High-quality weight loss in obesity: importance of skeletal muscle
Open accessAbstract
Treatment responses to behavioral, surgical, and pharmacological approaches in obesity are highly variable in quantity and quality. Here we refer to high-quality weight loss as a high proportion of fat to skeletal muscle mass lost. Given the role of skeletal muscle in energy expenditure, glucose homeostasis, metabolic flexibility, mobility, and strength, excessive loss of skeletal muscle during weight loss is a concern for overall health. Challenges in accurately measuring body composition, especially skeletal muscle, limit our understanding of muscle loss during obesity treatment. Recent incretin-related pharmacotherapies improve muscle metabolic health by enhancing glucose uptake and reducing muscle lipids but, like other weight loss interventions, are associated with muscle loss. Newer pharmacological interventions are being developed to minimize muscle loss, but many questions remain. This article examines the metabolic importance of skeletal muscle and its measurement clinically, as well as key genetic and metabolic factors influencing skeletal muscle and the quality of weight loss. Genetics can affect muscle composition (e.g., fiber types) and function. Together with metabolic factors, including neurohormonal responses and skeletal muscle metabolic efficiency and adaptation, there is variability in weight loss outcomes. In future research investigators should continue to focus on factors affecting skeletal muscle and on personalized strategies to optimize weight loss quality preserving the physical and metabolic functions of skeletal muscle. Article Highlights: High-quality weight loss, i.e., a high proportion of fat to skeletal muscle lost during the treatment of obesity, is advantageous for metabolic and physical health. Precise and accurate determinations of skeletal muscle mass in clinical settings are often challenging. In prevention of excessive loss of skeletal muscle during weight loss, advantages include minimization of metabolic adaptation that makes it difficult to sustain weight loss, improved glucose homeostasis and metabolic flexibility, and better mobility and strength. Effective approaches to preserving skeletal muscle include sufficient dietary protein and inclusion of exercise (especially resistance exercise) during weight loss; new pharmacological approaches are under development.
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Skeletal muscle plays a central role in metabolic regulation.
“skeletal muscle plays a central role in metabolic regulation”
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Once-Weekly Semaglutide in Adults with Overweight or Obesity
Wilding, J. P. H., Batterham, R. L., Calanna, S., Davies, M., Van Gaal, L. F., Lingvay, I., McGowan, B. M., Rosenstock, J., Tran, M. T. D., Wadden, T. A., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2032183 · Cited by 5,205 · see citing works
Tirzepatide Once Weekly for the Treatment of Obesity
Jastreboff, A. M., Aronne, L. J., Ahmad, N. N., Wharton, S., Connery, L., Alves, B., Kiyosue, A., Zhang, S., Liu, B., Bunck, M. C., et al. (2022) · New England Journal of Medicine · doi:10.1056/nejmoa2206038 · Cited by 3,838 · cited 2× · see citing works
“…Treatment Effect in People with Obesity (STEP) 1 (29) and Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight (SURMOUNT-1) (30), semaglutide (2.4 mg/week) and tirzepatide (5, 10, and 15 mg/week), respectively, were associated with net losses of 10.1% and 7.9% of initial…”
InfluentialChait, A., & den Hartigh, L. J. (2020) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2020.00022 · Cited by 1,529 · see citing works
The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review
Klok, M. D., Jakobsdottir, S., & Drent, M. L. (2007) · Obesity Reviews · doi:10.1111/j.1467-789x.2006.00270.x · Cited by 1,442 · see citing works
Myostatin Mutation Associated with Gross Muscle Hypertrophy in a Child
Schuelke, M., Wagner, K. R., Stolz, L. E., Hübner, C., Riebel, T., Kömen, W., Braun, T., Tobin, J. F., & Lee, S.-J. (2004) · New England Journal of Medicine · doi:10.1056/nejmoa040933 · Cited by 1,399 · see citing works
Definition and Diagnostic Criteria for Sarcopenic Obesity: ESPEN and EASO Consensus Statement
Donini, L. M., Busetto, L., Bischoff, S. C., Cederholm, T., Ballesteros-Pomar, M. D., Batsis, J. A., Bauer, J. M., Boirie, Y., Cruz-Jentoft, A. J., Dicker, D., et al. (2022) · Obesity Facts · doi:10.1159/000521241 · Cited by 1,019 · see citing works
Skeletal muscle metabolism is a major determinant of resting energy expenditure.
