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Effects of Moderate and Subsequent Progressive Weight Loss on Metabolic Function and Adipose Tissue Biology in Humans with Obesity
Open accessAbstract
SUMMARY Although 5%–10% weight loss is routinely recommended for people with obesity, the precise effects of 5% and further weight loss on metabolic health are unclear. We conducted a randomized controlled trial that evaluated the effects of 5.1±0.9% (n=19), 10.8±1.3% (n=9) and 16.4±2.1% (n=9) weight loss, and weight maintenance (n=14) on metabolic outcomes. Five percent weight loss improved adipose tissue, liver and muscle insulin sensitivity, and β-cell function, without a concomitant change in systemic or subcutaneous adipose tissue markers of inflammation. Additional weight loss further improved β-cell function and insulin sensitivity in muscle, and caused stepwise changes in adipose tissue mass, intrahepatic triglyceride content, and adipose tissue expression of genes involved in cholesterol flux, lipid synthesis, extracellular matrix remodeling and oxidative stress. These results demonstrate that moderate 5% weight loss improves metabolic function in multiple organs simultaneously, and progressive weight loss causes dose-dependent alterations in key adipose tissue biological pathways.
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“Weight loss clearly improves insulin sensitivity but the effects in different organ systems have individual variability depending upon the duration and extent of the metabolic dysregulation.”
From Effect of exercise training on insulin-stimulated glucose disposal: A systematic review and meta-analysis of randomized controlled trials (2023) · cites this paper as [63]
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“In addition, reductions in excess abnormal body fat ameliorate the systemic proinflammatory and prothrombotic milieu associated with obesity. 31”
From Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (2023) · cites this paper as [31]
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“A 10–15% loss may induce remission of T2D or MASLD.”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [71]
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“In general, insulin-mediated suppression of lipolysis in adipose tissue and suppression of HGP occur maximally at 5% to 8% weight loss 63, 64.”
From Effect of exercise training on insulin-stimulated glucose disposal: A systematic review and meta-analysis of randomized controlled trials (2023) · cites this paper as [63]
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“Insulin-mediated glucose disposal in skeletal muscle continues to increase with additional weight loss 63.”
From Effect of exercise training on insulin-stimulated glucose disposal: A systematic review and meta-analysis of randomized controlled trials (2023) · cites this paper as [63]
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“A weight loss of ≥ 5% represents the first clinically meaningful milestone, associated with improved metabolism, enhanced glucose metabolism and blood pressure.”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [71]
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“Interestingly, changes in hepatic and adipose tissue insulin sensitivity plateaued after 5 % weight loss, while insulin-mediated skeletal muscle glucose uptake as well as reduction of intrahepatic lipid content continued with progressive weight loss [45].”
From Obesity and MASLD: Is weight loss the (only) key to treat metabolic liver disease? (2024) · cites this paper as [45]
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“While > 20% is typically required to reverse advanced metabolic or hepatic disease [71].”
From Precision obesity medicine: A phenotype-guided framework for pharmacologic therapy across the lifespan (2025) · cites this paper as [71]
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Citations
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Anorectic state of obesity medications in the United States. Are leaner times ahead?
Li, X., & Bello, N. T. (2019) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2019.1692815 · Cited by 6
“the medical management of type II diabetes mellitus [26], two medications, dapagliflozin/metformin and MEDI0382, would tar-”
BackgroundRybka-Fraczek, A., Orzolek, I., & Dabrowska, M. (2026) · The Journal of Allergy and Clinical Immunology: In Practice · doi:10.1016/j.jaip.2025.10.014 · Cited by 7
N-acetylaspartate from fat cells regulates postprandial body temperature
Felix, J. B., Saha, P. K., de Groot, E. L., Tan, L., Sharp, R., Anaya, E. S., Li, Y., Quang, H., Saidi, N., Abushamat, L., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01334-6 · Cited by 6
Self-citationYeary, K. H. K., Johnson, D., Harris, N., Yu, H., Saad‐Harfouche, F. G., Dauphin, C., DiCarlo, E., Flores, T. F., Yao, S., Varady, K. A., et al. (2024) · Journal of the Academy of Nutrition and Dietetics · doi:10.1016/j.jand.2024.07.003 · Cited by 5
Li, Y., Zhang, J., Li, Y., Su, Y., & Li, N. (2026) · Journal of Functional Foods · doi:10.1016/j.jff.2026.107223 · Cited by 5
Bottino, R., Carbone, A., Formisano, T., D’Elia, S., Orlandi, M., Sperlongano, S., Molinari, D., Castaldo, P., Palladino, A., Barbareschi, C., et al. (2023) · Life · doi:10.3390/life13071552 · Cited by 5
“A previous study has evaluated how different degrees of weight loss may affect metabolic function and adipose tissue biology [69].”
