Incluso después de una pérdida drástica de peso, las células grasas del cuerpo conservan la “memoria” de la obesidad, un hallazgo que podría ayudar a explicar por qué puede ser difícil mantenerse en forma después de un programa de pérdida de peso. Este "recuerdo" surge porque la obesidad conduce a cambios en el epigenoma, que son un conjunto de etiquetas químicas que se pueden agregar o eliminar del ADN y las proteínas de las células que ayudan a aumentar o disminuir la actividad genética. En el caso de las células grasas, este cambio incapacitarlas para realizar su función normal.

Este deterioro, así como los cambios en la actividad genética, pueden persistir mucho después de haber alcanzado el peso ideal a niveles saludables. Las personas que intentan adelgazar a menudo necesitarán cuidados a largo plazo para evitar recuperar peso

Reducir y mantener el peso corporal es fundamental para combatir la obesidad, pero el organismo parece conservar una memoria metabólica que impide el éxito a largo plazo. En este trabajo exploramos este fenómeno y demostramos que las células del tejido adiposo humano y de ratón conservan una memoria obesogénica funcional tras una pérdida de peso

Las células adiposas guardan "memoria" de la obesidad, un indicio de por qué es difícil no engordar.

Los cambios duraderos en el epigenoma de las células están relacionados con el deterioro de su función.

Even after drastic weight loss, the body’s fat cells carry the ‘memory’ of obesity, research¹ shows — a finding that might help to explain why it can be hard to stay trim after a weight-loss programme.

This memory arises because the experience of obesity leads to changes in the epigenome — a set of chemical tags that can be added to or removed from cells’ DNA and proteins that help to dial gene activity up or down. For fat cells, the shift in gene activity seems to render them incapable of their normal function. This impairment, as well as the changes in gene activity, can linger long after weight has dropped to healthy levels, a study published today in Nature reports.

The results suggest that people trying to slim down will often require long-term care to avoid weight regain, says study co-author Laura Hinte, a biologist at ETH Zurich in Switzerland. “It means that you need more help, potentially,” she says. “It’s not your fault.”

Although we’ve long known that the body tends to revert to obesity after weight loss, “how and why this happens was almost like a black box”, says Hyun Cheol Roh, an epigenome specialist at Indiana University School of Medicine in Indianapolis who studies metabolism. The new results “show what’s happening at the molecular level, and that’s really cool”.

A lingering memory

To understand why weight can pile back on so quickly after it is lost, Hinte and her colleagues analysed fat tissue from a group of people with severe obesity, as well as from a control group of people who had never had obesity. They found that some genes were more active in the obesity group’s fat cells than in the control group’s fat cells, whereas other genes were less active.

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Even weight-loss surgery did not budge that pattern. Two years after the participants with obesity had had weight-reduction operations, they had lost large amounts of weight — but their fat cells’ genetic activity still displayed the obesity-linked pattern. The scientists found similar results in mice that had lost large amounts of weight.

In the fat cells of both humans and mice, the genes dialled up during obesity are involved in spurring inflammation and fibrosis — the formation of stiff, scar-like tissue. The genes that are turned down help fat cells to function normally. Research on mice traced these shifts in gene activity to changes in the epigenome, which has a powerful effect on how active a gene is, including whether it is turned on at all.

The scientists tested the durability of these changes by putting obese mice on a diet. A few months after the mice had become lean again, the changes in their epigenomes persisted, as if the cells ‘remembered’ being in a body with obesity.

Rapid regain

It’s not clear how long the body remembers obesity for, says study co-author Ferdinand von Meyenn, an epigenome specialist at ETH Zurich. “There may be a time window when this memory will be lost,” he says. “But we don’t know.”

To better understand the effects of this memory, the researchers studied fat cells from mice that had slimmed down after being obese. These cells absorbed more sugar and fat than did fat cells from control mice that had never been obese. The formerly obese mice also gained weight faster on a high-fat diet than control mice did.

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But scientists not involved in the study, including Roh, note that the paper doesn’t prove that the epigenetic alterations caused the physical changes in the mice. The paper’s list of epigenetic alterations in fat cells is valuable, says biologist Evan Rosen at Beth Israel Deaconess Medical Center in Boston, Massachusetts, who studies fat tissue, but it will be difficult to determine which of those changes drive the fat cells’ lingering memory.

“It’s not yet a causal link,” agrees von Meyenn. “It’s correlation. … We’re working on this.”

