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Obesogenic memory can confer long-term increases in adipose tissue but not liver inflammation and insulin resistance after weight loss
Open accessAbstract
OBJECTIVE: Obesity represents a major risk factor for the development of type 2 diabetes mellitus, atherosclerosis and certain cancer entities. Treatment of obesity is hindered by the long-term maintenance of initially reduced body weight, and it remains unclear whether all pathologies associated with obesity are fully reversible even upon successfully maintained weight loss. METHODS: We compared high fat diet-fed, weight reduced and lean mice in terms of body weight development, adipose tissue and liver insulin sensitivity as well as inflammatory gene expression. Moreover, we assessed similar parameters in a human cohort before and after bariatric surgery. RESULTS: Compared to lean animals, mice that demonstrated successful weight reduction showed increased weight gain following exposure to ad libitum control diet. However, pair-feeding weight-reduced mice with lean controls efficiently stabilized body weight, indicating that hyperphagia was the predominant cause for the observed weight regain. Additionally, whereas glucose tolerance improved rapidly after weight loss, systemic insulin resistance was retained and ameliorated only upon prolonged pair-feeding. Weight loss enhanced insulin action and resolved pro-inflammatory gene expression exclusively in the liver, whereas visceral adipose tissue displayed no significant improvement of metabolic and inflammatory parameters compared to obese mice. Similarly, bariatric surgery in humans (n = 55) resulted in massive weight reduction, improved hepatic inflammation and systemic glucose homeostasis, while adipose tissue inflammation remained unaffected and adipocyte-autonomous insulin action only exhibit minor improvements in a subgroup of patients (42%). CONCLUSIONS: These results demonstrate that although sustained weight loss improves systemic glucose homeostasis, primarily through improved inflammation and insulin action in liver, a remarkable obesogenic memory can confer long-term increases in adipose tissue inflammation and insulin resistance in mice as well as in a significant subpopulation of obese patients.
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“Moreover, others have shown that 12 months after bariatric surgery, AT inflammation remained elevated in approximately 40% of patients (117).”
From The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. (2017) · cites this paper as [117]
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Adipose tissue inflammation and metabolic dysfunction in obesity
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“Specifically, some studies have shown obesogenic memory leading to sustained AT inflammation in previously obese mice despite subsequent weight loss 115,116 .”
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“These observations support the concept that obesity followed by weight loss establishes an ‘obesogenic memory’, also referred to as an ‘obesity memory’ 15 ; that is, a combination of factors originating during obesity and subsequent weight loss, which confers a risk of returning to the obese state.”
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Self-citationObesogenic Memory Maintains Adipose Tissue Inflammation and Insulin Resistance
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“unveiled persistent macrophage-dominated inflammation in AT even after prolonged weight loss [33, 34], which was shown to further contribute to the persistent AT dysfunction and high risks of metabolic”
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“AT biopsies were obtained from 135 individuals (37 men, 98 women, age 16 – 70) with morbid obesity in the context of a two-step bariatric surgery approach 11 , which in most cases included a sleeve gastrectomy as the fi rst step and laparoscopic Roux-en-Y gastric bypass as second step.”
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Cifarelli, V., Smith, G. I., González-Nieves, S., Samovski, D., Palacios, H. H., Yoshino, J., Stein, R. I., Fuchs, A. G., Wright, T. F., & Klein, S. (2024) · Diabetes · doi:10.2337/db24-0890 · Cited by 27
Infectious and lifestyle modifiers of immunity and host resilience
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BackgroundMacrophages Mediate Increased CD8 T Cell Inflammation During Weight Loss in Formerly Obese Mice
Surendar, J., Indulekha, K., Frohberger, S. J., Koschel, M., Hoerauf, A. M., & Hübner, M. P. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00257 · Cited by 23
“(4) have shown that despite improving glucose tolerance, weight loss could not successfully ameliorate adipose tissue inflammation and improve insulin sensitivity.”
BackgroundEffect of Marked Weight Loss on Adipose Tissue Biology in People With Obesity and Type 2 Diabetes
Samovski, D., Smith, G. I., Palacios, H. H., Pietka, T., Fuchs, A. G., Patti, G. J., Nawaz, A., Kahn, C. R., & Klein, S. (2025) · Diabetes Care · doi:10.2337/dc24-2739 · Cited by 23
Adipocytes control food intake and weight regain via Vacuolar-type H+ ATPase
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Sucrose overconsumption impairs AgRP neuron dynamics and promotes palatable food intake
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“32,33,37,38 39–41 Obesity causes macronutrient-independent attenuation of chow intake and AgRP neuron responses to chow presentation HFD-induced obesity congruently blunts AgRP neural responses to chow presentation and chow consumption following a fast.”
