Low energy availability, not exercise stress, suppresses the diurnal rhythm of Leptin in healthy young women
Open accessAbstract
Because the effect of exercise on leptin was not established, we controlled energy intake (I) and exercise energy expenditure (E) to distinguish the independent effects of energy availability (A = I − E) and exercise stress (everything associated with exercise except its energy cost) on the diurnal leptin rhythm in healthy young women. In random order, we set A = 45 and 10 kcal ⋅ kg lean body mass−1(LBM) ⋅ day−1 for 4 days during the early follicular phase of separate menstrual cycles in sedentary (S, n = 7) and exercising (X, n = 9: E = 30 kcal ⋅ kg LBM−1 ⋅ day−1) women. Low energy availability suppressed the 24-h mean ( P < 10−6) and amplitude ( P < 10−5), whereas exercise stress did not (both P> 0.2). Suppressions of the 24-h mean (−72 ± 3 vs. −53 ± 3%, P < 0.001) and amplitude (−85 ± 3 vs. −58 ± 6%, P < 0.001) were more extreme in S vs. X than previously reported effects on luteinizing hormone pulsatility and carbohydrate availability. Thus the diurnal rhythm of leptin depends on energy, or carbohydrate, availability, not intake, and exercise has no suppressive effect on the diurnal rhythm of leptin beyond the impact of its energy cost on energy availability.
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Studies of LEA exposure have identified a somewhat more prominent effect of poor EI, rather than excessive EEE, in causing most of the physiological perturbations.
“Studies of LEA exposure have identified a somewhat more prominent effect of poor EI, rather than excessive EEE, in causing most of the physiological perturbations.127 160”
From 2023 international olympic committee's (IOC) consensus statement on relative energy deficiency in sport (REDs) (2023) · cites this paper as [160]
The paper’s summary (in the section labeled “Associated effects on LH pulsatility,” pp. E43–E49) reports that low energy availability suppressed leptin rhythms, and that the effects were greater when low availability was caused by dietary restriction than by exercise energy expenditure. This supports the intake-versus-expenditure comparison for leptin, but the paper does not establish that poor energy intake causes most physiological perturbations generally. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn the same study, leptin levels decreased by 50% in response to dietary restriction, and this difference is proportional to reductions in carbohydrate intake.
“In this same study, leptin levels decreased by 50% in response to dietary restriction, and this difference is proportional to the reductions in CHO intake [45].”
From Considerations of Low Carbohydrate Availability (LCA) to Relative Energy Deficiency in Sport (RED-S) in Female Endurance Athletes: A Narrative Review (2023) · cites this paper as [45]
The Carbohydrate availability section says leptin falls by 50% during dietary restriction and declines in proportion to reduced dietary carbohydrate, but cites Jenkins et al. (reference 15) for both statements. The Energy availability section reports a 72% reduction in 24-hour mean leptin in this paper’s own dietary-restriction experiment. Thus the findings are reported in the source, but the claim incorrectly presents the 50% figure as a result of this same study. (LLM, conf=0.91)
Experimental — accuracy not yet measuredLH pulsatility may depend on CHO as opposed to EA, as evidenced by disruption to LH pulsatility at a level of CHO availability between 90-130 g/d of glucose.
“Furthermore, luteinizing hormone (LH) pulse frequency suggests that LH pulsatility may depend on CHO as opposed to EA, as evidenced by disruption to LH pulsatility at a level of CHO availability between 90–130 g/d of glucose [23,45].”
From Considerations of Low Carbohydrate Availability (LCA) to Relative Energy Deficiency in Sport (RED-S) in Female Endurance Athletes: A Narrative Review (2023) · cites this paper as [45]
The ‘Associated effects on LH pulsatility’ section suggests that LH pulsatility may depend on carbohydrate rather than energy availability. It does not report disruption of LH pulsatility specifically at 90–130 g/day of glucose; the ‘Carbohydrate availability’ section gives different quantities and discusses glucose infusion in relation to leptin suppression. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSkeletal muscle alters its fuel source in response to low energy availability conditions, oxidizing less carbohydrate and more fat during exercise.