BackgroundPark, D., Shin, M., & Magkos, F. (2024) · CardioMetabolic Syndrome Journal · doi:10.51789/cmsj.2024.4.e13 · Cited by 5
Self-citationKim, M.-J., Kim, S.-W., Ha, B., Kim, H. S., Kwon, S., Jin, J., Choi, Y.-K., Park, K., Kim, J. G., Lee, I., et al. (2025) · The Korean Journal of Internal Medicine · doi:10.3904/kjim.2024.221 · Cited by 5
“Weight loss is known to be effective in reducing metabolic risks [21].”
Ahn, C., Tamburini, I. J., Sanford, J. A., Zhou, M., Gamie, F., Yeo, R. X., Filho, C., Pino, M., Whytock, K. L., Oberlin, L. E., et al. (2025) · Molecular Metabolism · doi:10.1016/j.molmet.2025.102213 · Cited by 5
“Given that both exercise training and diet-induced weight loss attenuate ASAT inflammation [95,96], it is possible that reduced MMP9 expression may contribute to this anti-inflammatory effect.”
Lehn‐Stefan, A., Peter, A., Machann, J., Schick, F., Randrianarisoa, E., Heni, M., Wagner, R. J., Birkenfeld, A. L., Fritsche, A., Schulze, M. B., et al. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac091 · Cited by 5
Targeting the Enteroendocrine System for Treatment of Obesity
Miedzybrodzka, E. L., Gribble, F. M., & Reimann, F. M. (2022) · Handbook of experimental pharmacology · doi:10.1007/164_2022_583 · Cited by 5
Metabolic Profile and Metabolite Analyses in Extreme Weight Responders to Gastric Bypass Surgery
Fries, C., Haange, S., Rolle-Kampczyk, U. E., Till, A., Lammert, M., Grasser, L., Medawar, E., Dietrich, A., Horstmann, A., von Bergen�, M., et al. (2022) · Metabolites · doi:10.3390/metabo12050417 · Cited by 6
“A very elegant study has recently shown, that in a controlled weight loss intervention in obese patients 5% weight loss was sufficient to improve organ tissue insulin sensitivity and ß-cell function, while further weight loss of up to 10 to 15% is required to cause dose-dependent alterations in key adipose tissue biol…”
BackgroundStéatose hépatique non alcoolique : diagnostic et traitement en 2022
Tagkou, N. M., & Goossens, N. (2023) · Schweizer Gastroenterologie · doi:10.1007/s43472-023-00091-9 · Cited by 8
Dorsal striatal response to taste is modified by obesity and insulin resistance
Dunn, J. P., Lamichhane, B., Smith, G. I., Garner, A., Wallendorf, M., Hershey, T. G., & Klein, S. (2023) · Obesity · doi:10.1002/oby.23799 · Cited by 5
“Plasma glucose tracer to tracee ratios were determined by using gas chromatography/mass spectrometry (HewlettPackard MSD 5973 system with capillary column) with glucose rate of disappearance (Rd) calculated as previously described [25].”
MethodSelf-citationAvery, A., Toon, J., Holloway, L., Bennett, S., Lavin, J. H., & Pallister, C. (2023) · Clinical Nutrition Open Science · doi:10.1016/j.nutos.2023.07.003 · Cited by 5
Current and Emerging Parenteral and Peroral Medications for Weight Loss: A Narrative Review
Lawati, A. A., Alhabsi, A. N., Rahul, R., Savino, M.-L., Alwahaibi, H., Das, S., & Lawati, H. A. (2025) · Diseases · doi:10.3390/diseases13050129 · Cited by 5
“A 5% weight reduction can considerably reduce the blood concentrations of substances associated with cardiometabolic diseases and enhance beta-cell function and insulin sensitivity of multiple organs, including the liver and adipose tissue [16,17].”