BackgroundDynamic chromatin architecture of the porcine adipose tissues with weight gain and loss
Jin, L. G., Wang, D., Zhang, J., Liu, P., Wang, Y., Yu, L., Liu, C., Han, Z., Long, K., Li, D., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39191-0 · Cited by 21
Tissue-specific inflammation and insulin sensitivity in subjects with obesity
Oussaada, S. M., Kiliçarslan, M., de Weijer, B. A., Gilijamse, P. W., Şekercan, A., Virtue, S., Janssen, I. M. C., van de Laar, A. W. J. M., Demirkıran, A., van Wagensveld, B. A., et al. (2024) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2024.111663 · Cited by 21
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“This challenges the efforts to establish clear contributions of specific cell types to obesity-associated metabolic deterioration, even for adipose tissue macrophages [3] (also recently reviewed in [4,5]).”
BackgroundMethodSelf-citationGálvez, I., Navarro, M. D. C., Martín-Cordero, L., Otero, E., Hinchado, M. D., & Ortega, E. (2022) · Nutrients · doi:10.3390/nu14030612 · Cited by 21
“Schmitz and colleagues demonstrated that weight loss resolved pro-inflammatory gene expression exclusively in the liver, whereas visceral adipose tissue displayed no significant improvement of metabolic and inflammatory markers in comparison to obese mice [130].”
Backgroundde León‐Guerrero, S. D., Salazar‐León, J., Meza‐Sosa, K. F., Valle‐García, D., Aguilar‐León, D., Pedraza‐Alva, G., & Pérez‐Martínez, L. (2022) · Disease Models & Mechanisms · doi:10.1242/dmm.048936 · Cited by 20
la Cruz-Color, L. D., Domı́nguez-Rosales, J. A., Maldonado‐González, M., Ruiz‐Madrigal, B., Sánchez-Muñoz, M. P., Zaragoza-Guerra, V. A., Espinoza-Padilla, V. H., Ruelas-Cinco, E. D. C., Ramírez-Meza, S. M., Torres-Baranda, J. R., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25126420 · Cited by 18
“However, there is still a lack of knowledge on the progression of MASLD to MASH and the possibility of these liver diseases developing into a metabolic disorder [54,66] or remission of MASLD [67].”
BackgroundYin, H., Yuan, F., Jiao, F., Niu, Y., Jiang, X., Deng, J., Guo, Y., Chen, S., Zhai, Q., Hu, C., et al. (2021) · Diabetes · doi:10.2337/db21-0336 · Cited by 15
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Loft, A., Rydbirk, R., Gammelmark, E., Hauwaert, E. L. V., Wernberg, C. W., Møller, A. F., Dam, T. V., Hassan, M. N., Maniyadath, B., Nielsen, R., et al. (2026) · Nature Metabolism · doi:10.1038/s42255-025-01433-4 · Cited by 17
“…weight loss has been reported to either decrease 12 , increase 13,14 or have no effect 15–17 on AT inflammation; however, overall, it seems that the beneficial systemic changes, such as increased insulin sensitivity and decreased systemic inflammation, precede reversal of AT inflammation 15,18,19 .”
Physical Inactivity and Chronic Disease
García-Pérez-de-Sevilla, G., & Pinto, B. S.-P. (2022) · Nutrition Today · doi:10.1097/nt.0000000000000556 · Cited by 15
Bernecker, M., Lin, A., Feuchtinger, A., Molenaar, A., Schriever, S. C., & Pfluger, P. T. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-024-06039-0 · Cited by 14
“Murine models of dietary weight loss thereby revealed a persistent inflammatory signature in both liver and adipose tissues, suggesting an obesogenic memory that may promote weight regain [17–19].”
Revisiting the role of IL-27 in obesity-related metabolic diseases: safeguard or perturbation?
An, J., Fu, D., Chen, X., Guan, C., Li, L., Bai, J., & Lv, H. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1498288 · Cited by 11
Edillor, C. R., Parks, B. W., Mehrabian, M., Lusis, A. J., & Pellegrini, M. A. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00882 · Cited by 11
“It has been hypothesized that thesemethylation changesmay be involved in a “memory” mechanism of weight-regain or persistent accelerated epigenetic aging after weight loss (22).”
