Abstract
During aerobic exercise, women oxidize significantly more lipids and less carbohydrates than men. This sexual dimorphism in substrate metabolism has been attributed, in part, to the observed differences in epinephrine and glucagon levels between men and women during exercise. To identify the underpinning candidate physiological mechanisms for these sex differences, we developed a sex-specific multi-scale mathematical model that relates cellular metabolism in the organs to whole-body responses during exercise. We conducted simulations to test the hypothesis that sex differences in the exercise-induced changes to epinephrine and glucagon would result in the sexual dimorphism of hepatic metabolic flux rates via the glucagon-to-insulin ratio (GIR). Indeed, model simulations indicate that the shift towards lipid metabolism in the female model is primarily driven by the liver. The female model liver exhibits resistance to GIR-mediated glycogenolysis, which helps maintain hepatic glycogen levels. This decreases arterial glucose levels and promotes the oxidation of free fatty acids. Furthermore, in the female model, skeletal muscle relies on plasma free fatty acids as the primary fuel source, rather than intramyocellular lipids, whereas the opposite holds true for the male model.
Similar content being viewed by others
Data Availability
The code and data that support the findings of this study are openly available on GitHub: https://github.com/Layton-Lab/Sex-Specific-Exercise-Model.git.
References
Abo S, Smith D, Stadt M, Layton A (2022) Modelling female physiology from head to toe: impact of sex hormones, menstrual cycle, and pregnancy. J Theor Biol 540:111074. https://doi.org/10.1016/j.jtbi.2022.111074
Ahrén B (2000) Autonomic regulation of islet hormone secretion-implications for health and disease. Diabetologia 43:393–410. https://doi.org/10.1007/s001250051322
Arner P, Kriegholm E, Engfeldt P, Bolinder J et al (1990) Adrenergic regulation of lipolysis in situ at rest and during exercise. J Clin Invest 85(3):893–898. https://doi.org/10.1172/JCI114516
Bailey SP, Zacher CM, Mittleman KD (2000) Effect of menstrual cycle phase on carbohydrate supplementation during prolonged exercise to fatigue. J Appl Physiol 88(2):690–697. https://doi.org/10.1152/jappl.2000.88.2.690
Benoit V, Valette A, Mercier L, Meignen J, Boyer J (1982) Potentiation of epinephrine-induced lipolysis in fat cells from estrogen-treated rats. Biochem Biophys Res Commun 109(4):1186–1191. https://doi.org/10.1016/0006-291X(82)91902-7
Bergström J, Hultman E (1966) Muscle glycogen synthesis after exercise: an enhancing factor localized to the muscle cells in man. Nature 210(5033):309–310. https://doi.org/10.1038/210309a0
Blatchford FK, Knowlton RG, Schneider DA (1985) Plasma FFA responses to prolonged walking in untrained men and women. Eur J Appl Physiol Occup Physiol 53(4):343–347. https://doi.org/10.1007/BF00422851
Brundin T, Wahren J (1993) Whole body and splanchnic oxygen consumption and blood flow after oral ingestion of fructose or glucose. Am J Physiol Endocrinol Metab 264(4):504–513. https://doi.org/10.1152/ajpendo.1993.264.4.E504
Burguera B, Proctor D, Dietz N, Guo Z, Joyner M, Jensen MD (2000) Leg free fatty acid kinetics during exercise in men and women. Am J Physiol Endocrinol Metab 278(1):113–117. https://doi.org/10.1152/ajpendo.2000.278.1.E113
Cabrera ME, Saidel GM, Kalhan SC (1998) Role of o2 in regulation of lactate dynamics during hypoxia: mathematical model and analysis. Ann Biomed Eng 26(1):1–27. https://doi.org/10.1114/1.28
Cabrera ME, Saidel GM, Kalhan SC (1999) Lactate metabolism during exercise: analysis by an integrative systems model. Am J Physiol Regul Integr Comp Physiol 277(5):1522–1536. https://doi.org/10.1152/ajpregu.1999.277.5.R1522
Campbell S, Febbraio M (2002) Effect of the ovarian hormones on glut4 expression and contraction-stimulated glucose uptake. Am J Physiol Endocrinol Metab 282(5):1139–1146. https://doi.org/10.1152/ajpendo.00184.2001