Shukla, A. P., Mandel, L., Tchang, B. G., Litman, E. A., Cadwell, J. B., Kumar, R. B., Waitman, J. A., Igel, L. I., Christos, P. J., & Aronne, L. J. (2020) · Obesity · doi:10.1002/oby.22903 · Cited by 6
“The benefits of clinically significant weight loss, defined as greater than or equal to 5% of the baseline weight (19), extend beyond cardiovascular protection and mitigation of these comorbidities (20).”
BackgroundPhysiological and Anti-obesity Effects of Melatonin and Niacin Supplements in Rat Models
Keski̇n, A., Acı, R., Duran, U., & Sugeçti, S. (2021) · Caucasian Journal of Science · doi:10.48138/cjo.934158 · Cited by 5
Burns, R., Firman, E., & Huang, H. C. (2022) · Obesity · doi:10.1002/oby.23575 · Cited by 5
“Combined with the knowledge that CSWL is associated with improved health outcomes [29, 30], this review highlights the need for adequate government investment in evidence-based”
BackgroundChen, B., Sluiman, A. J., Khalid, W., Strachan, M. W. J., & Price, J. F. (2023) · Diabetic Medicine · doi:10.1111/dme.15063 · Cited by 5
“Primary school 1 (5) 2 (2) 1 (4) 1 (1)”
Inkretinbasierte Ko- und Triagonisten
Harger, A., Stemmer, K., Tschöp, M., & Müller, T. D. (2019) · Der Internist · doi:10.1007/s00108-019-0649-9 · Cited by 6
Blaszkiewicz, M., Johnson, C. P., Willows, J. W., Gardner, M. L., Taplin, D. R., Freitas, M. A., & Townsend, K. L. (2024) · Adipocyte · doi:10.1080/21623945.2024.2428938 · Cited by 4
“Weight loss of even 10% can lead to improvements in insulin resistance in obese individuals [1], underscoring how quickly adipose tissue can regain metabolic control.”
Alarfaj, S. J. (2025) · Medicina · doi:10.3390/medicina61081393 · Cited by 5
“In addition to improved glycemic control, weight loss of more than 5% was associated with improved insulin sensitivity and metabolic profile, a decrease in the number of antidiabetic medications used, and an improvement in quality of life [1,20,22].”
Bays, H. E., Varney, C., Alexander, L., Ng, J., Tondt, J., Weber, C., Christensen, S. M., Burridge, K., Brown, C., Bindlish, S., et al. (2026) · Obesity Pillars · doi:10.1016/j.obpill.2026.100283 · Cited by 4
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M1 Polarized Macrophages Persist in Skin of Post-Bariatric Patients after 2 Years
Amaral, C., da Costa, J. R., Costa, M. O., Verbicario, J. P., Dias, L., Gontijo-de-Amorim, N. F., Charles-de-Sá, L., & Takiya, C. M. (2021) · Aesthetic Plastic Surgery · doi:10.1007/s00266-021-02649-x · Cited by 4
“In addition, long-term studies provide evidence that bariatric surgery leads to a substantial reduction in the risk of developing new comorbidities, which is in part due to the decrease in the levels of obesityassociated inflammatory molecules [8, 9].”
BackgroundImpact of interpregnancy weight changes and perinatal outcomes: A retrospective study in Japan
Yamamoto, M., Aoki, S., Shinoda, S., Ishikawa, H., & Miyagi, E. (2024) · PLoS ONE · doi:10.1371/journal.pone.0299794 · Cited by 4
The vices and virtues of medical models of obesity
Sholl, J., & BLOCK, A. D. (2024) · Obesity Reviews · doi:10.1111/obr.13828 · Cited by 5
Petrovic, A., Jovičić, S. Ž., Dodevska, M. S., Djordjevic, B. I., Milinković, N., & Ivanović, N. (2024) · Nutrients · doi:10.3390/nu16203453 · Cited by 4
“The literature data confirmed the positive influence of energy-restricted diets on cardiometabolic risk factors, such as blood pressure, dyslipidemia, and glucose intolerance, which often improve after only a 5% loss of initial BW [6].”