Zurlo, F., Larson, K., Bogardus, C., & Ravussin, E. (1990) · Journal of Clinical Investigation · doi:10.1172/jci114857 · Cited by 959 · see citing works
Mechanisms of muscle atrophy and hypertrophy: implications in health and disease
Sartori, R., Romanello, V., & Sandri, M. (2021) · Nature Communications · doi:10.1038/s41467-020-20123-1 · Cited by 940 · see citing works
Pitfalls in the measurement of muscle mass: A need for a reference standard
Buckinx, F., Landi, F., Cesari, M., Fielding, R. A., Visser, M., Engelke, K., Maggi, S., Dennison, E., Al‐Daghri, N. M., Allepaerts, S., et al. (2018) · Journal of Cachexia, Sarcopenia and Muscle · doi:10.1002/jcsm.12268 · Cited by 765 · see citing works
Mechanick, J. I., Apovian, C., Brethauer, S., Garvey, W. T., Joffe, A. M., Kim, J., Kushner, R. F., Lindquist, R., Pessah-Pollack, R., Seger, J., et al. (2020) · Surgery for Obesity and Related Diseases · doi:10.1016/j.soard.2019.10.025 · Cited by 608 · see citing works
Obesity management as a primary treatment goal for type 2 diabetes: time to reframe the conversation
Lingvay, I., Sumithran, P., Cohen, R. V., & le Roux, C. W. (2022) · The Lancet · doi:10.1016/s0140-6736(21)01919-x · Cited by 581 · see citing works
Intramuscular lipid content is increased in obesity and decreased by weight loss
Goodpaster, B. H., Theriault, R., Watkins, S. C., & Kelley, D. E. (2000) · Metabolism · doi:10.1016/s0026-0495(00)80010-4 · Cited by 526 · see citing works
Muscle fiber type is associated with obesity and weight loss
Tanner, C. J., Barakat, H. A., Dohm, G. L., Pories, W. J., MacDonald, K. G., Cunningham, P. R. G., Swanson, M. S., & Houmard, J. A. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00416.2001 · Cited by 493 · see citing works
Preserving Healthy Muscle during Weight Loss
Cava, E., Yeat, N. C., & Mittendorfer, B. (2017) · Advances in Nutrition · doi:10.3945/an.116.014506 · Cited by 452 · see citing works
Heymsfield, S. B., Coleman, L. A., Miller, R., Rooks, D. S., Laurent, D., Petricoul, O., Praestgaard, J., Swan, T., Wade, T., Perry, R. G., et al. (2021) · JAMA Network Open · doi:10.1001/jamanetworkopen.2020.33457 · Cited by 338 · see citing works
Schroeder, E. C., Franke, W. D., Sharp, R. L., & Lee, D.-C. (2019) · PLoS ONE · doi:10.1371/journal.pone.0210292 · Cited by 295 · see citing works
Effects of experimental weight perturbation on skeletal muscle work efficiency in human subjects
Rosenbaum, M., Vandenborne, K., Goldsmith, R., Simoneau, J.-A., Heymsfield, S., Joanisse, D. R., Hirsch, J., Murphy, E., Matthews, D., Segal, K. R., et al. (2003) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00474.2002 · Cited by 255 · see citing works
Prevalence and Risk Factors of Sarcopenia in Patients With Diabetes: A Meta-analysis
Feng, L., Gao, Q., Hu, K., Wu, M., Wang, Z., Chen, F., Mei, F., Zhao, L., & Ma, B. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab884 · Cited by 243 · see citing works
Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice
Porporato, P. E., Filigheddu, N., Reano, S., Ferrara, M., Angelino, E., Gnocchi, V. F., Prodam, F., Ronchi, G., Fagoonee, S., Fornaro, M., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci39920 · Cited by 190 · see citing works
