Maintaining weight loss remains a formidable challenge in the treatment of obesity, despite its numerous benefits for metabolic health and associated comorbidities. Recent research has shed light on the concept of “obesogenic memory,” where the body retains a cellular recollection of previous weight states, hindering sustained weight loss[1],[2]
This short piece aims to dissect the molecular mechanisms underlying this phenomenon, exploring the role of epigenetic modifications in adipose tissue and their implications for clinical practice.
Obesity and Metabolic Health
Obesity is a multifactorial disease characterised by an imbalance in energy metabolism, leading to excessive adiposity and an increased risk of chronic diseases such as type 2 diabetes and cardiovascular disease[3]. Despite the complexity of obesity, recent advances in epigenetics have shed light on the critical role of epigenetic modifications in regulating energy metabolism and expenditure[4].
The Concept of Obesogenic Memory
Recent studies and the one presented in Nature in November 2024 have demonstrated that adipose tissue exhibits cellular transcriptional changes after substantial weight loss, suggesting the presence of an obesogenic memory. This phenomenon is thought to contribute to the “yo-yo” effect observed in individuals who experience repeated cycles of weight loss and regain.
Epigenetic Modifications in Adipose Tissue
Epigenetic changes, particularly DNA methylation and histone modification, play a crucial role in regulating gene expression in response to environmental cues. Epigenetics focuses on modifications to our genetic material that don’t alter the underlying DNA sequence but involve small, distinct chemical markers attached to the genetic building blocks. While the DNA sequence itself evolves over generations and is inherited from our parents, epigenetic markers are far more dynamic. They can be influenced by environmental factors, dietary habits, and physiological conditions, such as obesity, throughout an individual’s lifetime[5].
Despite their flexibility, these markers can remain stable for years, even decades, playing a critical role in regulating gene activity. Essentially, epigenetics acts as a cellular guide, instructing each cell on its identity and function. The authors of the Nature paper demonstrate that obesity induces persistent epigenetic alterations in adipocytes, affecting their function and response to metabolic stimuli. They also report that whilst the incretin receptor agonists, such as semaglutide and tirzepatide, have gained recognition as promising non-invasive strategies for achieving significant weight loss, the durability of the weight loss and associated physiological changes following treatment cessation remains insufficiently explored. Research on these agents indicates that substantial weight regain occurs after discontinuation, suggesting that these treatments do not produce stable or lasting effects. That they do not reset epigenetic influences and that other, more progressive lifestyle behaviour adoptions and specific nutrients need to be persistently implemented.
Lifestyle Interventions
- Diet: Nutrients and dietary patterns can influence epigenetic modifications. For example:
- Folate, vitamin B12, and other methyl-donor nutrients can impact DNA methylation[6].
- Polyphenols (e.g., from green tea or curcumin) have been shown to modulate histone acetylation and methylation[7]. Epigenetic dysregulations can be restored, and it has been reported that certain natural products obtained from plants, such as tea polyphenols, ellagic acid, urolithins, curcumin, genistein, isothiocyanates, and citrus isoflavonoids, were shown to inhibit weight gain. These substances have great antioxidant potential and are of great interest because they can also modify epigenetic mechanisms.
- Physical Activity: Exercise has been linked to changes in DNA methylation and histone modifications, particularly in genes associated with metabolism and inflammation.
- Stress Reduction: Psychological stress influences epigenetic markers, and interventions such as mindfulness or therapy may help modulate these effects.
Prevention
The duration of obesity-related epigenetic memory in fat cells remains unclear. Fat cells, which have an average lifespan of approximately ten years before being replaced, may retain these marks for extended periods. Currently, there are no pharmaceutical, but there are nutritional and nutraceutical interventions available to alter or erase the relevant epigenetic markers within the cell nucleus. Avoiding obesity in the first place is the most effective way to mitigate the yo-yo phenomenon. This message is particularly directed at children, adolescents, and their parents.
The researchers’ work demonstrates for the first time that fat cells harbour an epigenetic memory of obesity. However, they propose that other cell types may also retain such memory. It is plausible that cells in the brain, blood vessels, or other organs contribute to the yo-yo effect. Future research will aim to determine whether these additional cell types are involved in the phenomenon.
Clinical Implications and Future Directions
Understanding the molecular mechanisms underlying obesogenic memory offers valuable insights for developing novel therapeutic strategies aimed at improving long-term weight management and metabolic health. Potential approaches include:
- Nutritional and lifestyle interventions designed to reverse epigenetic changes
- Combination therapies incorporating existing weight loss management with epigenetic modulators
By acknowledging the complexities of obesity and its associated epigenetic landscape, practitioners can better support patients in achieving sustainable weight loss and improved metabolic well-being.
References
[1] Hinte, L.C., Castellano-Castillo, D., Ghosh, A. et al. Adipose tissue retains an epigenetic memory of obesity after weight loss. Nature (2024).
[2] Nordmo M, Danielsen YS, Nordmo M. The challenge of keeping it off, a descriptive systematic review of high-quality, follow-up studies of obesity treatments. Obes Rev. 2020 Jan;21(1):e12949.
[3] Smith ENL, Chandanathil M, Millis RM. Epigenetic Mechanisms in Obesity: Broadening Our Understanding of the Disease. Cureus. 2023 Oct 28;15(10):e47875.
[4] Mahmoud AM. An Overview of Epigenetics in Obesity: The Role of Lifestyle and Therapeutic Interventions. Int J Mol Sci. 2022 Jan 25;23(3):1341.
[5] Contreras RE, Schriever SC, Pfluger PT. Physiological and Epigenetic Features of Yoyo Dieting and Weight Control. Front Genet. 2019 Dec 11;10:1015
[6] Nicoletti CF, Assmann TS, Souza LL, Martinez JA. DNA methylation and non-coding RNAs in metabolic disorders: Epigenetic Roles of Nutrients, Dietary Patterns and Weight Loss Interventions for Precision Nutrition. Lifestyle Genom. 2024 Oct 31:1-27.
[7] Chen P, Wang Y, Chen F, Zhou B. Epigenetics in obesity: Mechanisms and advances in therapies based on natural products. Pharmacol Res Perspect. 2024 Feb;12(1):e1171.
