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Effects of Moderate and Subsequent Progressive Weight Loss on Metabolic Function and Adipose Tissue Biology in Humans with Obesity
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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
Cites
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InfluentialCorrect Homeostasis Model Assessment (HOMA) Evaluation Uses the Computer Program
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“Insulin resistance develops early with weight gain [3, 4], and even moderate weight loss with caloric restriction is associated with improved insulin sensitivity and β-cell function [5].”
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Kheniser, K. G., Aminian, A., & Kashyap, S. R. (2022) · Metabolic Syndrome and Related Disorders · doi:10.1089/met.2022.0039 · Cited by 3
How Could Taxes on Sugary Drinks and Foods Help Reduce the Burden Of Type 2 Diabetes?
Reyes-García, A., Junquera-Badilla, I., Batis, C., Colchero, M. A., Miranda, J. J., Barrientos‐Gutiérrez, T., & Basto-Abreu, A. C. (2023) · Current Diabetes Reports · doi:10.1007/s11892-023-01519-x · Cited by 3
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“In adults with obesity, maximal benefits of improved insulin sensitivity of the adipose tissue and liver occur at 5 % weight loss [32] and in adults living with T2D, a larger magnitude of weight loss was associated with greater HbA1c reduction [33].”
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“This is significant because obese individuals who lose 5% of their weight have been shown to experience improved insulin sensitivity and β-cell function.(25) These favorable changes in body composition for the Bariatric Wellness cohort are clinically meaningful, as bariatric patients often face health concerns that in…”
BackgroundThe outcome of a multicomponent lifestyle intervention in patients with obesity: A cohort study
Kierkegaard, S., Sørensen, U. M., Lange, L. B., Mortensen, L. S., & Bruun, J. M. (2023) · European Journal of Integrative Medicine · doi:10.1016/j.eujim.2023.102259 · Cited by 3
Obesity and Diabetes Mellitus 2: Interrelated Relative Relationship
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“It was shown that a weight reduction of 5% from baseline is “clinically meaningful” (62) and is associated with a decline of 13% in intra-hepatic tri - glycerides (63).”
Setting Expectations When Prescribing Medication for the Treatment of Patients With Obesity
Fitch, A. (2025) · Mayo Clinic Proceedings Innovations Quality & Outcomes · doi:10.1016/j.mayocpiqo.2025.100621 · Cited by 2
“37 Therefore, treatment goals should focus on achieving a reduction in risks associated with comorbidities.”
Víctor de la, O., de Cuevillas, B., Henkrich, M. M., Vizmanos-Lamotte, B., Núñez-García, M., Sajoux, I., de Luis, D. A., & Martínez, J. A. (2025) · Journal of Personalized Medicine · doi:10.3390/jpm15060251 · Cited by 2
“%) is considered to be clinically significant as it reduces cardiometabolic risk factors and reduces obesity-related comorbidities in subjects with excessive adiposity [29], which is achieved differently depending on sex, age and initial adiposity (BMI).”
Popp, C. J., Wang, C., Berube, L. T., Curran, M., Hu, L., Pompeii, M. L., Barua, S., Li, H., St‐Jules, D. E., Schoenthaler, A., et al. (2025) · Nutrients · doi:10.3390/nu17132178 · Cited by 3
“A weight loss of 5% is considered clinically meaningful and is associated with a significant reduction in metabolic risk associated with adiposity-based chronic diseases [15].”
Santhosh, C., Bhargav, H., Varambally, S. S., Chikkanna, U., Jasti, N., Amritha, S. M., & Kumar, R. K. (2025) · Journal of Ayurveda and Integrative Medicine · doi:10.1016/j.jaim.2025.101198 · Cited by 2
“Current clinical guidelines suggest that a reduction of at least 1 – 2 kg/m 2 in BMI or 5 – 7 %of initial body weight is necessary to achieve substantial improvements in metabolic parameters (Magkos et al., 2016[42]).”
Moloi, L. D., Samson, S., Tshiyoyo, K. S., Maluleke, K., Oberholzer, M., Baloyi, I. T., & Malgas, S. (2025) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.1080/14756366.2025.2564800 · Cited by 2
“…the risk of obesity-associated comorbidities such as coronary heart disease, non-alcoholic fatty liver, hypertension, and type ii diabetes (t2D) 8 . t2D is a metabolic disease in which tissues resist insulin exposure 9 . insulin is produced and secreted by pancreatic β-cells in response to…”
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“28,29 Behavioral changes associated with GLP-1a treatment, including exercise, dietary modification, and eating patterns, could also contribute to the underlying mechanism.”
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Classification of Obesity Based on Weight History: Perceptions of People With Obesity
Halpern, B., van de Sande‐Lee, S., de Melo, M. E., Lamounier, R. N., Cercato, C., Miranda, P. A. C., Moreira, R. O., Carra, M. K., Boguszewski, C. L., & Mancini, M. C. (2026) · Clinical Obesity · doi:10.1111/cob.70068 · Cited by 2
“One critical finding from this survey, however, is that the wide-spread understanding—at least, in scientific literature—that modest weight reductions can lower overall risks and enhance health and quality of life [13, 14, 16, 39], is not reaching those who matter most, namely, PwO.”
Diet-based weight-loss intervention is not associated with a meaningful change in lean soft tissue
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“All P values for mean differences from paired t-tests were significant ( P < 0.001); exact P values are shown in Figure 4. with the majority of weight loss being from FM [7,28 – 30].”
InfluentialNowak, M. Z., Núñez, L. M., Pagliaro, T., Robson, M. D., Duncker, C. M., Kaplan, L. M., Heymsfield, S., Thomaides-Brears, H. B., Bell, J. D., & Thomas, E. L. (2026) · International Journal of Obesity · doi:10.1038/s41366-026-02037-y · Cited by 2
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InfluentialPereira, L. V., Coutinho, M. D. A. P., Hortiz, D., Xavier, A. L., & Lima, R. P. A. (2026) · Nutrients · doi:10.3390/nu18111725 · Cited by 4
“Intentional weight reduction improves glycemic regulation, lipid metabolism, and inflammatory tone [7,8].”
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“In general, the goal is to reduce 5 to 10% of the actual weight 28 .”
BackgroundBük, Ö. F., Ocak, S., Uyanık, M. S., Daldal, E., Avcı, M. A., & Akgün, C. (2023) · Medical Science Monitor · doi:10.12659/msm.942692 · Cited by 2
“Weight loss improves the metabolic functions of various organs and leads to alterations in adipose tissue biological pathways [2].”
BackgroundReducing cardiovascular outcomes with semaglutide: a metabolic route for a SELECT few
Liuzzo, G., & Patrono, C. (2023) · European Heart Journal · doi:10.1093/eurheartj/ehad823 · Cited by 2
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The WCIRDC 2023: Concepts of insulin resistance
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“Moreover, this study demonstrated that liver and adipose tissue sensitivity improved with a 5% weight reduction and remained stable, whereas muscle insulin sensitivity continued to improve with weight losses of 11% and 16%, respectively [46].”
BackgroundA case of new-onset Fulminant type 1 diabetes after secondary SARS-CoV-2 infection
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“Consistent with the finding that moderate weight loss is beneficial for improving multi-organ insulin sensitivity [13, 37] and that greater weight loss has a more significant effect on diabetes prevention in the general population than does less weight loss [38], our findings suggest that greater…”
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T cells are elevated in abdominal and femoral adipose tissue in females with type 2 diabetes
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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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