Campbell S, Angus D, Febbraio M (2001) Glucose kinetics and exercise performance during phases of the menstrual cycle: effect of glucose ingestion. Am J Physiol Endocrinol Metab. https://doi.org/10.1152/ajpendo.2001.281.4.E817
Cano A, Ventura L, Martinez G, Cugusi L, Caria M, Deriu F, Manca A (2022) Analysis of sex-based differences in energy substrate utilization during moderate-intensity aerobic exercise. Eur J Appl Physiol. https://doi.org/10.1007/s00421-021-04802-5
Carter S, Rennie C, Tarnopolsky M (2001) Substrate utilization during endurance exercise in men and women after endurance training. Am J Physiol Endocrinol Metab. https://doi.org/10.1152/ajpendo.2001.280.6.E898
Carter S, McKenzie S, Mourtzakis M, Mahoney D, Tarnopolsky M (2001) Short-term 17\(\beta \)-estradiol decreases glucose RA but not whole body metabolism during endurance exercise. J Appl Physiol 90(1):139–146. https://doi.org/10.1152/jappl.2001.90.1.139
Cheneviere X, Borrani F, Sangsue D, Gojanovic B, Malatesta D (2011) Gender differences in whole-body fat oxidation kinetics during exercise. Appl Physiol Nutr Metab 36(1):88–95. https://doi.org/10.1139/H10-086
Chowdhury B, Sjöström L, Alpsten M, Kostanty J, Kvist H, Löfgren R (1994) A multicompartment body composition technique based on computerized tomography. Int J Obes Relat Metab Disord 18(4):219–234
Cvitanović Tomaš T, Urlep Ž, Moškon M, Mraz M, Rozman D (2018) Liversex computational model: sexual aspects in hepatic metabolism and abnormalities. Front Physiol 9:360. https://doi.org/10.3389/fphys.2018.00360
Dash RK, DiBella JA, Cabrera ME (2007) A computational model of skeletal muscle metabolism linking cellular adaptations induced by altered loading states to metabolic responses during exercise. Biomed Eng Online 6(1):1–28. https://doi.org/10.1186/1475-925X-6-14
Davis SN, Galassetti P, Wasserman DH, Tate D (2000) Effects of gender on neuroendocrine and metabolic counterregulatory responses to exercise in normal man. J Clin Endocrinol Metab 85(1):224–230. https://doi.org/10.1210/jcem.85.1.6328
Davis SN, Galassetti P, Wasserman DH, Tate D (2000) Effects of gender on neuroendocrine and metabolic counterregulatory responses to exercise in normal man1. J Clin Endocrinol Metab 85(1):224–230. https://doi.org/10.1210/jcem.85.1.6328
D’Eon TM, Sharoff C, Chipkin SR, Grow D, Ruby BC, Braun B (2002) Regulation of exercise carbohydrate metabolism by estrogen and progesterone in women. Am J Physiol Endocrinol Metab 283(5):1046–1055. https://doi.org/10.1152/ajpendo.00271.2002
Deuster PA, Heled Y (2008) Chapter 41-testing for maximal aerobic power. In: Seidenberg PH, Beutler AI (eds) The sports medicine resource manual. W.B. Saunders, Philadelphia, pp 520–528. https://doi.org/10.1016/B978-141603197-0.10069-2
Devries MC (2016) Sex-based differences in endurance exercise muscle metabolism: impact on exercise and nutritional strategies to optimize health and performance in women. Exp Physiol 101(2):243–249. https://doi.org/10.1113/EP085369
Devries MC, Hamadeh MJ, Phillips SM, Tarnopolsky MA (2006) Menstrual cycle phase and sex influence muscle glycogen utilization and glucose turnover during moderate-intensity endurance exercise. Am J Physiol Regul Integr Comp Physiol. https://doi.org/10.1152/ajpregu.00700.2005
Devries MC, Lowther SA, Glover AW, Hamadeh MJ, Tarnopolsky MA (2007) IMCL area density, but not IMCL utilization, is higher in women during moderate-intensity endurance exercise, compared with men. Am J Physiol Regul Integr Comp Physiol 293(6):2336–2342. https://doi.org/10.1152/ajpregu.00510.2007
Doglioni C, Gambacorta M, Zamboni G, Coggi G, Viale G (1990) Immunocytochemical localization of progesterone receptors in endocrine cells of the human pancreas. Am J Pathol 137(5):999
Frayn KN (2009) Metabolic regulation: a human perspective, 3rd edn. Wiley, Oxford, pp 33–37