“it has been demonstrated that skeletal muscle alters its fuel source in response to LEA conditions, oxidizing less CHO and more fat during exercise [45].”
From Considerations of Low Carbohydrate Availability (LCA) to Relative Energy Deficiency in Sport (RED-S) in Female Endurance Athletes: A Narrative Review (2023) · cites this paper as [45]
In two conditions of identical low energy availability, carbohydrate availability was 57% higher in women who reduced energy availability via exercise compared to reduced energy availability via dietary restriction.
“In two conditions of identical LEA (with one achieved from dietary restriction and the other one achieved from exercise), CHO availability was 57% higher in women who reduced EA via exercise compared to reduced EA via dietary restriction [45].”
From Considerations of Low Carbohydrate Availability (LCA) to Relative Energy Deficiency in Sport (RED-S) in Female Endurance Athletes: A Narrative Review (2023) · cites this paper as [45]
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“Previous studies determined the influence of low EA onmetabolic hormones (leptin, insulin-like growth factor 1 [IGF-1], triiodothyronine, insulin) and reproductive hormones in both women (12,13) and men (14) in a controlled laboratory setting.”
BackgroundKeller, P., Keller, C., Steensberg, A., Robinson, L., & Pedersen, B. (2005) · Journal of applied physiology · doi:10.1152/japplphysiol.00592.2004 · Cited by 55 · see citing works
“was counteracted by CHO ingestion, which indicates sensitivity to energy availability or to hormones affected by the presence of CHO, as previously shown in rodents (35) and in humans (1, 15).”
BackgroundMars, M., de Graaf, C., de Groot, L. C. P. G. M., & Kok, F. (2005) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/81.3.570 · Cited by 54 · see citing works
“Several studies have shown that, during energy restriction, not only fasting leptin concentrations, but also the diurnal variation of these concentrations, is decreased (26, 27).”
BackgroundPoppitt, S. D., Leahy, F. E., Keogh, G. F., Wang, Y., Mulvey, T. B., Stojkovic, M., Chan, Y., Choong, Y. S., McArdle, B. H., & Cooper, G. J. S. (2005) · European Journal of Clinical Nutrition · doi:10.1038/sj.ejcn.1602270 · Cited by 53 · see citing works
“Fasting (Boden et al., 1996; Kolaczynski et al., 1996a; Weigle et al., 1997) and exercise (Hilton, 2000) cause an acute drop, and overfeeding a rise (Kolaczynski et al., 1996a) in leptin.”
BackgroundRelative Energy Deficiency in Sport (RED-S) in Adolescents – A Practical Review
Gould, R., Ridout, A., & Newton, J. (2021) · International Journal of Sports Medicine · doi:10.1055/a-1947-3174 · Cited by 51 · see citing works
“There is suppression of the normal diurnal rhythm of the anorexigenic hormone leptin, which is independent of exer - cise stress [62], adiponectin is raised in dancers with LEA [63], the orexigenic hormone ghrelin is raised in low energy states [64], and the appetite suppressant Peptide YY is…”
BackgroundWilliams, N., Statuta, S. M., & Austin, A. V. (2017) · Clinics in Sports Medicine · doi:10.1016/j.csm.2017.05.003 · Cited by 51 · see citing works
Ghrelin but Not Peptide YY Is Related to Change in Body Weight and Energy Availability
Scheid, J. L., Souza, M. J. D., Leidy, H. J., & Williams, N. I. (2011) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0b013e31821e52ab · Cited by 38 · see citing works
“(6) have shown that energy availability has been slTongly related fo changes in metabolic hormones such as triiodofhyronine (33), leptin (23), and ghrelin (6) in exercising women.”
BackgroundInfluentialEffects of exercise combined with caloric restriction on inflammatory cytokines
Reed, J. L., Souza, M. J. D., & Williams, N. I. (2010) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/h10-046 · Cited by 42 · see citing works
“More research is required to elucidate the mechanism underlying these changes (Hilton and Loucks 2000; Howell et al. 2009).”
