Researchers Uncover Cause Behind the “Yo-Yo Effect” of Weight Loss Diets

Anyone who has ever entered the vicious cycle of dieting has undoubtedly experienced this. After too rapid weight loss, weight regain occurs just as quickly, until the initial weight is exceeded. So we go back on the diet and lose more weight… only to gain even more back once the diet is over, and so on. This is what we call the “yo-yo effect”. A team of researchers closely studied the phenomenon to determine its root causes. They discovered the existence of a “memory of obesity”.

Currently, it is estimated that one in eight people in the world is obese. However, this chronic disease increases the risk of type 2 diabetes, heart disease and certain cancers. In addition, it seriously impacts daily life, generating significant musculoskeletal disorders that hamper mobility. To limit risks and improve quality of life, substantial weight loss is essential. However, maintaining weight loss is a considerable challenge.

Strategies based on behavioral and dietary changes often only result in short-term weight loss and are susceptible to the yo-yo effect. Research has suggested that this effect may result from a cellular memory of obesity. This would persist even after notable weight loss or metabolic improvements. The molecular mechanisms underlying this phenomenon were until now largely unknown. It was therefore difficult to ensure the long-term success of weight loss diets.

Persistent cellular changes

Researchers from ETH Zurich set out to study this memory of obesity more closely. They suspected epigenetic mechanisms of being at the origin of the phenomenon. As a reminder, epigenetics concerns not the genes themselves, but the chemical markers which determine the way in which they are expressed. We inherit our genes from our parents. Epigenetic markers, on the other hand, are dynamic and can change over the course of life. Different factors or experiences can modify them: the environment, diet, the state of the body, stress, etc.

They can also remain stable for many years, sometimes decades. They then play a key role in determining which genes are active in our cells and which are not. “ Epigenetics tells a cell what type of cell it is and what it should doe,” explains Laura Hinte, specialist in nutrition and metabolic epigenetics, and co-author of the study.

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To determine whether epigenetic mechanisms were indeed involved in metabolic memory, Hinte and his colleagues carried out RNA sequencing of adipose tissue cells from people of healthy weight, who had never been obese, and from people suffering from obesity, before and two years after bariatric surgery (having caused significant weight loss, with a BMI reduced by at least 25%).

The analysis showed that many genes were differentially expressed between healthy weight and obese individuals. The researchers also found that in obese people, many cell types retained these transcriptional differences after weight loss. Adipocytes, in particular, showed strong retention of these differences. “ These results indicate that obesity induces cellular and transcriptional (obesogenic) changes in adipose tissue, which are not resolved after significant weight loss. », they conclude in Nature.

Cells that react more quickly to sugar and fat

The team then performed the same analyzes on cells from normal weight, obese and formerly obese mice. Again, they observed the presence of numerous transcriptional changes in obesity, which persisted even after appreciable weight loss. Obesity therefore causes characteristic and lasting changes in the nucleus of adipose cells.

Their attention then focused on the mechanisms underlying this persistence. By carrying out an epigenetic analysis of mouse adipocytes, they found lasting alterations in the epigenome, induced by obesity. Hundreds of adipocyte promoters were marked differently in obese mice.

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These changes negatively affect adipocyte functions (e.g., adipogenesis, triglyceride synthesis, leptin and adiponectin signaling, etc.) and their response to nutritional stimuli. Indeed, adipocytes from mice that lost weight showed increased absorption of glucose and palmitate compared to controls. Thus, when they again had access to a richer diet, the mice carrying this obesogenic memory regained weight more quickly than the control mice, having never been obese.

Lare mice obese people put on a diet (HC) And mice who have always had a normal diet (CC) have received a high-fat diet (HFD) for 4 weeks. It appears that mice that had been obese regained weight more quickly, a characteristic of the yo-yo effect. Their gfasting blood sugar is also higher. Credits: Hinte et al., Nature (2024)

“ Lhe fat cells remember their previous obese state and probably aim to return to that state. This memory appears to prepare cells to respond more quickly, and perhaps also in unhealthy ways, to sugars or fatty acids », explains to Guardian Professor Ferdinand Von Meyenn, lead author of the study.

Avoiding excess weight remains the best prevention

Thanks to their work, the researchers demonstrated, for the first time, the existence of an epigenetic memory of obesity in adipocytes. Fat cells remember the overweight state and can return to it more easily: this is the molecular basis of the yo-yo effect. Changes induced by past obesity appear to prepare cells for pathological responses in an obesogenic environment. Targeting these changes in the future could improve long-term weight management and health outcomes.

Researchers have not yet determined how long fat cells can remember being overweight. But this effect could potentially last for years, because these cells have a long lifespan. “ On average, they live ten years before our body replaces them with new cells », specifies Laura Hinte. It is possible that maintaining a reduced or healthy weight for a sufficiently long period of time is sufficient to modify the relevant epigenetic markers and thus, erase the memory.

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Unfortunately, it is currently not possible to do this with medication. For now, we have to live with it. This is why it is so important to avoid being overweight from an early age. “ It is indeed the simplest way to combat the yo-yo phenomenon. », insists Von Meyenn.

Note that it could be that fat cells are not the only ones to have such a memory. Other body cells could also play a role in the yo-yo effect. Thus, brain cells, blood vessels or other organs could also remember past excess weight. This memory could affect the amount of food eaten and the amount of energy expended.

“ From an evolutionary perspective, this makes sense. Humans and other animals have adapted to preserve their weight rather than losing it, as food shortage was historically a common challenge », Notes Laura Hinte.