 427–437.Google Scholar
Sasaki, H, Hamatani, T, Kamijo, S, et al. (2019) Impact of oxidative stress on age-associated decline in oocyte developmental competence. Front Endocrinol 10, 811.Google Scholar
Yan, F, Zhao, Q, Li, Y, et al. (2022) The role of oxidative stress in ovarian aging: a review. J Ovarian Res 15, 100.Google Scholar
El-Zayat, SR, Sibaii, H & El-Shamy, KA (2019) Physiological process of fat loss. Bull Natl Res Centre 43, 208.Google Scholar
Harris, RB & Martin, RJ (1984) Specific depletion of body fat in parabiotic partners of tube-fed obese rats. Am J Physiol 247, R380–386.Google Scholar
Bindari, YR, Shrestha, S, Shrestha, N, et al. (2013) Effects of nutrition on reproduction – a review. Adv Appl Sci Res 4, 421–429.Google Scholar
Rojas, J, Chávez-Castillo, M, Olivar, LC, et al. (2015) Physiologic course of female reproductive function: a molecular look into the prologue of life. J Pregnancy 2015, 715735.Google Scholar
Cagampang, FR, Maeda, K, Yokoyama, A, et al. (1990) Effect of food deprivation on the pulsatile LH release in the cycling and ovariectomized female rat. Horm Metab Res 22, 269–272.Google Scholar
McClure, TJ & Saunders, J (1985) Effects of withholding food for 0–72 h on mating, pregnancy rate and pituitary function in female rats. J Reprod Fertil 74, 57–64.Google Scholar
Subih, M, Salem, H & Al Omari, D (2023) Evaluation of compassion fatigue and compassion satisfaction among emergency nurses in Jordan: a cross-sectional study. Int Emerg Nurs 66, 101232.Google Scholar
Domazetovic, V, Fontani, F, Marcucci, G, et al. (2017) Estrogen inhibits starvation-induced apoptosis in osteocytes by a redox-independent process involving association of JNK and glutathione S-transferase P1–1. FEBS Open Bio 7, 705–718.Google Scholar
Bronson, FH (1989) Mammalian Reproductive Biology. Chicago, IL: University of Chicago Press.Google Scholar
Martin, B, Golden, E, Carlson, OD, et al. (2008) Caloric restriction: impact upon pituitary function and reproduction. Ageing Res Rev 7, 209–224.Google Scholar
Cameron, JL & Nosbisch, C (1991) Suppression of pulsatile luteinizing hormone and testosterone secretion during short term food restriction in the adult male rhesus monkey (Macaca mulatta). Endocrinology 128, 1532–1540.Google Scholar
Marques, P, Skorupskaite, K, Rozario, KS, et al. (2000) Physiology of GnRH and gonadotropin secretion. In Endotext [Feingold, KR, Anawalt, B, Blackman, MR, et al., editors]. South Dartmouth, MA: MDText.com, Inc.Google Scholar
Wu, R, Van der Hoek, KH, Ryan, NK, et al. (2004) Macrophage contributions to ovarian function. Hum Reprod Update 10, 119–133.Google Scholar
de Morais Oliveira, DA, Lupi, LA, Silveira, HS, et al. (2021) Protein restriction during puberty alters nutritional parameters and affects ovarian and uterine histomorphometry in adulthood in rats. Int J Exp Pathol 102, 93–104.Google Scholar
Downs, JL & Wise, PM (2009) The role of the brain in female reproductive aging. Mol Cell Endocrinol 299, 32.Google Scholar
Broughton, DE & Moley, KH (2017) Obesity and female infertility: potential mediators of obesity’s impact. Fertil Steril 107, 840–847.Google Scholar
He, L, Zhang, J, Zhao, J, et al. (2018) Autophagy: the last defense against cellular nutritional stress. Adv Nutr 9, 493–504.Google Scholar
Shintani, T & Klionsky, DJ (2004) Autophagy in health and disease: a double-edged sword. Science 306, 990–995.Google Scholar
Parzych, KR & Klionsky, DJ (2014) An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal 20, 460–473.Google Scholar
Mejlvang, J, Olsvik, H, Svenning, S, et al. (2018) Starvation induces rapid degradation of selective autophagy receptors by endosomal microautophagy. J Cell Biol 217, 3640–3655.Google Scholar
