Epigenetics, Satiety, and Predictive Markers of Obesity

MADRID — Obesity rates and the growing prevalence of metabolic diseases present specialists with the need to look for tools that allow for a better diagnosis. They also suggest a need for the development of personalized therapeutic strategies. To this end, investigators have focused on identifying predictive markers that shed light on the mechanisms of obesity, the risk for associated complications, and the response to dietary intervention or to bariatric surgery.

Two sessions held at the XVIII National Congress of the Spanish Society on Obesity of 2022 presented analyses and provided updates on research in this area.

In the presentation, “The Epigenetic Basis of Obesity,” Ana Belén Crujeiras, MD, of the Epigenomic Unit of the Healthcare Research Institute of Santiago (IDIS)/Santiago de Compostela University Hospital Complex, presented the most recent evidence regarding the connection between epigenetics and obesity and associated diseases. She indicated that the study of epigenetic markers is a line of inquiry that arouses favorable expectations.

“We are all exposed to an obesogenic environment derived from the consumption of ultraprocessed foods and fast food, from elevated sedentarism and from environmental contamination: endocrine disruptors. However, not all the population has obesity. Rather, there are people that resist this effect of the obesogenic environment, while another group, to a greater extent, is susceptible to suffering from it.”

Crujeiras stated that among patients with obesity, responses to current treatment strategies (calorie restriction, physical activity, bariatric surgery, and drugs) are variable. Some respond well, and others are resistant to weight loss. Moreover, follow-up of responders at 12 to 24 months also reveals a variable response. Some individuals maintain their weight loss, while others regain weight.

“Therefore, we face three groups of patients with regard to the efficacy of the interventions to treat this disease: individuals prone to obesity, those resistant to weight loss, and those prone to regain the weight loss. These groups present the great challenge in the context of the fight against obesity.”

The Thrifty Phenotype

Crujeiras emphasized that more than 600 genes are associated with obesity. The evidence demonstrates that genetics alone explains 20% to 30% of the variability in treatment response and susceptibility to obesity. The rest of the variability (70%) is due to lifestyle (40%), sociocultural environment (15%), healthcare (10%), and the physical environment, especially the temperature to which we are exposed (5%).

The role of epigenetics revealed where its mechanisms connect the environment and genetics. “There is currently evidence that there are epigenetic mechanisms related to obesity, but we don’t know very well if it’s the obesity that induces these epigenetic markers or if it’s the epigenetic markers that predetermine the disease,” said Crujeiras. “But we know that these epigenetic markers are related to the diseases associated with obesity, such as metabolic syndrome, diabetes, and even cancer. Additionally, the characteristics of reversibility of the epigenetic mechanisms makes them very promising therapeutic objectives.”

Crujeiras shared the results of the studies of the Epigenomics in Endocrinology and Nutrition Research Group of the IDIS, which she leads. The studies have enabled the identification of an epigenetic signature of the obese adipose tissue that is reflected in peripheral blood leukocytes and supports what specialists have called the hypothesis of the thrifty phenotype.

“Applying the evidence of epigenetics to the three groups of patients that we referred to previously — predisposition to obesity, difficulty losing weight, and regaining weight — we situate the hypothesis of the thrifty phenotype, which would be conditioned by epigenetic memory induced by environmental factors and transgenerational heredity,” said Crujeiras. “Having these epigenetic markers (for example, biomarkers) that help us to detect the individuals who have this phenotype would allow for establishing therapies in the context of personalized medicine. They would be directed at the epigenetic markers that predetermine this thrifty phenotype.”

Optimizing Epigenetic Reversibility

The studies of Crujeiras and colleagues have also suggested that by employing a nutritional strategy based on a very-low-calorie ketogenic diet, the profile of these epigenetic markers of obesity is reversed, and it more closely approximates the profile of healthy individuals of normal weight.

