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).

Yaskolka Meir A, Tsaban G, Zelicha H, Rinott E, Kaplan A, Youngster I, Rudich A, Shelef I, Tirosh A, Brikner D, Pupkin E, Sarusi B, Blüher M, Stümvoll M, Thiery J, Ceglarek U, Stampfer MJ, Shai I. A Green-Mediterranean Diet, Supplemented with Mankai Duckweed, Preserves Iron-Homeostasis in Humans and Is Efficient in Reversal of Anemia in Rats. J Nutr. 2019 Mar 27. pii: nxy321.


Kaplan A, Zelicha H, Tsaban G, Yaskolka Meir A, Rinott E, Kovsan J, Novack L, Thiery J, Ceglarek UBurkhardt R, Willenberg A, Tirosh A, Cabantchik I, Stampfer MJ, Shai I. Protein bioavailability of Wolffia globosa duckweed, a novel aquatic plant, - A randomized controlled trial. Clin Nutr. 2018 Dec 11. pii: S0261-5614(18)32577-9. 


Tene L, Shelef I, Schwarzfuchs D, Gepner Y, Yaskolka Meir A, Tsaban G, Zelicha H, Bilitzky A, Komy O, Cohen N, Bril N, Rein M, Serfaty D, Kenigsbuch S, Chassidim Y, Sarusy B, Ceglarek U, Stumvoll M, Blüher M, Thiery J, Stampfer MJ, Rudich A, Shai I. The effect of long-term weight-loss intervention strategies on the dynamics of pancreatic-fat and morphology: An MRI RCT study.Clin Nutr ESPEN. 2018 Apr;24:82-89.


Gepner Y, Shelef I, Schwarzfuchs D, Cohen N, Bril N, Rein M, Tsaban G, Zelicha H, Yaskolka Meir A, Tene L, Sarusy B, Rosen P, Hoffman JR, Stout JR, Thiery J, Ceglarek U, Stumvoll M, Blüher M, Stampfer MJ, Shai I. Intramyocellular triacylglycerol accumulation across weight loss strategies; Sub-study of the CENTRAL trial. PLoS One. 2017;12:e0188431.


Gepner Y, Shelef I, Schwarzfuchs D, Zelicha H, Tene L, Yaskolka Meir A, Tsaban G, Cohen N, Bril N, Rein M, Serfaty D, Kenigsbuch S, Komy O, Wolak A, Chassidim Y, Golan R, Avni-Hassid H, Bilitzky A, Sarusi B, Goshen E, Shemesh E, Henkin Y, Stumvoll M, Blüher M, Thiery J, Ceglarek U, Rudich A, Stampfer MJ, Shai I. Effect of distinct lifestyle interventions on mobilization of fast storage pools: the CENTRAL MRI randomized control trial. Circulation. 2017; Epub ahead of print.


Tsaban G, Wolak A, Avni-Hassid H, Gepner Y, Shelef I, Henkin Y, Schwarzfuchs D, Cohen N, Bril N, Rein M, Serfaty D, Kenigsbuch S, Tene L, Zelicha H, Yaskolka-Meir A, Komy O, Bilitzky A, Chassidim Y, Ceglarek U, Stumvoll M, Blüher M, Thiery J, Dicker D, Rudich A, Stamper MJ, Shai I. Dynamics of intrapericardial and extrapericardial fat tissues during long-term, dietary-induced, moderate weight loss. Am J Clin Nutr. 2017;106:984-95.


Meir AY, Tene L, Cohen N, Shelef I, Schwarzfuchs D, Gepner Y, Zelicha H, