Cumulus cells protect the oocyte against saturated free fatty acids
In the cow a major characteristic of metabolic stress is an elevated level of plasma free fatty acid, due to increased lipid mobilization from adipose tissue. Elevated levels of free fatty acids in blood (complexed to albumin) are associated with increased lipotoxicity in non-adipose tissue. An overview is provided on the negative impact of free fatty acids and the metabolic stress imposed on the oocyte and early embryo and thus on bovine fertility. There is increasing evidence that in vitro as well as in vivo the elevated levels of free fatty acids in blood during metabolic stress can severely hamper oocyte and embryo development. However, fatty acids do also form an essential nutrient source for the oocyte and embryo, which indicates that these good and bad effects of fatty acids should be in subtle balance to optimize the developmental competence of the oocyte and embryo.
Aardema H, Vos PL, Lolicato F, Roelen BA, Knijn HM, Vaandrager AB, Helms JB, Gadella BM. 2011. Oleic acid prevents detrimental effects of saturated fatty acids on bovine oocyte developmental competence. Biol Reprod, 85:62-69.
Aardema H, Lolicato F, van de Lest CH, Brouwers JF, Vaandrager AB, van Tol HT, Roelen BA, Vos PL, Helms JB, Gadella BM. 2013. Bovine cumulus cells protect maturing oocytes from increased fatty acid levels by massive intracellular lipid storage. Biol Reprod, 88:164. doi: 10.1095/biolreprod.112.106062.
Aardema H, Gadella BM, van de Lest CH, Brouwers JF, Stout TA, Roelen BA, Vos PL. 2015. Free fatty acid levels in fluid of dominant follicles at the preferred insemination time in dairy cows are not affected by early postpartum fatty acid stress. J Dairy Sci, 98:2322-2336.
Aardema H, van Tol HTA, Wubbolts RW, Brouwers JFHM, Gadella BM, Roelen BAJ. 2017. Stearoyl-CoA desaturase activity in bovine cumulus cells protects the oocyte against saturated fatty acid stress. Biol Reprod, 96:982-992.
Ambruosi B, Lacalandra GM, Iorga AI, De Santis T, Mugnier S, Matarrese R, Goudet G, Dell'aquila ME. 2009. Cytoplasmic lipid droplets and mitochondrial distribution in equine oocytes: Implications on oocyte maturation, fertilization and developmental competence after ICSI. Theriogenology, 71:1093-1104.
Auclair S, Uzbekov R, Elis S, Sanchez L, Kireev I, Lardic L, Dalbies-Tran R, Uzbekova S. 2013. Absence of cumulus cells during in vitro maturation affects lipid metabolism in bovine oocytes. Am J Physiol Endocrinol Metab, 304:E599-613.
Broughton DE, Moley KH. 2017. Obesity and female infertility: potential mediators of obesity's impact. Fertil Steril, 107:840-847.
Brown DA. 2001. Lipid droplets: proteins floating on a pool of fat. Curr Biol, 11:R446-9.
Cetica P, Pintos L, Dalvit G, Beconi M. 2002. Activity of key enzymes involved in glucose and triglyceride catabolism during bovine oocyte maturation in vitro. Reproduction, 124:675-681.
Coll T, Eyre E, Rodriguez-Calvo R, Palomer X, Sanchez RM, Merlos M, Laguna JC, Vazquez-Carrera M. 2008. Oleate reverses palmitate-induced insulin resistance and inflammation in skeletal muscle cells. J Biol Chem, 283:11107-11116.
Del Collado M, da Silveira JC, Sangalli JR, Andrade GM, Sousa LRDS, Silva LA, Meirelles FV, Perecin F. 2017. Fatty acid binding protein 3 and transzonal projections are involved in lipid accumulation during in vitro maturation of bovine oocytes. Sci Rep, 7:2645-017-02467-9. doi: 10.1038/s41598-017-02467-9.
Downs SM, Mosey JL, Klinger J. 2009. Fatty acid oxidation and meiotic resumption in mouse oocytes. Mol Reprod Dev, 76:844-853.