BackgroundCurrent Status of the Female Athlete Triad: Update and Future Directions
Souza, M. D. D., Koltun, K. J., Etter, C. V., & Southmayd, E. A. (2017) · Current Osteoporosis Reports · doi:10.1007/s11914-017-0412-x · Cited by 47 · see citing works
Sports medicine in the Netherlands
Durstine, J. L., Thompson, R. W., Drowatzky, K., & Bartoli, W. (2001) · British Journal of Sports Medicine · doi:10.1136/bjsm.35.1.5 · Cited by 47
Hickey, M., & Calsbeek, D. (2001) · Sports Medicine · doi:10.2165/00007256-200131080-00003 · Cited by 45 · see citing works
“As Hilton and Loucks[20] suggest, this would imply that there is a threshold reduction in energy availability that must be reached to alter the”
BackgroundInfluentialModified activity-stress paradigm in an animal model of the female athlete triad.
DiMarco, N., Dart, L., & Sanborn, C. (2007) · Journal of applied physiology · doi:10.1152/japplphysiol.01137.2005 · Cited by 44 · see citing works
“The anabolic effects of voluntary wheel running in ad libitum-fed rats have been shown to have a positive and significant impact on multiple axial and appendicular skeletal sites (9, 35, 40, 66, 90, 96).”
BackgroundSaeidi, A., Haghighi, M. M., Kolahdouzi, S., Daraei, A., Abderrahman, A. B., Essop, M. F., Laher, I., Hackney, A. C., & Zouhal, H. (2020) · Obesity Reviews · doi:10.1111/obr.13090 · Cited by 48 · see citing works
“and this depends on energy defects during excess post-exercise oxygen consumption.(216,217) However, extended exercise periods decrease leptin concentrations more immediately,(218) and this is likely due to lower leptin mRNA expression levels.”
BackgroundWhipple, T., Sharkey, N., Demers, L., & Williams, N. (2002) · Clinical Endocrinology · doi:10.1046/j.1365-2265.2002.01630.x · Cited by 41 · see citing works
Circulating leptin concentrations do not distinguish menstrual status in exercising women
Corr, M., Souza, M. J. D., Toombs, R. J., & Williams, N. I. (2011) · Human Reproduction · doi:10.1093/humrep/deq375 · Cited by 36 · see citing works
The Olympic textbook of medicine in sport
Schwellnus, M. (2008) · Wiley eBooks · doi:10.1002/9781444300635 · Cited by 39 · see citing works
“Subsequent investigations have reinforced this finding in both human and nonhuman primates (Hilton & Loucks 2000; Williams et al. 2001a,b).”
BackgroundMatthews, B., Bennell, K., McKay, H., Khan, K., Baxter-Jones, A., Mirwald, R., & Wark, J. (2006) · Annals of Human Biology · doi:10.1080/03014460600635951 · Cited by 39 · see citing works
Energy availability and infertility
Loucks, A. (2007) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0b013e3282f1cb6a · Cited by 38 · see citing works
Self-citationLeptin responses to glucose infusions in obesity-prone rats.
Levy, J. R., Lesko, J. M., Krieg, R. J., Adler, R. A., & Stevens, W. (2000) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.279.5.e1088 · Cited by 35 · see citing works
“A diurnal variation of plasma leptin has been observed in humans (55), and the diurnal rhythm of plasma leptin has been shown to be entrained to meal timing (52) and to be dependent on energy availability (24).”
BackgroundA Review of Nonpharmacological Strategies in the Treatment of Relative Energy Deficiency in Sport.
Kuikman, M., Mountjoy, M., Stellingwerff, T., & Burr, J. (2021) · International Journal of Sport Nutrition & Exercise Metabolism · doi:10.1123/ijsnem.2020-0211 · Cited by 34 · see citing works
“LEA suppresses leptin levels in both females (Hilton & Loucks, 2000) and males (Dubuc et al., 1998; Koehler, Hoerner, et al., 2016).”