Preventing obesity to begin with is key, von Meyenn adds. People who lose weight “can [stay] lean, but it will require a lot of effort and energy to do that”, he says, adding that his team’s findings could help to remove some of the stigma surrounding obesity.

doi: https://doi.org/10.1038/d41586-024-03614-9

References

Hinte, L. C. et al. Nature https://doi.org/10.1038/s41586-024-08165-7 (2024).

https://www.nature.com/articles/d41586-024-03614-9

Adipose tissue retains an epigenetic memory of obesity after weight loss

Nature (2024)Cite this article

Abstract

Reducing body weight to improve metabolic health and related comorbidities is a primary goal in treating obesity^1,2. However, maintaining weight loss is a considerable challenge, especially as the body seems to retain an obesogenic memory that defends against body weight changes^3,4. Overcoming this barrier for long-term treatment success is difficult because the molecular mechanisms underpinning this phenomenon remain largely unknown. Here, by using single-nucleus RNA sequencing, we show that both human and mouse adipose tissues retain cellular transcriptional changes after appreciable weight loss. Furthermore, we find persistent obesity-induced alterations in the epigenome of mouse adipocytes that negatively affect their function and response to metabolic stimuli. Mice carrying this obesogenic memory show accelerated rebound weight gain, and the epigenetic memory can explain future transcriptional deregulation in adipocytes in response to further high-fat diet feeding. In summary, our findings indicate the existence of an obesogenic memory, largely on the basis of stable epigenetic changes, in mouse adipocytes and probably other cell types. These changes seem to prime cells for pathological responses in an obesogenic environment, contributing to the problematic ‘yo-yo’ effect often seen with dieting. Targeting these changes in the future could improve long-term weight management and health outcomes.

Main

Obesity and its related comorbidities represent substantial health risks¹. A primary clinical objective in managing obesity is to achieve appreciable weight loss (WL), typically through rigorous dietary and lifestyle interventions, pharmaceutical treatments or bariatric surgery (BaS)². Strategies relying on behavioural and dietary changes frequently only result in short-term WL and are susceptible to the ‘yo-yo’ effect, in which individuals regain weight over time^3,5,6. This recurrent pattern may be partially attributable to an (obesogenic) metabolic memory that persists even after notable WL^4,7,8,9,10 or metabolic improvements^11,12,13. Indeed, lasting phenotypic changes from previous metabolic states, that is, metabolic memory, have been reported in mouse adipose tissue (AT) or the stromal vascular fraction (SVF)^14,15,16, whereas in liver these were reversible^15,16,17. Persistent alterations after WL in the immune compartment¹⁸, and transcriptional and functional memory of obesity in endothelial cells of many organs^19,20,21,22, have also been reported.

Epigenetic mechanisms and modifications are essential for development, differentiation and identity maintenance of adipocytes in vitro and in vivo^{23,24,25,26,27}, but are also expected to be crucial contributors to the cellular memory of obesity^4,7. For example, lasting chromatin accessibility changes have been associated with pathological memory of obesity in mouse myeloid cells²⁸ and, also, cold exposure studies have indicated the existence of (epigenetic) cellular memory^26,29. Hitherto, most human studies have focused on DNA methylation analysis in bulk tissues or whole blood to assess putative cellular memory^30,31,32,33. These reports might be confounded by variations in cell type composition, which are poorly characterized in the AT during WL, and therefore serve foremost as indicators of cellular epigenetic memory.

In summary, it remains unresolved whether individual cells retain a metabolic memory and whether it is conferred through epigenetic mechanisms. Here, we set out to address this by first performing single-nucleus RNA sequencing (snRNA-seq) of AT from individuals living with obesity before and after significant WL, as well as lean, obese and formerly obese mice, confirming the presence of retained transcriptional changes, and, second, by characterizing the epigenome of mouse adipocytes, which revealed the long-term persistence of an epigenetic obesogenic memory.

Transcriptional changes in human AT

To explore whether signatures of previous obesogenic states persist in humans after appreciable WL, we obtained subcutaneous AT (scAT) and omental AT (omAT) biopsies from individuals with healthy weight who have never had obesity (called healthy weight here) and people living with obesity (but without diabetes) before (T0) and 2 yr after (T1) BaS from multiple independent studies (Fig. 1a).

https://www.nature.com/articles/s41586-024-08165-7

The Ghost of Obesity Past : How Adipose Tissue Remembers Obesity

Reducing and maintaining body weight are key in tackling obesity, but the body seems to retain a metabolic memory impeding long-term success. Here, we explore this phenomenon and show that cells in human and mouse adipose tissue retain a functional obesogenic memory after substantial weight loss.

How It All Began

This project stemmed from our curiosity about whether cells retain an epigenetic memory of prior metabolic states. Epigenetic memory is well-known for explaining how daughter cells maintain their transcriptional identity through cell division, playing a vital role in development, regeneration, and growth. But what about non-dividing cells? They too must adapt to external stimuli and therefore undergo epigenetic adaptations. If so, are these changes embedded in the epigenome during chronic conditions like obesity? And, most importantly, are they fully reversible?

Obesity is a chronic condition with significant metabolic consequences, strongly linked to various metabolic and cardiovascular diseases. A well-documented observation is that the body tends to defend increased body weight, making weight loss and maintenance notoriously challenging. This could be due to a type of "metabolic memory," where the body remembers and strives to return to its former state of obesity. This notion has been explored in the context of improving glycemic control in diabetes, where metabolic improvements can have lasting effects, even if control is lost again.