Friedlander AL, Casazza GA, Horning MA, Huie MJ, Piacentini MF, Trimmer JK, Brooks GA (1998) Training-induced alterations of carbohydrate metabolism in women: women respond differently from men. J Appl Physiol 85(3):1175–1186. https://doi.org/10.1152/jappl.1998.85.3.1175
Gustafsson J-A, Mode A, Norstedt G, Skett P (1983) Sex steroid induced changes in hepatic enzymes. Annu Rev Physiol 45(1):51–60. https://doi.org/10.1146/annurev.ph.45.030183.000411
Hansen FM, Fahmy N, Nielsen JH (1980) The influence of sexual hormones on lipogenesis and lipolysis in rat fat cells. Eur J Endocrinol 95(4):566–570. https://doi.org/10.1530/acta.0.0950566
Hatta H, Atomi Y, Shinohara S, Yamamoto Y, Yamada S (1988) The effects of ovarian hormones on glucose and fatty acid oxidation during exercise in female ovariectomized rats. Horm Metab Res 20(10):609–611. https://doi.org/10.1055/s-2007-1010897
Heinemann A, Wischhusen F, Püschel K, Rogiers X (1999) Standard liver volume in the Caucasian population. Liver Transpl Surg 5(5):366–368. https://doi.org/10.1002/lt.500050516
Heinonen I, Kalliokoski KK, Hannukainen JC, Duncker DJ, Nuutila P, Knuuti J (2014) Organ-specific physiological responses to acute physical exercise and long-term training in humans. Physiology. https://doi.org/10.1152/physiol.00067.2013
Hernández-Cascales J (2018) Does glucagon have a positive inotropic effect in the human heart? Cardiovasc Diabetol 17(1):148. https://doi.org/10.1186/s12933-018-0791-z
Hirsch I, Marker JC, Smith LJ, Spina RJ, Parvin C, Holloszy J, Cryer P (1991) Insulin and glucagon in prevention of hypoglycemia during exercise in humans. Am J Physiol Endocrinol Metab 260(5):695–704. https://doi.org/10.1152/ajpendo.1991.260.5.E695
Ho K-C, Roessmann U, Straumfjord J, Monroe G (1980) Analysis of brain weight. i. Adult brain weight in relation to sex, race, and age. Arch Pathol Lab Med 104(12):635–639
Horton TJ, Pagliassotti MJ, Hobbs K, Hill JO (1998) Fuel metabolism in men and women during and after long-duration exercise. J Appl Physiol 85(5):1823–1832. https://doi.org/10.1152/jappl.1998.85.5.1823
Horton TJ, Miller EK, Glueck D, Tench K (2002) No effect of menstrual cycle phase on glucose kinetics and fuel oxidation during moderate-intensity exercise. Am J Physiol Endocrinol Metab 282(4):752–762. https://doi.org/10.1152/ajpendo.00238.2001
Horton TJ, Grunwald GK, Lavely J, Donahoo WT (2006) Glucose kinetics differ between women and men, during and after exercise. J Appl Physiol 100(6):1883–1894. https://doi.org/10.1152/japplphysiol.01431.2005
Hunter SK (2014) Sex differences in human fatigability: mechanisms and insight to physiological responses. Acta Physiol (Oxf) 210(4):768–789. https://doi.org/10.1111/apha.12234
ICRP: Annual Report of the International Commission on Radiological Protection 2002. Pergamon Press, Oxford (2003)
Janah L, Kjeldsen S, Galsgaard KD, Winther-Sørensen M, Stojanovska E, Pedersen J, Knop FK, Holst JJ, Wewer Albrechtsen NJ (2019) Glucagon receptor signaling and glucagon resistance. Int J Mol Sci 20(13):3314. https://doi.org/10.3390/ijms20133314
Joyner MJ, Casey DP (2015) Regulation of increased blood flow (hyperemia) to muscles during exercise: a hierarchy of competing physiological needs. Physiol Rev. https://doi.org/10.1152/physrev.00035.2013
Kalkhoff RK (1982) Metabolic effects of progesterone. Am J Obstet Gynecol 142(6):735–738. https://doi.org/10.1016/S0002-9378(16)32480-2
Karastergiou K, Smith SR, Greenberg AS, Fried SK (2012) Sex differences in human adipose tissues-the biology of pear shape. Biol Sex Differ 3(1):1–12. https://doi.org/10.1186/2042-6410-3-13
Kim J, Saidel GM, Cabrera ME (2006) Multi-scale computational model of fuel homeostasis during exercise: effect of hormonal control. Ann Biomed Eng. https://doi.org/10.1007/s10439-006-9201-x
Krekels EHJ, Rower JE, Constance JE, Knibbe CAJ, Sherwin CMT (2017) Chapter 8-hepatic drug metabolism in pediatric patients. In: Xie W (ed) Drug metabolism in diseases. Academic Press, Boston, pp 181–206. https://doi.org/10.1016/B978-0-12-802949-7.00008-0