BackgroundMethodInfluentialU.S. weight trends: a longitudinal analysis of an NIH-partnered dataset
Jawara, D., Krebsbach, C., Venkatesh, M., Murtha, J. A., Hanlon, B. M., Lauer, K. V., Stalter, L. N., & Funk, L. M. (2024) · International Journal of Obesity · doi:10.1038/s41366-024-01661-w · Cited by 4
“Bivariate analyses were performed to evaluate the relationships between patient characteristics and %TBW change using t -tests and Analysis of Variance (ANOVA) F - tests (Supplementary Materials).”
Kuhlemeier, A., Horn, D. J., Jaki, T., Wilson, D. K., Resnicow, K., Jimenez, E. Y., & Horn, M. L. V. (2025) · Obesity · doi:10.1002/oby.24258 · Cited by 4
“Although the 5% weight reduction suggested by public health agencies and professional societies [14] alleviates some risk factors and high prevalence diseases [15], weight loss beyond 5% results in additional benefits for most health outcomes [16].”
Sparks, J. R., Porter, R. R., Youngstedt, S. D., Bowyer, K. P., Durstine, J. L., & Wang, X. (2020) · SLEEP Advances · doi:10.1093/sleepadvances/zpab001 · Cited by 4
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Mittendorfer, B., Patterson, B. W., Magkos, F., Yoshino, M., Bradley, D. P., Eagon, J. C., & Klein, S. (2023) · JCI Insight · doi:10.1172/jci.insight.170307 · Cited by 4
“Methods The data in this manuscript represent a secondary analysis of data obtained from 3 previously published prospective clinical trials (8, 9, 20) and data obtained from additional participants who fulfilled the same inclusion criteria and completed the same study protocols (ClinicalTrials.”
InfluentialSelf-citationPiacquadio, K. A., Margolis, L. M., Gwin, J. A., & Leidy, H. J. (2024) · Journal of Nutrition · doi:10.1016/j.tjnut.2024.04.026 · Cited by 5
Gestational weight gain: an ounce of prevention is still worth a pound of cure
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Gewichtsstabilisierung nach Gewichtsreduktion
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Role of Inflammation in Neuropsychiatric Comorbidity of Obesity: Experimental and Clinical Evidence
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Aliashrafi, S., Arefhosseini, S. R., Lotfi‐Dizaji, L., & Ebrahimi‐Mameghani, M. (2019) · Health Promotion Perspectives · doi:10.15171/hpp.2019.36 · Cited by 4
Lessons Learned from Telemedicine in Adolescent Obesity: Results of a Pilot Study
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“As mentioned earlier, a weight loss of 5% in adults usually positively impacts cardiometabolic complications [7,8].”
Background
Metadata
- Authors
- Magkos, F., Fraterrigo, G., Yoshino, J., Luecking, C., Kirbach, K., Kelly, S. C., de las Fuentes, L., He, S., Okunade, A. L., Patterson, B. W., & Klein, S.
- Affiliations
- Agency for Science, Technology and Research (SG)
- Washington University in St. Louis (US)
- Corresponding author
- Klein, Samuel
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 23
- Issue
- 4
- Pages
- 591-601
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC4833627
- OpenAlex
- W2283809486
- Semantic Scholar
- 22c2c95f3eae678f67267c186f68d979ed5b03d6
- Cited by
- 886
- References
- 47
- Citations by year
- 2026: 83 · 2025: 92 · 2024: 95 · 2023: 90 · 2022: 108 · 2021: 97 · 2020: 93 · 2019: 79 · 2018: 64 · 2017: 57 · 2016: 26
- FWCI
- 70.57
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Longer Life Foundation
- Pershing Square Foundation
- National Institutes of Health (5p60dk020579-35, KL2TR000450, UL1TR000448)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK37948, DK20579, DK56341, R01DK104995, R01DK037948, DK104995, P60-DK-020579, P30DK092950, P30DK056341, P30DK020579)
- National Center for Research Resources (RR-024992, UL1RR024992)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Disease and Adiposity
- Keywords
- obesity, weight loss, weight maintenance, insulin sensitivity, beta-cell function, adipose tissue, liver, skeletal muscle, intrahepatic triglyceride, adipose tissue inflammation, cholesterol flux, lipogenesis, extracellular matrix remodeling, oxidative stress, dose-dependent effects
- MeSH terms
- Adipose Tissue, Adult, Female, Humans, Insulin, Insulin Resistance, Liver, Male, Middle Aged, Muscles, Obesity, Weight Loss, Insulin-Secreting Cells
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