Cells in the body remember obesity. Here’s what that means for weight loss

These cells in the body remember fat. Here’s what that means for weight loss

By Lori Youmshajekian edited by Lauren J. Young

Weight loss is notoriously difficult to maintain. Within a few years, most people regain the pounds they initially lose, whether through dieting, exercise, surgery, or weight loss medications such as the popular glucagon-like peptide 1 (GLP-1) drugs. Recent research suggests that the fat cells’ “memory” may explain why.

Fat-storing cells, or adipocytes, and immune cells, such as macrophages, which live in adipose tissue, can remember weight long after it has been lost. And researchers suggest that obesity causes lasting changes in those cells that make it easier to return to a state of obesity, even after significant weight loss. The changes are etched into the cells’ epigenome, the instructions that tell each cell to read specific genes that control their function, explains Ferdinand von Meyenn, who studies nutrition and metabolic epigenetics at the Swiss Federal Institute of Technology Zurich. This ensures that a liver cell does not suddenly behave like a neuron, for example. In people with obesity, permanent epigenetic changes can make it easier for the body to gain weight if they consume more calories.

Von Meyenn’s team measured gene activity in individual cells using a technique called RNA sequencing to compare adipose tissue from people with obesity before they had bariatric surgery with similar tissue from people who did not have obesity. Even after the obese participants had lost about 25 percent of their body mass index after surgery, some of their genes remained out of whack. This suggests that some adipose tissue did not recover from obesity—certain genes that control metabolic function and inflammation remained abnormally turned on or off, for example, von Meyenn explains.

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Previous studies showed that fat cells in obese mice also retain epigenetic changes even after the animals lose weight. When later fed a high-fat diet, these mice gained weight faster than the control animals. Laboratory tests showed that fat cells from obese mice absorbed glucose and lipids more easily. Fat cells normally take in sugar and lipids, says von Meyenn, but these obesity-altered cells seemed “slightly shifted” to absorb more of these nutrients.

Other research groups have shown that immune cells can also remember previous weight. When a person gains weight, different types of immune cells infiltrate expanding fat tissue, probably as a stress response, explains William Scott, an obesity researcher at Imperial College London. His research showed that, after bariatric surgery, the number of immune cells in people’s adipose tissue dropped dramatically, but not everything was completely restored. The immune cells retained the inflammatory properties that developed when people were overweight.

Research in mice has replicated this finding; even after weight loss, macrophages retain epigenetic changes that keep inflammatory genes more active than usual. Another mouse study shows that weight cycling—losing and gaining weight—can intensify these immune cell changes and worsen metabolic health more than never losing weight.

How long this epigenetic memory lasts is not clear, but fat cells can persist for up to a decade in humans, giving these cells the potential to maintain changes in the long term, says von Meyenn. And fat may not be the only tissue involved. “I think changes are happening in the brain, in the liver, in the muscle,” says von Meyenn, who plans to investigate these areas next.

These findings do not mean that weight loss is pointless; even short-term weight loss correlates with improvements in metabolic health. But the research can help explain why weight relapse is so common and why it is important to avoid weight gain. In an environment and society that makes weight gain widespread, prevention is much easier said than done, says von Meyenn. Researchers, including von Meyenn, are now investigating whether fat cells can be treated to rewrite these epigenetic changes to make weight loss more sustainable and whether different types of weight loss intervention have different effects on these cells.

“There’s a big drive to make our weight-loss drugs (like GLP-1 drugs) more potent” to cause greater weight reductions, Scott says, “but we really need to get better at sustaining weight loss once it happens.”

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