Egan, DF, Shackelford, DB, Mihaylova, MM, et al. (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461.Google Scholar
Glick, D, Barth, S & Macleod, KF (2010) Autophagy: cellular and molecular mechanisms. J Pathol 221, 3–12.Google Scholar
Kim, YJ, Baek, E, Lee, JS, et al. (2013) Autophagy and its implication in Chinese hamster ovary cell culture. Biotechnol Lett 35, 1753–1763.Google Scholar
Kroemer, G, Mariño, G & Levine, B (2010) Autophagy and the integrated stress response. Mol Cell 40, 280–293.Google Scholar
Ktistakis, NT & Tooze, SA (2016) Digesting the expanding mechanisms of autophagy. Trends Cell Biol 26, 624–635.Google Scholar
Kang, R, Zeh, HJ, Lotze, MT, et al. (2011) The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 18, 571–580.Google Scholar
Molejon, MI, Ropolo, A, Re, AL, et al. (2013) The VMP1-Beclin 1 interaction regulates autophagy induction. Sci Rep 3, 1055.Google Scholar
Kaur, S & Changotra, H (2020) The beclin 1 interactome: modification and roles in the pathology of autophagy-related disorders. Biochimie 175, 34–49.Google Scholar
Maiuri, MC, Zalckvar, E, Kimchi, A, et al. (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol 8, 741–752.Google Scholar
Kabeya, Y, Mizushima, N, Ueno, T, et al. (2000) LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19, 5720–5728.Google Scholar
Eskelinen, E-L (2005) Maturation of autophagic vacuoles in Mammalian cells. Autophagy 1, 1–10.Google Scholar
Czaja, MJ, Ding, W-X, Donohue, TM, et al. (2013) Functions of autophagy in normal and diseased liver. Autophagy 9, 1131–1158.Google Scholar
Saftig, P & Klumperman, J (2009) Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat Rev Mol Cell Biol 10, 623–635.Google Scholar
Yadav, PK, Gupta, A, Sharma, A, et al. (2020) Fate of the germ cells in mammalian ovary: a review. JRHM 1, 3.Google Scholar
Berens, HM & Tyler, KL (2011) The proapoptotic bcl-2 protein bax plays an important role in the pathogenesis of reovirus encephalitis. J Virol 85, 3858–3871.Google Scholar
Wang, C & Youle, RJ (2009) The role of mitochondria in apoptosis. Annu Rev Genet 43, 95–118.Google Scholar
Wei, MC, Zong, WX, Cheng, EHY, et al. (2001) Proapoptotic bax and bak: a requisite gateway to mitochondrial dysfunction and death. Science 292, 727–730.Google Scholar
Chaube, SK, Prasad, PV, Khillare, B, et al. (2006) Extract of Azadirachta indica (neem) leaf induces apoptosis in rat oocytes cultured in vitro
. Fertil Steril 85, 1223–1231.Google Scholar
Chaube, SK, Prasad, PV, Thakur, SC, et al. (2005) Hydrogen peroxide modulates meiotic cell cycle and induces morphological features characteristic of apoptosis in rat oocytes cultured in vitro
. Apoptosis 10, 863–874.Google Scholar
Tiwari, M, Tripathi, A & Chaube, SK (2017) Presence of encircling granulosa cells protects against oxidative stress-induced apoptosis in rat eggs cultured in vitro
. Apoptosis 22, 98–107.Google Scholar
Tripathi, A, PremKumar, KV, Pandey, AN, et al. (2011) Melatonin protects against clomiphene citrate-induced generation of hydrogen peroxide and morphological apoptotic changes in rat eggs. Eur J Pharmacol 667, 419–424.Google Scholar
Escobar, ML, Echeverría, OM, Sánchez-Sánchez, L, et al. (2010) Analysis of different cell death processes of prepubertal rat oocytes in vitro
. Apoptosis 15, 511–526.Google Scholar
Escobar, ML, Echeverría, OM, Ortíz, R, et al. (2008) Combined apoptosis and autophagy, the process that eliminates the oocytes of atretic follicles in immature rats. Apoptosis 13, 1253–1266.Google Scholar
Escobar Sánchez, ML, Echeverría Martínez, OM & Vázquez-Nin, GH (2012) Immunohistochemical and ultrastructural visualization of different routes of oocyte elimination in adult rats. Eur J Histochem 56, e17.Google Scholar