Lavoie J-M, Dionne N, Helie R, Brisson G (1987) Menstrual cycle phase dissociation of blood glucose homeostasis during exercise. J Appl Physiol 62(3):1084–1089. https://doi.org/10.1152/jappl.1987.62.3.1084
Layton AT (2021) His and her mathematical models of physiological systems. Math Biosci 338:108642. https://doi.org/10.1016/j.mbs.2021.108642
Loon LJ, Greenhaff PL, Constantin-Teodosiu D, Saris WH, Wagenmakers AJ (2001) The effects of increasing exercise intensity on muscle fuel utilisation in humans. J Physiol 536(1):295–304. https://doi.org/10.1111/j.1469-7793.2001.00295.x
Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90(1):207–258. https://doi.org/10.1152/physrev.00015.2009
Marie LS, Palmiter RD (2003) Norepinephrine and epinephrine-deficient mice are hyperinsulinemic and have lower blood glucose. Endocrinology 144(10):4427–4432. https://doi.org/10.1210/en.2003-0561
Marliss EB, Kreisman SH, Manzon A, Halter JB, Vranic M, Nessim SJ (2000) Gender differences in glucoregulatory responses to intense exercise. J Appl Physiol 88(2):457–466. https://doi.org/10.1152/jappl.2000.88.2.457
McGregor AJ, Hasnain M, Sandberg K, Morrison MF, Berlin M, Trott J (2016) How to study the impact of sex and gender in medical research: a review of resources. Biol Sex Differ 7:61–72. https://doi.org/10.1186/s13293-016-0099-1
Mittendorfer B, Horowitz JF, Klein S (2002) Effect of gender on lipid kinetics during endurance exercise of moderate intensity in untrained subjects. Am J Physiol Endocrinol Metab 283(1):58–65. https://doi.org/10.1152/ajpendo.00504.2001
Müller MJ, Langemann D, Gehrke I, Later W, Heller M, Glüer CC, Heymsfield SB, Bosy-Westphal A (2011) Effect of constitution on mass of individual organs and their association with metabolic rate in humans-a detailed view on allometric scaling. PLoS ONE 6(7):22732. https://doi.org/10.1371/journal.pone.0022732
Müller MJ, Bosy-Westphal A, Braun W, Wong MC, Shepherd JA, Heymsfield SB (2022) What is a 2021 reference body? Nutrients 14(7):1526. https://doi.org/10.3390/nu14071526
Oosthuyse T, Bosch AN (2012) Oestrogen’s regulation of fat metabolism during exercise and gender specific effects. Curr Opin Pharmacol 12(3):363–371. https://doi.org/10.1016/j.coph.2012.02.008
Palmisano BT, Zhu L, Stafford JM (2017). In: Mauvais-Jarvis F (ed) Role of estrogens in the regulation of liver lipid metabolism. Springer, Cham, pp 227–256. https://doi.org/10.1007/978-3-319-70178-3_12
Palmisano BT, Zhu L, Eckel RH, Stafford JM (2018) Sex differences in lipid and lipoprotein metabolism. Mol Metab 15:45–55. https://doi.org/10.1016/j.molmet.2018.05.008
Palumbo MC, Morettini M, Tieri P, Diele F, Sacchetti M, Castiglione F (2018) Personalizing physical exercise in a computational model of fuel homeostasis. PLoS Comput Biol 14(4):1006073. https://doi.org/10.1371/journal.pcbi.1006073
Pate R, Sargent R, Baldwin C, Burgess M (1990) Dietary intake of women runners. Int J Sports Med 11(06):461–466. https://doi.org/10.1055/s-2007-1024838
Piña IL, Apstein CS, Balady GJ, Belardinelli R, Chaitman BR, Duscha BD, Fletcher BJ, Fleg JL, Myers JN, Sullivan MJ (2003) Exercise and heart failure: a statement from the American heart association committee on exercise, rehabilitation, and prevention. Circulation 107(8):1210–1225. https://doi.org/10.1161/01.CIR.0000055013.92097.40
Price PS, Conolly RB, Chaisson CF, Gross EA, Young JS, Mathis ET, Tedder DR (2003) Modeling interindividual variation in physiological factors used in PBPK models of humans. Crit Rev Toxicol 33(5):469–503. https://doi.org/10.1080/10408440390242324
Qiu S, Vazquez JT, Boulger E, Liu H, Xue P, Hussain MA, Wolfe A (2017) Hepatic estrogen receptor \(\alpha \) is critical for regulation of gluconeogenesis and lipid metabolism in males. Sci Rep 7(1):1661. https://doi.org/10.1038/s41598-017-01937-4