BackgroundPost-Dieting Weight Gain: The role of Persistent Microbiome Changes
Thaiss, C. A., Shapiro, H., & Elinav, E. (2017) · Future Microbiology · doi:10.2217/fmb-2017-0045 · Cited by 11
Altered expression of inflammation-associated genes in the hypothalamus of obesity mouse models
Park, J. H., Yoo, Y., Han, J., & Park, Y. J. (2018) · Nutrition Research · doi:10.1016/j.nutres.2018.06.006 · Cited by 11
Lipid-associated macrophages and metabolic inflammatory diseases
Zheng, Y., Tu, D., Dong, C., Zhao, H., & Wang, H. (2026) · Cell Insight · doi:10.1016/j.cellin.2026.100312 · Cited by 12
“…the lipid-regulatory function of LAMs (Jaitin et al., 2019); inhibiting p53 can reduce abnormal LAM accumulation and improve weight loss outcomes (Schmitz et al., 2016); targeting CD36 can block the formation of foam cell-like phenotypes in LAMs and maintain the thermogenic properties of brown…”
Schenk, S., Ravussin, Y., Lacroix, A., Quansah, D. Y., & Puder, J. J. (2024) · Nutrients · doi:10.3390/nu16040560 · Cited by 10
“Moreover, adipocytes can retain a transcriptional memory of obesity that persists even after weight loss [39].”
BackgroundChen, S., Fu, J., Yan, J., Zhao, R., Qian, C., Yisimayili, Z., & Wu, J. (2025) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00071.2025 · Cited by 10
The role of immune cells in obesogenic memory
Sun, M., Zheng, S. Y., Gao, X., & Lin, Z. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-0448-1 · Cited by 10
Mechanisms of Lipid‐Associated Macrophage Accrual in Metabolically Stressed Adipose Tissue
Reinisch, I., Enzenhofer, S., & Prokesch, A. (2025) · BioEssays · doi:10.1002/bies.202400203 · Cited by 11
“Additionally, following bariatric surgery, AT often retains its inflammatory state, as if “remembering” the obese condition despite ongoing weight loss [20].”
Interactions Between the Neuroendocrine System and T Lymphocytes in Diabetes
Andreone, L., Gimeno, M. L., & Perone, M. J. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00229 · Cited by 9
“Interestingly, recent evidences in mice and human suggested that the adipose tissue inflammation associated with obesity, in particular the T cell imbalance, and the impairment in insulin sensitivity, persist even after weight reduction (124, 125).”
BackgroundRodrigues, M. O. M., Evangelista-Silva, P. H., Neves, N. N., Moreno, L. G., Santos, C. S., Rocha, K. L. S., Ottone, V. O., Batista-da-Silva, B., Dias‐Peixoto, M. F., Magalhães, F. D. C., et al. (2020) · Applied Physiology, Nutrition, and Metabolism · doi:10.1139/apnm-2020-0220 · Cited by 11
“Other authors suggested that weight loss does not completely resolve obesity-induced ATM activation, which may have an obesogenic memory, contributing to persistent adipose tissue damage (Kosteli et al. 2010; Schmitz et al. 2016).”
BackgroundEmiliano, A. B., Lopatinsky, N. R., Kraljević, M., Higuchi, S., He, Y., Haeusler, R. A., & Schwartz, G. J. (2022) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00017.2022 · Cited by 9
Identification of adipose tissue transcriptomic memory of anorexia nervosa
Zapata, R. C., Nasamran, C. A., Chilin-Fuentes, D., Dulawa, S. C., & Osborn, O. (2023) · Molecular Medicine · doi:10.1186/s10020-023-00705-7 · Cited by 9
“We and others have reported significant adipose tissue gene expression changes induced by either obesity or caloric restriction-induced weight loss, that persist after restoration of a normal body weight (Hernandez-Carretero et al. 2018; Zapata et al. 2022; Schmitz et al. 2016; Hahn et al. 2019).”
BackgroundRemission of type 2 diabetes: position statement of the Italian society of diabetes (SID)
Capoccia, D., Leonetti, F., Natali, A., Tricò, D., Perrini, S., Sbraccia, P., Guglielmi, V., & On behalf of the Italian Society of Diabetes (SID) (2024) · Acta Diabetologica · doi:10.1007/s00592-024-02317-x · Cited by 10
“…both cellular and humoral, characterizing obesity, remains unchanged even after weight loss [131–134], determining the so-called “inflammatory memory” of obesity [135], to which the immunometabolic and epigenetic reprogramming of bone marrow myeloid precursors may also contribute [133, 136, 137].”