Dumesic DA, Meldrum DR, Katz-Jaffe MG, Krisher RL, Schoolcraft WB. 2015. Oocyte environment: follicular fluid and cumulus cells are critical for oocyte health. Fertil Steril, 103:303-316.
Dunning KR, Cashman K, Russell DL, Thompson JG, Norman RJ, Robker RL. 2010. Beta-oxidation is essential for mouse oocyte developmental competence and early embryo development. Biol Reprod, 83:909-918.
Dunning KR, Akison LK, Russell DL, Norman RJ, Robker RL. 2011. Increased beta-oxidation and improved oocyte developmental competence in response to l-carnitine during ovarian in vitro follicle development in mice. Biol Reprod, 85:548-555.
Dunning KR, Watson LN, Sharkey DJ, Brown HM, Norman RJ, Thompson JG, Robker RL, Russell DL. 2012. Molecular filtration properties of the mouse expanded cumulus matrix: controlled supply of metabolites and extracellular signals to cumulus cells and the oocyte. Biol Reprod, 87:89. doi: 10.1095/biolreprod.111.096271.
Dunning KR, Russell DL, Robker RL. 2014. Lipids and oocyte developmental competence: the role of fatty acids and beta-oxidation. Reproduction, 148:R15-27.
Fair T, Hulshof SC, Hyttel P, Greve T, Boland M. 1997. Oocyte ultrastructure in bovine primordial to early tertiary follicles. Anat Embryol (Berl), 195:327-336.
Fayezi S, Ghaffari Novin M, Darabi M, Norouzian M, Nouri M, Farzadi L, Darabi M. 2018. Primary culture of human cumulus cells requires stearoyl-coenzyme a desaturase 1 activity for steroidogenesis and enhancing oocyte in vitro maturation. Reprod Sci, 25:844-853.
Ferguson EM, Leese HJ. 2006. A potential role for triglyceride as an energy source during bovine oocyte maturation and early embryo development. Mol Reprod Dev, 73:1195-1201.
Feuerstein P, Cadoret V, Dalbies-Tran R, Guerif F, Bidault R, Royere D. 2007. Gene expression in human cumulus cells: one approach to oocyte competence. Hum Reprod, 22:3069-3077.
Fleming WN, Saacke RG. 1972. Fine structure of the bovine oocyte from the mature graafian follicle. J Reprod Fertil, 29:203-213.
Fortune JE. 1994. Ovarian follicular growth and development in mammals. Biol Reprod, 50:225-232.
Garbacz WG, Lu P, Miller TM, Poloyac SM, Eyre NS, Mayrhofer G, Xu M, Ren S, Xie W. 2016. Hepatic overexpression of CD36 improves glycogen homeostasis and attenuates high-fat diet-induced hepatic steatosis and insulin resistance. Mol Cell Biol, 36:2715-2727.
Gautier T, Becker S, Drouineaud V, Menetrier F, Sagot P, Nofer JR, von Otte S, Lagrost L, Masson D, Tietge UJ. 2010. Human luteinized granulosa cells secrete apoB100-containing lipoproteins. J Lipid Res, 51:2245-2252.
Genicot G, Leroy JL, Soom AV, Donnay I. 2005. The use of a fluorescent dye, Nile red, to evaluate the lipid content of single mammalian oocytes. Theriogenology, 63:1181-1194.
Gosden RG, Hunter RH, Telfer E, Torrance C, Brown N. 1988. Physiological factors underlying the formation of ovarian follicular fluid. J Reprod Fertil, 82:813-825.
Guo J, Shu G, Zhou L, Zhu X, Liao W, Wang S, Yang J, Zhou G, Xi Q, Gao P, Zhang Y, Zhang S, Yuan L, Jiang Q. 2013. Selective transport of long-chain fatty acids by FAT/CD36 in skeletal muscle of broilers. Animal, 7:422-429.
Henique C, Mansouri A, Fumey G, Lenoir V, Girard J, Bouillaud F, Prip-Buus C, Cohen I. 2010. Increased mitochondrial fatty acid oxidation is sufficient to protect skeletal muscle cells from palmitate-induced apoptosis. J Biol Chem, 285:36818-36827.
