Fat cells’ ‘memory’ of prediabetes could make maintaining weight loss after bariatric surgery more difficult

Prediabetes may leave a lasting molecular “footprint” on adipose (fat) tissue which appears to make maintaining weight loss after bariatric surgery more difficult, according to new research being presented at the European Congress on Obesity (ECO) in Istanbul, Turkey (12–15 May).

“Our findings suggest that prediabetes is associated with persistent changes in fat tissue that may limit its ability to fully adapt after weight loss,” said author Camila Milad from Hospital Clinic de Barcelona, Barcelona, Spain. “This could help explain why some patients are more prone to weight regain despite initial success with weight loss after bariatric surgery.”

She added, “We found that in women with severe obesity and prediabetes, fat tissue does not fully recover its normal function after weight loss. This means it may struggle to process fats efficiently, which could make it harder to maintain the benefits of bariatric surgery over time.”

Bariatric surgery induces marked weight loss and metabolic improvement in people with severe obesity, including remission of prediabetes in many cases. However, long-term outcomes remain variable, with a significant proportion of patients experiencing weight regain or metabolic relapse.

The extent to which prediabetes may induce persistent molecular changes in adipose tissue, potentially influencing the response to surgery, remains poorly understood.

To find out more, Spanish researchers set out to investigate whether prediabetes is associated with sustained changes in gene expression in fat tissue after bariatric surgery, and whether these changes relate to weight outcomes in 78 women with severe obesity (25–65 years; BMI 39–49 kg/m²) attending a specialized obesity unit at Hospital Clinic de Barcelona, Spain.

Participants were classified into two groups based on fasting glucose and HbA1c levels. The group with normal glucose tolerance (43 women) had fasting glucose below 100 mg/dL and HbA1c below 5.7%. The prediabetes group (35 women) had fasting glucose between 100 and 125 mg/dL and/or HbA1c between 5.7% and 6.4%.

Researchers analyzed gene expression in subcutaneous fat tissue samples collected at the time of surgery and one year later, using microarray technology, in a representative subgroup of 11 women from each group.

They also measured participants’ height, weight, and body mass index (BMI), along with fasting glucose, insulin responses and lipid profile (including cholesterol and triglycerides). In addition, body composition (fat and lean mass) was assessed by DEXA, and liver fat was evaluated using ultrasound. A mixed-meal test was performed to examine the metabolic response to food. Weight changes were tracked for up to three years.

An epigenetic memory of prediabetes

The researchers found that before surgery, women with prediabetes had higher glucose and insulin responses during the mixed-meal test, a higher prevalence of fatty liver (hepatic steatosis; 88% vs. 57%), and a less favorable lipid profile, including higher cholesterol and triglyceride levels, compared with women with normal glucose tolerance.

One year after surgery, glycemic and metabolic parameters had improved markedly in both groups. Fasting and postprandial glucose (level of sugar in the blood after a meal) and insulin levels were no longer different between groups, and short-term weight loss was similar, with women in the prediabetes group losing 32.3% of body weight compared with 35.5% in the control group.

Cholesterol and triglyceride levels also fell after surgery, although total and non-HDL (non-high-density lipoprotein or “the good”) cholesterol remained slightly higher in the prediabetes group.

However, despite this clinical improvement, one year after surgery, gene activity in fat tissue remained clearly distinct between groups. In women with prediabetes, genes involved in lipid metabolism remained less active, including key regulators such as SREBF1 and FADS2, suggesting a persistent impairment in the ability of adipose tissue to handle fats efficiently after surgery.

Importantly, this blunted lipid metabolism was accompanied by higher cholesterol levels and greater weight regain over three years of follow-up in women with prediabetes compared with women with normal glucose tolerance. On average, women with prediabetes regained around 5–6 kg between years 1 and 3, while weight regain in the control group was minimal (average 1–2 kg).

In contrast, women with normal glucose tolerance showed activation of genes involved in lipid metabolism and cholesterol handling, suggesting that their fat tissue was better able to handle fats after weight loss.

“Our study shows that prediabetes is associated with persistent changes in fat tissue that are not fully reversed by bariatric surgery,” said lead author Dr. Ana de Hollanda from Hospital Clínic de Barcelona.

“These alterations in lipid metabolism may reduce the ability of adipose tissue to adapt after weight loss, potentially contributing to weight regain over time. Importantly, these changes may not be permanent, and could potentially be modified through targeted interventions such as diet, pharmacological treatments or lifestyle strategies aimed at improving adipose tissue function.”

She continued, “Our next steps are to investigate whether these molecular alterations can be reversed, and to identify strategies that improve adipose tissue function and its ability to adapt after weight loss.

“We also aim to determine whether similar patterns of adipose tissue dysfunction are present in other patients, beyond those with prediabetes, and whether they could be used to identify individuals at higher risk of weight regain.”

According to the authors, the study has some limitations. As an observational study, it does not establish a causal relationship between these molecular changes and weight regain. Other factors, including behavioral aspects such as diet are also likely to contribute.

Additionally, the study included only women, predominantly of European origin, which may limit the generalizability of the findings. They say that larger and more diverse studies are needed to confirm these results.

Provided by
European Association for the Study of Obesity