Ramos-Jiménez A, Hernández-Torres RP, Torres-Durán PV, Romero-Gonzalez J, Mascher D, Posadas-Romero C, Juárez-Oropeza MA (2008) The respiratory exchange ratio is associated with fitness indicators both in trained and untrained men: a possible application for people with reduced exercise tolerance. Clin Med Circ Respirat Pulm Med 2:449. https://doi.org/10.4137/ccrpm.s449
Roepstorff C, Steffensen CH, Madsen M, Stallknecht B, Kanstrup I-L, Richter EA, Kiens B (2002) Gender differences in substrate utilization during submaximal exercise in endurance-trained subjects. Am J Physiol Endocrinol Metab 282(2):435–447. https://doi.org/10.1152/ajpendo.00266.2001
Romijn JA, Coyle E, Sidossis L, Gastaldelli A, Horowitz J, Endert E, Wolfe R (1993) Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. Am J Physiol Endocrinol Metab 265(3):380–391. https://doi.org/10.1152/ajpendo.1993.265.3.E380
Ruby BC, Robergs RA, Waters DL, Burge M, Mermier C, Stolarczyk L (1997) Effects of estradiol on substrate turnover during exercise in amenorrheic females. Med Sci Sports Exerc 29(9):1160–1169. https://doi.org/10.1097/00005768-199709000-00007
Saunders PT, Koeslag JH, Wessels JA (1998) Integral rein control in physiology. J Theor Biol 194(2):163–173. https://doi.org/10.1006/jtbi.1998.0746
Shen M, Shi H et al (2015) Sex hormones and their receptors regulate liver energy homeostasis. Int J Endocrinol. https://doi.org/10.1155/2015/294278
Snyder WS, Cook M, Nasset E, Karhausen L, Tipton IH (1975) Report of the task group on reference man. Pergamon Press, Oxford
Soldin OP, Mattison DR (2009) Sex differences in pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 48(3):143–157. https://doi.org/10.2165/00003088-200948030-00001
Tarnopolsky L, MacDougall J, Atkinson S, Tarnopolsky M, Sutton J (1990) Gender differences in substrate for endurance exercise. J Appl Physiol 68(1):302–308. https://doi.org/10.1152/jappl.1990.68.1.302
Tarnopolsky M, Atkinson S, Phillips S, MacDougall J (1995) Carbohydrate loading and metabolism during exercise in men and women. J Appl Physiol 78(4):1360–1368. https://doi.org/10.1152/jappl.1995.78.4.1360
Tarnopolsky M, Bosman M, Macdonald J, Vandeputte D, Martin J, Roy B (1997) Postexercise protein-carbohydrate and carbohydrate supplements increase muscle glycogen in men and women. J Appl Physiol 83(6):1877–1883. https://doi.org/10.1152/jappl.1997.83.6.1877
Thiele I, Sahoo S, Heinken A, Hertel J, Heirendt L, Aurich MK, Fleming RM (2020) Personalized whole-body models integrate metabolism, physiology, and the gut microbiome. Mol Syst Biol 16(5):8982. https://doi.org/10.15252/msb.20198982
Van Loon LJ, Koopman R, Stegen JH, Wagenmakers AJ, Keizer HA, Saris WH (2003) Intramyocellular lipids form an important substrate source during moderate intensity exercise in endurance-trained males in a fasted state. J Physiol 553(2):611–625. https://doi.org/10.1113/jphysiol.2003.052431
Varlamov O, Bethea CL, Roberts CT Jr (2015) Sex-specific differences in lipid and glucose metabolism. Front Endocrinol 5:241. https://doi.org/10.3389/fendo.2014.00241
Wasserman DH, Vranic M (1986) Interaction between insulin and counterregulatory hormones in control of substrate utilization in health and diabetes during exercise. Diabetes Metab Rev 1(4):359–384. https://doi.org/10.1002/dmr.5610010403
Welle S, Tawil R, Thornton CA (2008) Sex-related differences in gene expression in human skeletal muscle. PLoS ONE 3(1):1385. https://doi.org/10.1371/journal.pone.0001385
Zouhal H, Jacob C, Delamarche P, Gratas-Delamarche A (2008) Catecholamines and the effects of exercise, training and gender. Sports Med 38:401–423. https://doi.org/10.2165/00007256-200838050-00004
Acknowledgements
This work was supported by the Canadian Institutes of Health Research (CIHR) and the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery award.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Abo, S.M.C., Casella, E. & Layton, A.T. Sexual Dimorphism in Substrate Metabolism During Exercise. Bull Math Biol 86, 17 (2024). https://doi.org/10.1007/s11538-023-01242-4
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11538-023-01242-4