Homa ST, Racowsky C, McGaughey RW. 1986. Lipid analysis of immature pig oocytes. J Reprod Fertil, 77:425-434.
Hua W, Huang HZ, Tan LT, Wan JM, Gui HB, Zhao L, Ruan XZ, Chen XM, Du XG. 2015. CD36 mediated fatty acid-induced podocyte apoptosis via oxidative stress. PLoS One, 10:e0127507. doi: 10.1371/journal.pone.0127507.
Hughes J, Kwong WY, Li D, Salter AM, Lea RG, Sinclair KD. 2011. Effects of omega-3 and -6 polyunsaturated fatty acids on ovine follicular cell steroidogenesis, embryo development and molecular markers of fatty acid metabolism. Reproduction, 141:105-118.
Hyttel P, Fair T, Callesen H, Greve T. 1997. Oocyte growth, capacitation and final maturation in cattle. Theriogenology, 47:23-32.
Jaspard B, Fournier N, Vieitez G, Atger V, Barbaras R, Vieu C, Manent J, Chap H, Perret B, Collet X. 1997. Structural and functional comparison of HDL from homologous human plasma and follicular fluid. A model for extravascular fluid. Arterioscler Thromb Vasc Biol, 17:1605-1613.
Jungheim ES, Macones GA, Odem RR, Patterson BW, Lanzendorf SE, Ratts VS, Moley KH. 2011.
Associations between free fatty acids, cumulus oocyte complex morphology and ovarian function during in vitro fertilization. Fertil Steril, 95:1970-1974.
Kane MT. 1987. Minimal nutrient requirements for culture of one-cell rabbit embryos. Biol Reprod, 37:775-778.
Kim DH, Cho YM, Lee KH, Jeong SW, Kwon OJ. 2017. Oleate protects macrophages from palmitate-induced apoptosis through the downregulation of CD36 expression. Biochem Biophys Res Commun, 488:477-482.
Kim JY, Kinoshita M, Ohnishi M, Fukui Y. 2001. Lipid and fatty acid analysis of fresh and frozen-thawed immature and in vitro matured bovine oocytes. Reproduction, 122:131-138.
Kruip TAM, Cran DG, Beneden TH, Dieleman SJ. 1983. Structural changes in bovine oocytes during final maturation in vivo. Gamete Res, 8:29-47.
Leroy JL, Vanholder T, Mateusen B, Christophe A, Opsomer G, de Kruif A, Genicot G, Van Soom A. 2005. Non-esterified fatty acids in follicular fluid of dairy cows and their effect on developmental capacity of bovine oocytes in vitro. Reproduction, 130:485-495.
Listenberger LL, Han X, Lewis SE, Cases S, Farese RV Jr, Ory DS, Schaffer JE. 2003.Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc Natl Acad Sci USA, 100:3077-3082.
Lolicato F, Brouwers JF, de Lest CH, Wubbolts R, Aardema H, Priore P, Roelen BA, Helms JB, Gadella BM. 2015. The cumulus cell layer protects the bovine maturing oocyte against fatty acid-induced lipotoxicity. Biol Reprod, 92:16. doi: 10.1095/biolreprod.114.120634.
Ly LD, Xu S, Choi SK, Ha CM, Thoudam T, Cha SK, Wiederkehr A, Wollheim CB, Lee IK, Park KS. 2017. Oxidative stress and calcium dysregulation by palmitate in type 2 diabetes. Exp Mol Med, 49:e291. doi: 10.1038/emm.2016.157.
Mardomi A, Nouri M, Farzadi L, Zarghami N, Mehdizadeh A, Yousefi M, Shanebandi D, Shaaker M, Darabi M. 2018. Human charcoal-stripped serum supplementation enhances both the stearoyl-coenzyme a desaturase 1 activity of cumulus cells and the in vitro maturation of oocytes. Hum Fertil (Camb), 1-7. doi: 10.1080/14647273.2018.1466400.
Marei WF, Wathes DC, Fouladi-Nashta AA. 2009. The effect of linolenic Acid on bovine oocyte maturation and development. Biol Reprod, 81:1064-1072.