A Large Multiethnic Genome-Wide Association Study of Adult Body Mass Index Identifies Novel Loci
Hoffmann, T. J., Choquet, H., Yin, J., Banda, Y., Kvale, M. N., Glymour, M. M., Schaefer, C. A., RISCH, N. J., & Jorgenson, E. (2018) · Genetics · doi:10.1534/genetics.118.301479 · Cited by 186 · see citing works
Ukropcova, B., Sereda, O., de Jonge, L., Bogacka, I., Nguyen, T., Xie, H., Bray, G. A., & Smith, S. R. (2007) · Diabetes · doi:10.2337/db06-0521 · Cited by 165 · see citing works
Locatelli, J. C., Costa, J. G., Haynes, A., Naylor, L. H., Fegan, P. G., Yeap, B. B., & Green, D. J. (2024) · Diabetes Care · doi:10.2337/dci23-0100 · Cited by 152 · see citing works
Seimon, R. V., Wild-Taylor, A. L., Keating, S. E., McClintock, S., Harper, C., Gibson, A. A., Johnson, N. A., Fernando, H. A., Markovic, T. P., Center, J. R., et al. (2019) · JAMA Network Open · doi:10.1001/jamanetworkopen.2019.13733 · Cited by 152 · see citing works
Strategies for minimizing muscle loss during use of incretin‐mimetic drugs for treatment of obesity
Mechanick, J. I., Butsch, W. S., Christensen, S. M., Hamdy, O., Li, Z., Prado, C. M., & Heymsfield, S. B. (2025) · Obesity Reviews · doi:10.1111/obr.13841 · Cited by 149 · see citing works
Stefanakis, K., Kokkorakis, M., & Mantzoros, C. S. (2024) · Metabolism · doi:10.1016/j.metabol.2024.156057 · Cited by 142 · see citing works
Interrelationships between muscle morphology, insulin action, and adiposity
Kriketos, A. D., Pan, D. A., Lillioja, S., Cooney, G. J., Baur, L. A., Milner, M. R., Sutton, J. R., Jenkins, A. B., BOGARDUS, C., & Storlien, L. H. (1996) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1996.270.6.r1332 · Cited by 137 · see citing works
Factors affecting weight loss variability in obesity
Dent, R., McPherson, R., & Harper, M.-E. (2020) · Metabolism · doi:10.1016/j.metabol.2020.154388 · Cited by 131 · see citing works
Self-citationBody fat and fat-free mass inter-relationships: Forbes's theory revisited
Hall, K. D. (2007) · British Journal of Nutrition · doi:10.1017/s0007114507691946 · Cited by 129 · see citing works
Harper, M.-E., Dent, R., Monemdjou, S., Bézaire, V., Van Wyck, L., Wells, G., Kavaslar, G. N., Gauthier, A., Tesson, F., & McPherson, R. (2002) · Diabetes · doi:10.2337/diabetes.51.8.2459 · Cited by 129 · see citing works
Self-citationMazzali, G., Di Francesco, V., Zoico, E., Fantin, F., Zamboni, G., Benati, C., Bambara, V., Negri, M., Bosello, O., & Zamboni, M. (2006) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/84.5.1193 · Cited by 120 · see citing works
Changes in Subcutaneous Fat Cell Volume and Insulin Sensitivity After Weight Loss
Andersson, D. P., Hogling, D. E., Thorell, A., Toft, E., Qvisth, V., Näslund, E. B., Thörne, A., Wirén, M., Löfgren, P., Hoffstedt, J., et al. (2014) · Diabetes Care · doi:10.2337/dc13-2395 · Cited by 107 · see citing works
Changes in Muscle Myostatin Expression in Obese Subjects after Weight Loss
Milan, G., Nora, E. D., Pilon, C., Pagano, C., Granzotto, M., Manco, M., Mingrone, G., & Vettor, R. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2003-032047 · Cited by 100 · see citing works
Splanchnic and leg substrate exchange after ingestion of a natural mixed meal in humans.
