Researchers at ETH Zurich have discovered a mechanism behind the yo-yo effect: fat cells have a memory based on epigenetics.

Zurich, November 18, 2024 Anyone who has put on a few extra kilos and tried dieting is familiar with the phenomenon: the pounds tumble off, but after a few weeks they are back again. The yo-yo effect has struck. Researchers at ETH Zurich have now been able to show what this has to do with: epigenetics.

Epigenetics is the part of genetics that is not based on the sequence of genetic building blocks, but on small but characteristic chemical markers on these building blocks. The sequence of building blocks has evolved over a long period of time; we have all inherited them from our parents. Epigenetic marks, on the other hand, are more dynamic: environmental influences, eating habits and the condition of the body – such as obesity – can change them over the course of a lifetime. They remain stable over many years, sometimes decades. During this time, they play a key role in determining which genes are active in our cells and which are not. ‘Epigenetics tells a cell what kind of cell it is and what it should do,’ says Laura Hinte. She is a doctoral student in the group of Ferdinand von Meyenn, Professor of Nutrition and Metabolic Epigenetics.

Fat cells remember their overweight state

Hinte, von Meyenn and their former colleague Daniel Castellano Castillo looked for the molecular causes of the yo-yo effect in mice. They analysed fat cells from overweight mice and those that had lost their excess weight following a diet. They were able to show that Obesity leads to characteristic epigenetic markings in the nucleus of fat cells. The special thing about this is that these marks remain even after a diet. ‘The fat cells remember the overweight state and can be returned to it more easily,’ says von Meyenn. The scientists were able to show that mice with these epigenetic marks gained weight more quickly when they had access to a high-fat diet again. ‘We have thus found a molecular basis for the yo-yo effect.’

There is also evidence that appears to confirm this mechanism in humans: The ETH researchers analysed fat tissue biopsies from formerly overweight people who had undergone stomach reduction or gastric bypass surgery. The tissue samples were taken from various studies conducted at the Karolinska Institute in Stockholm and at hospitals in Leipzig, Dresden and Karlsruhe. In these samples, the researchers analysed gene activity rather than epigenetic markers. However, the results are consistent with those of the mice. The researchers report their findings in the current issue of the scientific journal Nature.

Prevention is the key

The researchers have not investigated how long fat cells can remember obesity. ‘Fat cells are long-lived cells. They live for an average of ten years before our body replaces them with new cells,’ says Hinte.

At present, it is not possible to change the epigenetic marks in the cell nucleus with drugs and thus erase the epigenetic memory. ‘Perhaps this will be possible in the future,’ says Hinte. ‘But for now, we have to live with this memory effect.’ Von Meyenn adds: ‘It is precisely because of the memory effect that it is so important to avoid obesity in the first place. Because then it is easiest to do something about it’. The researchers are directing this message primarily at children and young people and their parents.

With their work, the ETH researchers have shown for the first time that fat cells have an epigenetic memory for obesity. However, they do not assume that fat cells are the only cells with such a memory. ‘Other body cells could also contribute to the yo-yo effect,’ says von Meyenn. It is quite conceivable that cells in the brain, blood vessels or other organs also remember obesity and contribute to the effect. The researchers next want to find out whether this is actually the case.

Originalpublication:

Hinte LC, Castellano Castillo D, Ghosh A, Melrose K, Gasser E, Noé F, Massier L, Dong H, Sun W, Hoffmann A, Wolfrum C, Rydén M, Mejhert N, Blüher M, von Meyenn F: Adipose tissue retains an epigenetic memory of obesity that persists after weight loss. Nature, 18. November 2024, doi: 10.1038/s41586-024-08165-7

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