Marei WFA, De Bie J, Mohey-Elsaeed O, Wydooghe E, Bols PEJ, Leroy JLMR. 2017. Alpha-linolenic acid protects the developmental capacity of bovine cumulus-oocyte complexes matured under lipotoxic conditions in vitro. Biol Reprod, 96:1181-1196.
McEvoy TG, Coull GD, Broadbent PJ, Hutchinson JS, Speake BK. 2000. Fatty acid composition of lipids in immature cattle, pig and sheep oocytes with intact zona pellucida. J Reprod Fertil, 118:163-170.
McKeegan PJ, Sturmey RG. 2012. The role of fatty acids in oocyte and early embryo development. Reprod Fertil Dev, 24:59-67.
Moreau C, Froment P, Tosca L, Moreau V, Dupont J. 2006. Expression and regulation of the SCD2 desaturase in the rat ovary. Biol Reprod, 74:75-87.
Mu YM, Yanase T, Nishi Y, Tanaka A, Saito M, Jin CH, Mukasa C, Okabe T, Nomura M, Goto K, Nawata H. 2001. Saturated FFAs, palmitic acid and stearic acid, induce apoptosis in human granulosa cells. Endocrinology, 142:3590-3597.
Paczkowski M, Silva E, Schoolcraft WB, Krisher RL. 2013. Comparative importance of Fatty Acid Beta-oxidation to nuclear maturation, gene expression, and glucose metabolism in mouse, bovine, and porcine cumulus oocyte complexes. Biol Reprod, 88:111. doi: 10.1095/biolreprod.113.108548.
Pizzo P, Pozzan T. 2007. Mitochondria-endoplasmic reticulum choreography: structure and signaling dynamics. Trends Cell Biol, 17:511-517.
Robenek H, Hofnagel O, Buers I, Robenek MJ, Troyer D, Severs NJ. 2006. Adipophilin-enriched domains in the ER membrane are sites of lipid droplet biogenesis. J Cell Sci, 119:4215-4224.
Russell DL, Gilchrist RB, Brown HM, Thompson JG. 2016. Bidirectional communication between cumulus cells and the oocyte: Old hands and new players? Theriogenology, 86:62-68.
Schumann J. 2016. It is all about fluidity: Fatty acids and macrophage phagocytosis.. Eur J Pharmacol, 785:18-23.
Somfai T, Kaneda M, Akagi S, Watanabe S, Haraguchi S, Mizutani E, Dang-Nguyen TQ, Geshi M, Kikuchi K, Nagai T. 2011. Enhancement of lipid metabolism with L-carnitine during in vitro maturation improves nuclear maturation and cleavage ability of follicular porcine oocytes. Reprod Fertil Dev, 23:912-920.
Sturmey RG, O'Toole PJ, Leese HJ. 2006. Fluorescence resonance energy transfer analysis of mitochondrial:lipid association in the porcine oocyte. Reproduction, 132:829-837.
Sturmey RG, Reis A, Leese HJ, McEvoy TG. 2009. Role of fatty acids in energy provision during oocyte maturation and early embryo development. Reprod Domest Anim, 44(suppl. 3):50-58.
Sutton-McDowall ML, Feil D, Robker RL, Thompson JG, Dunning KR. 2012. Utilization of endogenous fatty acid stores for energy production in bovine preimplantation embryos. Theriogenology, 77:1632-1641.
Sutton-McDowall ML, Wu LL, Purdey M, Abell AD, Goldys EM, MacMillan KL, Thompson JG, Robker RL. 2016. Nonesterified fatty acid-induced endoplasmic reticulum stress in cattle cumulus oocyte complexes alters cell metabolism and developmental competence. Biol Reprod, 94:23. doi: 10.1095/biolreprod.115.131862.
Uzbekova S, Elis S, Teixeira-Gomes AP, Desmarchais A, Maillard V, Labas V. 2015. MALDI Mass spectrometry imaging of lipids and gene expression reveals differences in fatty acid metabolism between follicular compartments in porcine ovaries. Biology (Basel), 4:216-236.
Vahratian A. 2009. Prevalence of overweight and obesity among women of childbearing age: results from the 2002 National Survey of Family Growth. Matern Child Health J, 13:268-273.