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“…‘obesogenic memory’, whereby prior exposure to excess energy storage induces persistent cellular and molecular adaptations—including alterations in adipocyte biology, inflammatory signalling and epigenetic regulation—that favour the re-establishment of higher adiposity following weight loss [20].”
Ishaq, A., Dufour, D., Cameron, K., von Zglinicki, T., & Saretzki, G. C. (2018) · Experimental Gerontology · doi:10.1016/j.exger.2018.10.008 · Cited by 10
“, 2012), similar to other studies in C57BL/ 6 male mice (Selman and Hempenstall, 2012; Schmitz et al., 2016).”
IMPACT OF BARIATRIC SURGERY ON THE INFLAMMATORY STATE BASED ON CPR VALUE
Migliore, R., Gentile, J. K. D. A., Franca, F. T., Kappáz, G. T., de Souza, P. M. S. B., & Assef, J. C. (2018) · ABCD Arquivos Brasileiros de Cirurgia Digestiva (São Paulo) · doi:10.1590/0102-672020180001e1402 · Cited by 8
How does bariatric surgery remodel adipose tissue?
Lecoutre, S., Rebière, C., Marcelin, G., & Clément, K. (2024) · Annales d Endocrinologie · doi:10.1016/j.ando.2024.05.008 · Cited by 8
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Self-citationGLP-1–Mediated Targeting of Inflammation Corrects Obesogenic Memory in Male Mice
Leon, S., Benoit, J., Clark, S., Zizzari, P., Yang, B. S., Dugail, I., Merabtene, F., Clément, K., Eygret, L., Dupuy, N., et al. (2025) · Diabetes · doi:10.2337/db24-1071 · Cited by 7
CD9 regulates macrophage-mediated remodeling of adipose tissue in obesity
Chini, J., DeMarco, N., Mitchell, D. V., McCright, S. J., Shen, K. M., Pandey, D., Clement, R. L., Miller, J., Jain, R., Taylor, D. M., et al. (2026) · JCI Insight · doi:10.1172/jci.insight.193837 · Cited by 7
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Identification of Lipid Droplet-Associated Genes in Breast Cancer Patients
Doğan, Ş., Leopold, J., Hoffmann, D. T., Kubitschke, H., Blauth, E., Ficorella, C., Zschau, A., Schiller, J., & Käs, J. A. (2024) · Lipidology · doi:10.3390/lipidology1010005 · Cited by 5
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“A recent study found that pair-feeding mice that underwent diet-induced weight reduction with lean control animals efficiently stabilized body weight, indicating that hyperphagia may also be an important contributor to weight regain after a diet change (26).”
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“These phenomena bear similarities to the obe-sogenic memory observed in human WAT that leaves the tissue prone to long-term inflammation and insulin resistance even after obesity is reduced 66–68 .”
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“In the state of energy surplus, the expansion of adipose tissue can occur through two primary mechanisms: adipocyte hyperplasia and hypertrophy [2, 3].”
Why weight loss is only half the battle: The epigenetic memory of adipose tissue
Chew, V. (2025) · Journal of Hepatology · doi:10.1016/j.jhep.2024.12.011 · Cited by 4
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Metadata
- Authors
- Schmitz, J., Evers, N., Awazawa, M., Nicholls, H. T., Brönneke, H. S., Dietrich, A., Mauer, J., Blüher, M., & Brüning, J. C.
- Affiliations
- University of Cologne (DE)
- Leipzig University (DE)
- Corresponding author
- Brüning, J.C.
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 5
- Issue
- 5
- Pages
- 328-339
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC4837291
- OpenAlex
- W2239531983
- Cited by
- 148
- References
- 48
- Citations by year
- 2026: 22 · 2025: 17 · 2024: 17 · 2023: 16 · 2022: 13 · 2021: 14 · 2020: 15 · 2019: 12 · 2018: 8 · 2017: 10 · 2016: 4
- FWCI
- 10.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Surgery › Bariatric Surgery and Outcomes
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- weight regain, weight loss, insulin resistance, liver inflammation, adipose tissue inflammation, hyperphagia, pair feeding, bariatric surgery, glucose homeostasis, type 2 diabetes, visceral adipose tissue, high-fat diet
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