Could epigenetic changes at the cellular level drive this metabolic memory in obesity? One metabolic organ heavily impacted by both obesity and weight loss is adipose tissue. Adipocytes, with a remarkable lifespan of around 10 years, do not divide, making them an ideal model for studying epigenetic memory. Additionally, adipose tissue is easily accessible for human biopsies, allowing for longitudinal studies—something not feasible for most other organs.

Our study focused on three main areas:

The cellular remodeling of adipose tissue after weight loss.
Investigating transcriptional memory across all adipose tissue cell types using single-nucleus RNA sequencing (snRNAseq).
Using mouse models to analyze the epigenetic changes in adipocytes and assess their retention post-obesity.

What we found

We collected human subcutaneous and visceral adipose tissue biopsies from 20 individuals living with obesity but without metabolic disease. These samples were obtained both pre- and post-bariatric surgery, with substantial weight loss over two years. Collaborators from Germany and Sweden provided the biopsies. Using snRNAseq, we compared gene expression across various cell types in adipose tissue during obesity and after weight loss to cells from normal weight donors.

Unsurprisingly, we found differences in gene expression between cells from obese and lean individuals. However, the most striking discovery was that many of these differences persisted even after significant weight loss. This phenomenon was especially prominent in adipocytes, endothelial cells, and precursor cells, suggesting that these cells retain a transcriptional memory of obesity that remains long after weight reduction.

However, given the inherent limitations of human studies, such as genetics, nutritional status, the environment etc., we extended our analysis to mice. We induced obesity in mice through a high-fat diet (HFD) and then reversed it by switching them back to a standard chow diet. Unlike most dieting humans, mice achieved rapid weight loss, reaching body weights comparable to age-matched controls within 4-8 weeks. They exhibited normal metabolic function, including liver fat clearance, normalised insulin and leptin levels, and showing a near-complete restoration of energy expenditure.

Despite these apparent recoveries, the snRNAseq analysis of their adipose tissue revealed that adipocytes, endothelial cells, and precursors retained a transcriptional memory of obesity, consistent with our human data. This finding confirmed that metabolic memory is not exclusive to humans.

To further explore the epigenetic landscape of adipocytes, we leveraged two advanced techniques: Adipocyte specific reporter mice and chromatin profiling methods (CUT&Tag), allowing us to examine four specific epigenetic marks (H3K4me3, H3K27me3, H3K4me1, H3K27ac) known to regulate gene expression and chromatin structure. We specifically analyzed adipocytes that had existed prior to HFD exposure to ensure consistency across experimental and control groups. Our results showed obesity-induced epigenetic changes at thousands of loci, affecting all four marks and accessbility. In line with our transcriptomic findings, many of these changes persisted after weight loss. For instance, promoters that should be active remained silenced, and the enhancer landscape was remodeled, suggesting that adipocytes truly retain an epigenetic memory of obesity.

Cuando desafiamos a estos adipocitos retenedores de memoria con palmitato y glucosa ex vivo, mostraron una respuesta más rápida en comparación con los controles. Del mismo modo, los ratones recuperaron peso más rápidamente cuando se les reintrodujo una dieta rica en grasas, y su tejido adiposo se expandió a mayor velocidad. La memoria epigenética pudo incluso predecir diferencias en la expresión génica tras la reintroducción. Estas observaciones indican que la memoria epigenética predispone a los individuos anteriormente obesos a recuperar peso más fácilmente, lo que pone de relieve las consecuencias a largo plazo de la obesidad sobre la función del tejido adiposo.

Why It Matters

This is one of the first studies to demonstrate that specific cell types can retain an epigenetic memory of a prior metabolic state. This finding has profound implications for our understanding of obesity, weight loss, and weight maintenance. On a societal level, this could offer some solace to individuals struggling with obesity, as it suggests that the difficulty in maintaining weight loss may not be due solely to a lack of willpower or motivation, but rather to a deeper cellular memory that actively resists change.

Moreover, if such epigenetic memories are found in other cell types, such as neurons, or in contexts like addiction, it could open new avenues for therapeutic interventions. Understanding and potentially reversing these epigenetic changes could have far-reaching implications for treating chronic conditions associated with metabolic memory.

What’s Next?

The question remains: why isn’t this epigenetic memory erased over time? Could it be because adipocytes do not divide? Or perhaps other cell types are similarly affected? Could it be that we merely need to stay lean long enough for the memory to vanish? The next steps will involve developing tools to precisely modify the epigenome at hundreds of loci to test whether altering these marks can reverse the obesogenic memory and its associated phenotypes. Additionally, it will be crucial to investigate whether long-lived cells, such as neurons in the hypothalamus, also retain an epigenetic memory of obesity.

https://communities.springernature.com/posts/the-ghost-of-obesity-past-how-adipose-tissue-remembers-obesity

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lunes, 18 de noviembre de 2024

El fantasma de la obesidad del pasado: cómo el tejido adiposo recuerda la obesidad-Las células adiposas guardan "memoria" de la obesidad