Valckx SD, De Pauw I, De Neubourg D, Inion I,
Berth M, Fransen E, Bols PE, Leroy JL. 2012. BMI-related metabolic composition of the follicular fluid of women undergoing assisted reproductive treatment and the consequences for oocyte and embryo quality. Hum Reprod, 27:3531-3539.
Valckx SD, Arias-Alvarez M, De Pauw I, Fievez V, Vlaeminck B, Fransen E, Bols PE, Leroy JL. 2014. Fatty acid composition of the follicular fluid of normal weight, overweight and obese women undergoing assisted reproductive treatment: a descriptive cross-sectional study. Reprod Biol Endocrinol, 12:13. doi: 10.1186/1477-7827-12-13.
Van Hoeck V, Sturmey RG, Bermejo-Alvarez P, Rizos D, Gutierrez-Adan A, Leese HJ, Bols PE, Leroy JL. 2011. Elevated non-esterified fatty acid concentrations during bovine oocyte maturation compromise early embryo physiology. PLoS One, 6:e23183. doi: 10.1371/journal.pone.0023183.
Warzych E, Pawlak P, Pszczola M, Cieslak A, Lechniak D. 2017a. Prepubertal heifers versus cows:the differences in the follicular environment. Theriogenology, 87:36-47.
Warzych E, Pawlak P, Pszczola M, Cieslak A, Madeja ZE, Lechniak D. 2017b. Interactions of bovine oocytes with follicular elements with respect to lipid metabolism. Anim Sci J, 88:1491-1497.
Wathes DC, Clempson AM, Pollott GE. 2012. Associations between lipid metabolism and fertility in the dairy cow. Reprod Fertil Dev, 25:48-61.
Wilson CG, Tran JL, Erion DM, Vera NB, Febbraio M, Weiss EJ. 2016. Hepatocyte-specific disruption of CD36 attenuates fatty liver and improves insulin sensitivity in HFD-fed mice. Endocrinology, 157:570-585.
Wonnacott KE, Kwong WY, Hughes J, Salter AM, Lea RG, Garnsworthy PC, Sinclair KD. 2010. Dietary omega-3 and -6 polyunsaturated fatty acids affect the composition and development of sheep granulosa cells, oocytes and embryos. Reproduction, 139:57-69.
Wu LL, Dunning KR, Yang X, Russell DL, Lane M, Norman RJ, Robker RL. 2010. High-fat diet causes lipotoxicity responses in cumulus-oocyte complexes and decreased fertilization rates. Endocrinology, 151:5438-5445.
Wu LL, Russell DL, Norman RJ, Robker RL. 2012. Endoplasmic reticulum (ER) stress in cumulus-Oocyte complexes impairs pentraxin-3 secretion, mitochondrial membrane potential (ΔΨm), and embryo development. Mol Endocrinol, 26:562-573.
Xu M, Zeng Y, Chi D, Si L, Qu X, Li J. 2018. The dynamic pattern of PLIN3 in pig oocytes and cumulus cells during in vitro maturation. Zygote, 26:40-49.
Xu S, Nam SM, Kim JH, Das R, Choi SK, Nguyen TT, Quan X, Choi SJ, Chung CH, Lee EY, Lee IK, Wiederkehr A, Wollheim CB, Cha SK, Park KS. 2015. Palmitate induces ER calcium depletion and apoptosis in mouse podocytes subsequent to mitochondrial oxidative stress. Cell Death Dis, 6:e1976. doi: 10.1038/cddis.2015.331.
Yang X, Wu LL, Chura LR, Liang X, Lane M, Norman RJ, Robker RL. 2012. Exposure to lipid-rich follicular fluid is associated with endoplasmic reticulum stress and impaired oocyte maturation in cumulus-oocyte complexes. Fertil Steril, 97:1438-1443.
Zeron Y, Ocheretny A, Kedar O, Borochov A, Sklan D, Arav A. 2001. Seasonal changes in bovine fertility: relation to developmental competence of oocytes, membrane properties and fatty acid composition of follicles. Reproduction, 121:447-454.