Capaldo, B., Gastaldelli, A., Antoniello, S., Auletta, M., Pardo, F., Ciociaro, D., Guida, R., Ferrannini, E., & Saccà, L. (1999) · Diabetes · doi:10.2337/diabetes.48.5.958 · Cited by 94 · see citing works
Toledo, F. G. S., & Goodpaster, B. H. (2013) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2013.06.018 · Cited by 82 · see citing works
Kim, D., Lee, J., Park, R., Oh, C., & Moon, S. (2023) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13397 · Cited by 82 · see citing works
Tinsley, G. M., & Heymsfield, S. B. (2024) · Journal of the Endocrine Society · doi:10.1210/jendso/bvae164 · Cited by 81 · see citing works
Weight Loss after Gastric Bypass Is Associated with a Variant at 15q26.1
Hatoum, I. J., Greenawalt, D. M., Cotsapas, C. J., Daly, M. J., Reitman, M. L., & Kaplan, L. M. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.04.009 · Cited by 65 · see citing works
Gerrits, M. F., Ghosh, S., Kavaslar, N., Hill, B., Tour, A., Seifert, E. L., Beauchamp, B., Gorman, S., Stuart, J., Dent, R., et al. (2010) · Journal of Lipid Research · doi:10.1194/jlr.p005298 · Cited by 64 · see citing works
Self-citationLaddu, D., Neeland, I. J., Carnethon, M., Stanford, F. C., Mongraw-Chaffin, M., Barone Gibbs, B., Ndumele, C. E., Longenecker, C. T., Chung, M. L., Rao, G., et al. (2024) · Circulation · doi:10.1161/cir.0000000000001221 · Cited by 62 · see citing works
Differential mechanisms affecting weight loss and weight loss maintenance
Rosenbaum, M., & Foster, G. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00864-1 · Cited by 61 · see citing works
Old, V. J., Davies, M. J., Papamargaritis, D., Choudhary, P., & Watson, E. L. (2025) · Journal of Cachexia, Sarcopenia and Muscle · doi:10.1002/jcsm.13677 · Cited by 55 · see citing works
Haines, M. S., Dichtel, L. E., Santoso, K., Torriani, M., Miller, K. K., & Bredella, M. A. (2020) · International Journal of Obesity · doi:10.1038/s41366-020-0590-y · Cited by 54 · see citing works
Leptin mediates the regulation of muscle mass and strength by adipose tissue
Collins, K. H., Gui, C., Ely, E. V., Lenz, K. L., Harris, C. A., Guilak, F., & Meyer, G. A. (2022) · The Journal of Physiology · doi:10.1113/jp283034 · Cited by 54 · see citing works
Proportion of caloric restriction‐induced weight loss as skeletal muscle
Heymsfield, S. B., Yang, S., McCarthy, C., Brown, J. B., Martin, C. K., Redman, L. M., Ravussin, E., Shen, W., Müller, M. J., & Bosy‐Westphal, A. (2024) · Obesity · doi:10.1002/oby.23910 · Cited by 53 · see citing works
Brennan, A. M., Standley, R. A., Anthony, S. J., Grench, K., Helbling, N. L., DeLany, J. P., Cornnell, H. H., Yi, F., Stefanović-Račić, M., Toledo, F. G. S., et al. (2021) · The Journals of Gerontology Series A · doi:10.1093/gerona/glab240 · Cited by 52 · see citing works
Effect of Bimagrumab on Body Composition: A Systematic Review and Meta-Analysis
Kanbay, M., Siriopol, D., Copur, S., Hasbal, N. B., Güldan, M., Kalantar-Zadeh, K., Garfias-Veitl, T., & von Haehling, S. (2024) · Aging Clinical and Experimental Research · doi:10.1007/s40520-024-02825-4 · Cited by 45 · see citing works
Association of muscle fiber type with measures of obesity: A systematic review
Damer, A., Meniawy, S. E., McPherson, R., Wells, G. A., Harper, M., & Dent, R. (2022) · Obesity Reviews · doi:10.1111/obr.13444 · Cited by 43 · see citing works
Self-citationHudson, J. L., Wang, Y., Bergia III, R. E., & Campbell, W. W. (2020) · Advances in Nutrition · doi:10.1093/advances/nmz106 · Cited by 41 · see citing works
Serrano, N., Hyatt, J. K., Houmard, J. A., Murgia, M., & Katsanos, C. S. (2023) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00190.2023 · Cited by 36 · see citing works
Skeletal muscle estimation: A review of techniques and their applications