BackgroundImpact of Body Mass Index on female fertility and ART outcomes
Imterat, M., Agarwal, A. K., Esteves, S. C., Meyer, J., & Harlev, A. (2019) · Panminerva Medica · doi:10.23736/s0031-0808.18.03490-0 · Cited by 42 · see citing works
Marathon Running: Physiology, Psychology, Nutrition and Training Aspects
Zinner, C., & Sperlich, B. (2016) · Cambridge International Law Journal · doi:10.1007/978-3-319-29728-6 · Cited by 34
“Gender and hormonal factors contribute to a higher risk of bone stress injury in women than men, particularly female athletes participating in leanness and endurance-focused sports (i.e. long-distance running) (Ihle and Loucks 2004; Hilton and Loucks 2000; Lawson et al. 2009).”
BackgroundLodge, M. T., Ward-Ritacco, C. L., & Melanson, K. J. (2023) · Nutrients · doi:10.3390/nu15204457 · Cited by 33 · see citing works
“In this same study, leptin levels decreased by 50% in response to dietary restriction, and this difference is proportional to the reductions in CHO intake [45].”
BackgroundInfluentialAppetite regulation in response to sitting and energy imbalance
Granados, K. E., Stephens, B. R., Malin, S. K., Zderic, T. W., Hamilton, M. T., & Braun, B. (2012) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/h2012-002 · Cited by 39 · see citing works
de Assis, G. D., & Murawska-Ciałowicz, E. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12134490 · Cited by 32 · see citing works
“The study by Hilton & Loucks [31] examined the effects of energy availability and exercise on diurnal leptin rhythms in non-overweight, young women by controlling energy”
BackgroundInfluentialKing, J. A., Garnham, J. O., Jackson, A. P., Kelly, B. M., Xenophontos, S., & Nimmo, M. A. (2015) · Physiology & Behavior · doi:10.1016/j.physbeh.2014.12.050 · Cited by 32 · see citing works
“Existing work has shown that circulating levels of leptin are highly responsive to alterations in energy balance/availability [44,45].”
A Displaced Femoral Neck Stress Fracture in an Amenorrheic Adolescent Female Runner
Goolsby, M. A., Barrack, M., & Nattiv, A. (2012) · Sports health · doi:10.1177/1941738111429929 · Cited by 32 · see citing works
“Previous research studies indicate that, in addition to menstrual dysfunction, chronic energy deficiency leads to hypothalamic and pituitary hormonal disturbances that negatively affect bone metabolism.(8,15,16) In a study of regularly menstruating young women, dietary intake and exercise expenditure were controlled f…”
BackgroundPlasma Leptin, Plasma Zinc, and Plasma Copper Are Associated in Elite Female and Male Judo Athletes
Casimiro-Lopes, G., de Oliveira-Junior, A. V., Portella, E. S., Lisboa, P., Donangelo, C., de Moura, E. D., & Koury, J. (2009) · Biological Trace Element Research · doi:10.1007/s12011-008-8236-2 · Cited by 32
“Many authors suggest that the hexosamine pathway could be related with leptin regulation in exercised individuals when the drop in leptinemia is not proportional to fat mass reduction [29, 33–35].”
BackgroundRahmani-Nia, F., Rahnama, N., Hojjati, Z., & Soltani, B. (2008) · Sport Sciences for Health · doi:10.1007/s11332-008-0050-x · Cited by 32 · see citing works
“There is clear evidence for the importance of exact control of energy balance in leptin and exercise studies [9].”
