People who are overweight often have difficulty losing weight permanently. Even after a successful diet, the excess pounds usually return quickly. A study has now identified a cause for this yo-yo effect. According to this, epigenetic changes ensure that the fat cells remember their previous state even after weight loss and tend to absorb more fat and sugar. However, it is still unclear how long this fat memory lasts.
Epigenetic changes form the link between our genes and our environment. Various environmental influences, including our lifestyle, can cause small chemical tags to attach to our DNA strands. These in turn influence which genes are read and how strongly. Among other things, they shape our metabolism, our susceptibility to certain diseases and our psyche. Unlike our genes, these epigenetic patterns can change throughout our lives. However, they are often stable over many years or decades.
Molecular basis of the yo-yo effect
A team led by Laura Hinte from ETH Zurich has now shown that obesity can affect our epigenetic code – and thus probably contributes to the yo-yo effect. In experiments with mice, the researchers found that obese individuals had different epigenetic patterns in the fat cells compared to their normal-weight counterparts. These patterns remained even when Hinte and her team put the fat mice on a diet until they reached normal weight.
When the researchers provided the mice with high-fat food again, the previously fat animals regained weight more quickly than individuals who had never been overweight before. “The fat cells remember the overweight state and can be returned to it more easily,” says Hinte’s colleague Ferdinand von Meyenn, describing the effect. “We have thus found a molecular basis for the yo-yo effect.”
Reminder of being overweight
In the experiment, the research team found that the fat cells of the formerly fat mice absorbed and stored more sugar and fat than the fat cells of the control mice. Analyzes of the epigenetic changes also revealed that several genes that are important for the normal function of fat cells were downregulated in the formerly overweight animals. Instead, genes that promote inflammation and contribute to the formation of fibrosis, i.e. stiff, scarred tissue, were overactive.
The researchers also found evidence of this mechanism in humans. To do this, they analyzed fatty tissue biopsies from formerly overweight people who had undergone stomach reduction or gastric bypass surgery and reduced their body mass index (BMI) by at least 25 percent. But as Hinte and her team found, the bodies of these people still seemed to “remember” their previous excess weight: even two years after the operation, the same genes associated with excess weight were still present in the fat cells of the formerly obese people read.
Long-lived cells – long memory?
How long the epigenetic patterns persist is still unclear. “Fat cells are long-lived cells. On average, they live ten years before our body replaces them with new cells,” says Hinte. This fat memory cannot yet be erased using current methods such as special medications. “Perhaps this will be possible in the future,” says Hinte. “But for now we have to live with this memory effect.” According to the researchers, it is all the more important to prevent obesity at an early stage. That would be easier than fighting it later. At the same time, they hope that their results will help reduce the stigmatization of overweight people. “It’s not your fault,” says Hinte.
However, it is not yet completely clear whether there is actually a causal relationship between the epigenetic changes and the yo-yo effect. “So far we can only prove a correlation,” says von Meyenn.
Source: Laura Hinte (ETH Zurich, Switzerland) et al., Nature, doi: 10.1038/s41586-024-08165-7