Obesity rates are increasing in the United States and around the world, and the condition has been linked to increases in the risks of a wide range of health disorders, including diabetes and cardiovascular disease. There are many different weight loss strategies, like dieting and medications, but studies have suggested that many people who lose weight fail to maintain that loss over long periods of time. This pattern, which was associated with dieting and weight loss prior to the emergence of new drugs such as Ozempic and Wegovy, is known as yo-yo dieting, or the yo-yo effect.
Scientists have now found a physiological explanation for the yo-yo effect, in which people who lose excess pounds have difficulty keeping the weight off. The research has shown that epigenetics, or changes to the genome that do not alter the DNA sequence but can affect gene expression, is to blame. The findings have been reported in Nature.
In this study, the researchers examined a mouse model of obesity, and focused on the genomes inside of the fat, or adipose cells. They analyzed the epigenetics of adipose cells from mice that were either overweight, or those that had loss weight after diet restriction. This effort showed that obesity alters the epigenetics of adipose cells. Those epigenetic alterations remained in place even when mice had loss weight.
The study authors suggested that these epigenetic factors act as a kind of cellular memory in fat cells, that makes it difficult for them to change. "The fat cells remember the overweight state and can return to this state more easily," said corresponding study author Ferdinand von Meyenn, a Professor of Nutrition and Metabolic Epigenetics at ETH Zurich.
Mice that carried certain epigenetic markers after obesity also regained weight faster when they were able to consume a high-fat diet again. "That means we've found a molecular basis for the yo-yo effect," suggested von Meyenn.
While these findings have not been confirmed in humans, there is evidence that the mechanism works in the same way in people as it did in mice.
The investigators also assessed biopsies of fat tissue obtained from stomach reduction or gastric bypass surgery patients. The analysis in this case was centered on gene expression levels, and not epigenetic data, but it did align with the findings from the mouse models.
There are still other questions, such as how long this epigenetic memory might be retained. First study author and graduate student Laura Hinte noted that fat cells can surive in the body for an average of ten years before they are replaced by new ones.
Right now, there aren't any medications that alter the epigenome. "It's precisely because of this memory effect that it's so important to avoid being overweight in the first place, because that's the simplest way to combat the yo-yo phenomenon," added von Meyenn.
The researchers also noted that while adipose cells were analyzed in this research study, there may be other cells that can influence the yo-yo effect, including neurons or vascular cells. They are interested in looking for other influential cells in future studies.
Sources: ETH Zurich, Nature