Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - OBEDIA-MARK (EPIGENETIC MARKERS OF DISEASE STATUS AND REVERSAL FOR PERSONALIZED MANAGEMENT OF OBESITY AND DIABETES)

Teaser

What is the problem/issue being addressed?Current genetic biomarkers have low power to predict the onset of lifestyle-related disease such as obesity and type-2 diabetes as they cannot account for environmental factors, which play a major role in the development of these...

Summary

What is the problem/issue being addressed?

Current genetic biomarkers have low power to predict the onset of lifestyle-related disease such as obesity and type-2 diabetes as they cannot account for environmental factors, which play a major role in the development of these conditions.
Why is it important for society?

Obesity and associated diseases such as type 2 diabetes are one of the leading causes of death and public expenditure worldwide. Early detection of these diseases before symptoms arise may enable effective prevention and intervention thus turning the tide against these diseases.

What are the overall objectives?

The overall goal of OBEDIA-MARK is to advance the field of precision medicine for obesity-associated diseases such as type-2 diabetes by identifying biomarkers and individual characteristics that enable early detection and personalized intervention.

The project had three specific objectives:

Objective 1: Identification of epigenetic biomarkers of type-2 diabetes for the development of preventive personalized dietary intervention. Epigenetic modifications are chemical groups that bind to our genes turning them on or off. Unlike genetic sequence epigenetic “switches” dynamically change in response to environmental factors, such as diet, thereby affecting our health and disease risk.

Objective 2: Assessing sex differences in weight loss response for the development of preventive personalized dietary intervention. Men and women differ in their body composition, energy expenditure, and hormonal status. These biological sex differences together with sociocultural gender norms lead to differences in the way men and women follow a certain diet and lose weight on it.

Objective 3: Determining diet-specific metabolic changes for the development of preventive personalized dietary intervention.

Work performed

\"Results of objective 1: We have measured a type of epigenetic “switch” called DNA methylation (DNAm) in 100 overweight individuals following either a low-carbohydrate diet (LCD) or a low-fat diet (LFD). We have identified two DNAm biomarkers that are strong predictors of baseline weight (the initial weight of the study participants) and that show more than 30% DNAm change after weight loss in the individuals who lost the greatest amount of weight (\"\"biggest losers\"\", n=8). This indicates that our epigenetic biomarkers can capture changes in body weight in both directions — gaining weight and losing weight — and may, therefore, be used for early detection of obesity-associated disease as well as personalized monitoring of its reversal. Strikingly, both biomarkers are located in a gene called ABCG1, a diabetes-related gene involved in insulin secretion. DNAm at ABCG1 has been shown to be a highly predictive marker of type-2 diabetes mellitus (T2DM) in a recent large-scale longitudinal epigenome-wide association study (EWAS, Wahl et al. Nature 2017). This exciting finding makes ABCG1 an extremely promising candidate as a DNAm marker of T2DM status and reversal. Follow up studies with the University of Vienna will test this hypothesis by measuring ABCG1 DNAm in T2DM patients and non-diabetic control subjects.

Results of objective 2: We have compared weight loss and diet adherence between 609 men and women following an LCD or LFD. Our results indicate that men lose significantly more weight and body fat on LCD than LFD, whereas women lose the same amount of weight and body fat on either diet. Interestingly, however, women were able to stick much better to LFD than LCD, possibly due to a perception of dietary fats as “fattening”. This suggests that women may increase their weight loss success on LCD by overcoming their fear of fat. These findings may guide healthcare providers to develop dietary strategies that take into account the different food attitudes of men and women to overcome potential gender-related roadblocks to weight-loss success.

Results of objective 3: We have found that a ketogenic diet or an Ornish diet induce distinct metabolic changes, despite inducing similar weight loss and reduction in blood glucose and insulin. A ketogenic diet induces improved levels of two metabolic markers compared to an Ornish diet: a significantly greater decrease in triglycerides and a concomitant significantly greater increase in “good” HDL cholesterol. On the other side, an Ornish diet induces a significantly greater decrease in LDL cholesterol, which is associated with decreased risk for cardiovascular disease. These diet-specific metabolic changes may inform the personalized treatment of metabolic imbalances using diets with extreme low-carbohydrate content (ketogenic diet) or extreme low-fat content (Ornish diet).

Dissemination

Project video: https://youtu.be/Y84g-5FLx1w (soon available on the University website)

Publications
• A systematic review of studies of DNA methylation in the context of a weight loss intervention”. Epigenomics. 2017 May;9(5):769-787. https://osf.io/28c5x/

• The Effect of Nutrition on Epigenetic Status, Growth, and Health. https://osf.io/jsb73/

• Changes in blood lipid concentrations associated with changes in intake of dietary saturated fat in the context of a healthy low-carbohydrate weight-loss diet: a secondary analysis of the Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) trial, The American Journal of Clinical Nutrition, Volume 109, Issue 2, February 2019, Pages 433–441 https://osf.io/sd5rb/

Submitted Manuscript
• Examining differences between overweight women and men in 12-month weight loss study comparing healthy low-carbohydrate vs. low-fat diets.

Other manuscripts in preparation
• Identification of weight loss-associated DNA methylation (DNAm) markers
• Effects of a Ketogenic-like, Mediterranean-like and Ornish-like\"

Final results

Progress beyond the state of the art

1. We have identified epigenetic biomarkers in the context of a randomized controlled study — the gold standard in clinical research — with a long duration (1 year) and a large population (n=609). This greatly enhances the ability to assess the stability of obesity-associated epigenetic biomarkers over-time and robustly validate them.

2. We have screened the entire set of epigenetic modifications across the DNA to identify epigenetic biomarkers, which represents an innovation compared with previous studies looking at single genes or isolated groups of genes.

3. We have analyzed additional biological factors beyond epigenetics that may facilitate the development of personalized dietary strategies. These include sex differences in weight loss response and distinct metabolic changes elicited by diets with extreme macronutrient composition such extremely low-carb ketogenic diets or extremely low-fat Ornish diets.

Potential impacts
The impact of the project has wider socio-economical implications. Demonstrating that gaining weight is associated with epigenetic changes tightly linked to disease will strongly support the need to focus on nutrition to prevent disease and promote health. This will, in turn, stimulate new dialogues between key stakeholders in the food industry, policymakers and consumer protection NGOs, which is a major objective of the EC Strategy On Nutrition, Overweight and Obesity-related Health Issues.

Website & more info

More info: https://youtu.be/Y84g-5FLx1w.