B11 - Adipokine, metabolite and epigenetic signatures of adipose tissue redistribution during a randomized controlled dietary intervention trial

Body weight regain after weight loss interventions occurs in the majority of patients with obesity and could serve as a model to understand how adipose tissue deposition is regulated. Following our 2-year dietary randomized clinical trial (RCT) and 4-year follow-up (DIRECT), we performed the 18-month CENTRAL RCT (2012–2014) addressing the effect of Low-fat vs. Mediterranean/Low-carbohydrate diets, with or without physical activity, on body fat redistribution (N=278, 18-month adherence:86.3%). We scanned adipose tissues and ectopic fat deposits in specific organs at 0, 6 and 18-months by whole-body MRI. Our initial results suggest that adipose tissue deposition dynamics significantly differs among specific sites/organs and depends on the intervention (exercise, diet strategy). These findings may imply differential effects of lifestyle interventions on specific organs/depots response and fat composition. Here, we aim to test the hypothesis that long-term lifestyle interventions are associated with epigenetic changes and alterations in biomarker profiles. These modifications may constitute a signature of organ-specific fat depots’ changes, addressing several questions:

I. Why are some people unresponsive to structured intervention to induce visceral adipose tissue (VAT) loss despite adherence? Is there a pre-defined fat distribution pattern that predicts "weight loss resistance"?

II. Is there evidence for an individual fat-depot distribution that is retained after weight loss and regain? Is it reflected or mediated by intervention-induced epigenetic and metabolite changes?

III. Can we identify the best biomarkers/patterns for VAT and VAT dynamics? Beyond VAT dynamics, which of the other fat depot changes are related to the intervention–induced improvements in cardio-metabolic risk parameters?
IV. Does the early (6-month) fat depot change predict the long-term fat redistribution?
V. Do the epigenetic changes (18-month) predict a post-intervention legacy effect, which could be observed up to 4-years after the intervention?

To address these questions, we will extent the available basic study data by additional measurements of specific biomarkers, metabolites and epigenetic markers. We will perform a systematic mining of the whole-body MRI library (of ~3000 slices) to quantify the dynamics of further fat storage sites. Finally, we will follow the CENTRAL participants 4 years after completion of the intervention to assess a potential post-intervention legacy effect. By integrating bioinformatics approaches, the project may unravel circulating markers of fat depot distribution changes and provide a better understanding of mechanisms underlying individual variations in fat deposition and resistance to lifestyle modification.

Figure 1. Dynamics of human fat depots/deposits during 18 months of intervention. MRI illustration of the human fat depots/deposits at baseline and after the 18-month intervention following moderate weight loss (6%): (I) Abdominal fat - visceral fat (green), deep SAT (light blue), superficial SAT (blue), non-classified fat (red), peri-muscular fat (purple); (II) Intra-hepatic fat; (III) Cardiac fat - of intra-pericardial fat (IPF, light blue) and a similar reduction of extra-pericardial fat (EPF, purple, n=80 for the cardiac sub-study); (IV) Pancreatic fat (red); (V) Renal sinus fat (blue); (VI) Femur intramuscular fat (green).

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Anat Yaskolka Meir, PhD student

Ehud Rinott, PhD student

Gal Tsaban, PhD student

Alon Kaplan, PhD student

Hila Zelicha, PhD student