BackgroundInfluentialLegakis, I., Mantzouridis, T., Saramantis, A., & Lakka-Papadodima, E. (2004) · Journal of Endocrinological Investigation · doi:10.1007/bf03346255 · Cited by 29 · see citing works
Leptin signaling in skeletal muscle after bed rest in healthy humans
Guerra, B., Ponce-González, J., Morales‐Alamo, D., Guadalupe-Grau, A., Kiilerich, K., Fuentes, T., Ringholm, S., Biensø, R., Santana, A., Lundby, C., et al. (2013) · European Journal of Applied Physiology · doi:10.1007/s00421-013-2779-4 · Cited by 28 · see citing works
Changes in serum leptin levels in strenuous exercise and its relation to zinc deficiency in rats
Gökbel, H., Baltacı, A., Uçok, K., Okudan, N., & Mogulkoc, R. (2005) · Biological Trace Element Research · doi:10.1385/bter:106:3:247 · Cited by 28
“The diurnal rhythm of leptin depends on energy availability, not intake (4).”
BackgroundEndocrine rhythms and sport: it is time to take time into account
Bellastella, G., Bellis, A. D., Maiorino, M., Paglionico, V. A., Esposito, K., & Bellastella, A. (2019) · Journal of Endocrinological Investigation · doi:10.1007/s40618-019-01038-1 · Cited by 27 · see citing works
Plasma leptin and energy expenditure during prolonged, moderate intensity, treadmill exercise
Zaccaria, M., Ermolao, A., Brugin, E., & Bergamin, M. (2012) · Journal of Endocrinological Investigation · doi:10.3275/8656 · Cited by 27 · see citing works
Braun, B., & Brooks, G. (2008) · Exercise and sport sciences reviews · doi:10.1097/jes.0b013e31815e42c2 · Cited by 27 · see citing works
“To address the question in a systematic way, Loucks and colleagues performed definitive studies in which they tested the hypothesis that energy deficit, not exercise itself, explained the disrupted menstrual function.”
BackgroundInfluentialLeptina: aspectos sobre o balanço energético, exercício físico e amenorréia do esforço
Ribeiro, S. M. L., dos Santos, Z. A., da Silva, R. J., Eliana, L. R., Donato, J., & Tirapegui, J. (2007) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/s0004-27302007000100005 · Cited by 18 · see citing works
Physical health of the female athlete: observations, effects, and causes of reproductive disorders.
Loucks, A. (2001) · Canadian Journal of Applied Physiology · doi:10.1139/h2001-052 · Cited by 27 · see citing works
Self-citationRecovery of menses after functional hypothalamic amenorrhoea: if, when and why
Pape, J., Herbison, A. E., & Leeners, B. (2020) · Human Reproduction Update · doi:10.1093/humupd/dmaa032 · Cited by 31 · see citing works
Comparison of plasma leptin and zinc levels in elite athletes and sedentary people
Arıkan, Ş., Akkuş, H., Halifeoğlu, I., & Baltacı, A. (2008) · Cell Biochemistry and Function · doi:10.1002/cbf.1480 · Cited by 26 · see citing works
Exercise Training in the Normal Female: Effects of Low Energy Availability on Reproductive Function
Loucks, A. (2020) · Endocrinology of Physical Activity and Sport · doi:10.1007/978-1-62703-314-5_11 · Cited by 24 · see citing works
Self-citation
- Authors
- Hilton, L. K., & Loucks, A. B.
- Affiliations
- Ohio University (US)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2000-01-01
- Volume
- 278
- Issue
- 1
- Pages
- E43-E49
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2152128405
- Cited by
- 214
- References
- 0
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 11 · 2022: 8 · 2021: 11 · 2020: 12 · 2019: 8 · 2018: 5 · 2017: 4 · 2016: 4 · 2015: 7 · 2014: 11 · 2013: 19 · 2012: 8
- FWCI
- 4.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health (1r55hd029547-01)
- Directorate for Biological Sciences
- National Center for Research Resources (M01-RR-00034, M01RR000034)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (1R55-HD-29547-01)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
- Keywords
- leptin, diurnal cycle, energy availability, exercise stress, energy expenditure, energy intake, carbohydrate availability, luteinizing hormone pulsatility, menstrual cycle, follicular phase, young women
- MeSH terms
- Adult, Energy Intake, Circadian Rhythm, Energy Metabolism, Female, Humans, Reference Values, Exercise, Leptin
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