Rodriguez, C., Mota, J. A., Palmer, T. B., Heymsfield, S. B., & Tinsley, G. M. (2024) · Clinical Physiology and Functional Imaging · doi:10.1111/cpf.12874 · Cited by 35 · see citing works
Age‐ and sex‐specific changes in visceral fat mass throughout the life‐span
Falkentoft, R. B. B., Jensen, M. R., Hansen, O. M., Haddock, B., Prescott, E., Hovind, P. H., Simonsen, L., Bülow, J., & Suetta, C. (2023) · Obesity · doi:10.1002/oby.23779 · Cited by 34 · see citing works
McCaffery, J. M., Papandonatos, G. D., Huggins, G. S., Peter, I., Erar, B., Kahn, S. E., Knowler, W. C., Lipkin, E. W., Kitabchi, A. E., Wagenknecht, L. E., et al. (2013) · Human Heredity · doi:10.1159/000353181 · Cited by 27 · see citing works
Exercise training enhances muscle mitochondrial metabolism in diet-resistant obesity
Pileggi, C., Blondin, D., Hooks, B. G., Parmar, G., Alecu, I., Patten, D., Cuillerier, A., O'Dwyer, C., Thrush, A. B., Fullerton, M., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.104192 · Cited by 27 · see citing works
Self-citationThrush, A. B., Zhang, R., Chen, W., Seifert, E. L., Quizi, J., McPherson, R., Dent, R., & Harper, M. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-1726 · Cited by 24 · see citing works
Self-citationAdeva‐Andany, M. M., Fernández‐Fernández, C., López-Pereiro, Y., Calvo‐Castro, I., & Carneiro-Freire, N. (2021) · Clinical Nutrition ESPEN · doi:10.1016/j.clnesp.2021.06.025 · Cited by 19 · see citing works
Rodrigues, P. S., Mendonça, F. M., Neves, J. S., Luís, C., Rodrigues, I., Moreno, T., Silva, D. F., Pedro, J. M. P., Varela, A. T. I. F., Fernandes, A., et al. (2024) · Obesity Surgery · doi:10.1007/s11695-024-07164-x · Cited by 18 · see citing works
Nikpay, M., Lau, P., Soubeyrand, S., Whytock, K. L., Beehler, K., Pileggi, C. A., Ghosh, S., Harper, M., Dent, R., & McPherson, R. (2020) · Diabetes · doi:10.2337/db20-0219 · Cited by 12 · see citing works
Self-citationGenetic variants in myostatin and its receptors promote elite athlete status
Leońska‐Duniec, A., Borczyk, M., Korostyński, M., Massidda, M., Maculewicz, E., & Cięszczyk, P. (2023) · BMC Genomics · doi:10.1186/s12864-023-09869-2 · Cited by 8 · see citing works
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Weight maintenance after discontinuation of GLP-1 therapies
Moiz, A., Filion, K. B., Knäuper, B., Tsoukas, M. A., Brazeau, A.-S., Zolotarova, T., Lelièvre, A., & Eisenberg, M. J. (2026) · EClinicalMedicine · doi:10.1016/j.eclinm.2026.103992 · Cited by 4 · see citing works
“73,74 Loss of lean mass during weight loss contributes to adaptive declines in energy expenditure and reduced metabolic efficiency, thereby promoting positive energy balance and increasing susceptibility to weight regain.”
- Authors
- Harper, M.-E., Dent, R. R. M., & McPherson, R.
- Affiliations
- University of Ottawa (CA)
- Ottawa Heart Institute (CA)
- Corresponding author
- Harper, Mary-Ellen
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2025-07-08
- Volume
- 74
- Issue
- 12
- Pages
- 2191-2198
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC12645252
- OpenAlex
- W4412105809
- Cited by
- 27
- References
- 58
- Citations by year
- 2026: 25 · 2025: 2
- FWCI
- 3.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Institute of Nutrition, Metabolism and Diabetes (183651)
- Topics
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Body Composition Measurement Techniques
- Keywords
- obesity, weight loss, skeletal muscle, muscle mass loss, body composition measurement, incretin-based therapy, muscle fiber type, metabolic adaptation, glucose homeostasis, metabolic flexibility, dietary protein, resistance training, genetic factors
- MeSH terms
- Body Composition, Energy Metabolism, Humans, Obesity, Weight Loss, Muscle, Skeletal
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