“Additionally, physical activity has been shown to reverse obesity-associated methylome, which at the same time is related to the metabolic benefits that physical activity induces,” she said. “Bariatric surgery is also capable of reversing obesity-associated methylome. And as occurs with the very-low-calorie ketogenic diet, we have seen that the Mediterranean diet is associated with changes in methylation in certain genes. And the beneficial effect of the Atlantic diet is also studied in this same manner.”

Crujeiras pointed out that all of these studies have led to the identification of biomarkers that, together with genomics, metabolomics, and the study of exposome, help to stratify patients and establish a more precise, personalized therapy for obesity. This therapy is based on nutrition, lifestyle patterns, supplements of bioactive compounds that moderate epigenetic markers, and, in more extreme cases, certain epigenetic drugs.

Regaining Weight

The complexity of maintaining weight loss over time and avoiding regain or a “rebound effect” for patients and specialists was addressed in the session entitled, “Do We Play With Foreseeing the Future?” Predictive markers were discussed.

Mónica Bulló, PhD, lecturer on nutrition and metabolism at the Rovira i Virgili University (Tarragona), commented, “Losing weight is easy, and we have strategies for it, but what is really complicated is maintaining that weight loss long term. For me, the great handicap is how to define ‘long term.’ It has been more than 20 years of carrying around the idea that losing between 5% and 10% of body weight and maintaining it for 1 year was a good option, but we must revise this criterion and advocate for weight loss that is maintained over time.

“Regarding the strategies that are currently used to approach obesity, reality demonstrates that if there is a formula that works to lose weight long term, it is bariatric surgery. The studies show that around 50% to 70% of patients maintain the weight loss after 10 years. However, we need to consider aspects such as the reoperation rate, which is not negligible. Therefore, bariatric surgery is a good option, but it is not indicated in all patients, and we must not forget that we are treating a community disease,” said Bulló.

“On the other hand, studies on dietary and lifestyle intervention demonstrate that in the end, all patients regain the weight lost after 2 years or more. These strategies tend to become chronic, and in a certain way, they go against the physiological changes that occur in the body,” she added.

Studies with large cohorts of patients suggest that greater weight loss at the start of treatment and a steady pace of weight loss predict greater success at maintaining weight loss for longer periods. “We also know that those that have been able to maintain this weight for 2 years have a better long-term prognosis,” said Bulló.

Satiety Is Key

Bulló explained that the metabolic adaptations that underlie the response to weight-loss intervention are not exactly known, although metabolomic studies could provide good strategies to profile the probabilities of an intervention’s success or failure.

“Therefore, some aspects such as appetite regulation and satiety are noted as a compensation strategy. It appears that subjects that experience this rebound effect have a greater capacity to feel satiated. Therefore, the effort needed for them to lose weight is even greater, a situation that causes them a greater sense of guilt. It also favors discouragement, and the risk of depression or anxiety increases,” Bulló added.

The nutrition and metabolic health research group of the Pere i Virgili Health Research Institute, where Bulló is a principal investigator, is seeking metabolites that could predict a greater satiating response after meals. “We have identified two metabolites whose circulating levels are associated with satiety in people who are overweight, but these results need to be verified. Through metabolite and intestinal microbiota studies, some markers with a certain predictive capacity are obtained, but with results that are still not conclusive.”

Bulló highlighted the need for objective indicators to predict the success, failure, and maintenance of weight loss. “We need to know what leads to the regain of body weight, thus the interest in looking for new markers that could determine with greater precision not only the subjects with greater risk of developing obesity, but also orientation regarding the results expected with certain treatment strategies and predicting the rebound effect. In this sense, omics may be a useful tool to discriminate individuals with a better or worse response in the control of body weight.”

Bulló underscored the complexity and chronicity that characterize obesity “and, therefore, require an approach that is also complex and chronic. Comprehensive management favors the success of the interventions for the control of body weight. Therefore, the integration of data supposes a new frontier for precision medicine in obesity.”

Crujeiras and Bulló disclosed have no relevant financial relationships.

Follow Carla Nieto of Medscape Spanish Edition on Twitter @carlanmartinez and on LinkedIn.

This article was translated from the Medscape Spanish edition.

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