Scientists have long suspected that biological “memories” of obesity may hinder weight loss maintenance. Now, a groundbreaking study confirms that, providing evidence of an “obesogenic memory” in adipose tissue that persists long after the weight is gone.

Your weight has an “inertia”

Weight loss is rarely easy. Despite significant advances in dietary regimens, pharmaceuticals, and surgical interventions, lost weight tends to come back. This is sometimes called the yo-yo effect: people who lose weight often gain it back, sometimes exceeding their initial weight.

The recurrence of weight gain was traditionally blamed on human failure — either a lapse in lifestyle or willpower. But a new study suggests otherwise: it’s influenced by a biological memory of obesity.

It’s not the first time researchers are discussing the idea of obesity memory. This phenomenon has previously been attributed to metabolic memory and was demonstrated in other tissues like liver and endothelial (skin) cells. However, this phenomenon has remained unexplained in adipose tissue — the body’s primary fat storage system.

This new study, conducted by an international team and published in Nature, reveals the molecular underpinnings of this phenomenon in both humans and mice, pointing to epigenetic changes in fat cells as a potential culprit for the yo-yo effect.

Genetics and The Yo-yo Effect

The researchers employed advanced single-nucleus RNA sequencing (snRNA-seq) to examine changes in adipose tissue (body fat) at the cellular level. They analyzed samples from humans undergoing bariatric surgery and obese mice subjected to weight-loss diets.

“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,” write the authors of the new research, spearheaded by Laura C. Hinte and Daniel Castellano-Castillo from ETH Zurich. “This recurrent pattern may be partially attributable to an (obesogenic) metabolic memory that persists even after notable weight loss or metabolic improvements.”

In mice, transcriptional changes persisted as they adhered to a weight loss diet. Transcriptional changes are alterations in gene activity, where specific genes are either turned on or off, leading to shifts in the production of proteins and the overall function of cells. These changes primed the fat cells to react abnormally when re-exposed to high-fat diets and promote accelerated weight regain.

Mice with a history of obesity gained weight faster than their counterparts when reintroduced to high-fat diets, underscoring the priming effect of epigenetic memory.

In humans, something similar happened. Patients continued to exhibit obesity-induced gene expression changes even after significant weight loss. These changes were most prominent in fat cells, progenitor cells (cells that can divide and differentiate into specific cell types.), and endothelial cells.

Epigenetics, not discipline

Epigenetics involves chemical modifications to DNA and associated proteins that regulate gene activity without altering the DNA sequence. These changes can persist long-term and influence how genes respond to environmental stimuli.

After obesity or significant weight gain kicks in, some cells seem to gain a “memory of it” and are prone to returning to this state. Even after weight normalization, many of these epigenetic modifications persisted.

The discovery of epigenetic memory in fat cells has profound implications for obesity treatment. It suggests that traditional approaches — diet, exercise, and even surgery — may not fully reset the body’s metabolic state. The researchers emphasize that in the light of the current Ozempic (semaglutide craze), this could be significant.

“Studies on semaglutide and on tirzepatide have shown that substantial weight regain occurs after their withdrawal indicating that at least these treatments do not induce stable, persistent changes. Whether this is also the case for other agonists remains to be investigated. Further studies are needed to elucidate whether these treatments could erase or diminish an obesogenic memory better than other non-surgery-based weight loss strategies.”

While the findings may be disheartening, it’s not all bad. This memory can probably be retrained. If you stabilize a new memory at the desired weight, it could even help you maintain your weight. Still, this is speculative and it’s not clear if the memory works both ways.

Technologies such as CRISPR-based tools could theoretically erase or rewrite obesity-induced epigenetic marks, offering a way to truly reset adipose tissue. Further, drugs aimed at modifying epigenetic pathways might help prevent the retention of obesogenic memory.

The Broader Significance

The persistence of an obesogenic memory in fat cells highlights the complexity of tackling obesity. Weight loss alone isn’t enough to erase the molecular traces of the past. However, by unraveling the epigenetic mechanisms underpinning this memory, researchers are paving the way for more effective, long-lasting treatments.

The concept of cellular memory extends beyond obesity. Similar mechanisms may be at play in other chronic conditions, such as diabetes or cardiovascular disease. Understanding how cells remember past states — and how to reset them — could revolutionize the treatment of these diseases.

Understanding individual epigenetic profiles could allow for more tailored weight management and healthcare strategies.

The study “Adipose tissue retains an epigenetic memory of obesity after weight loss” was published in Nature.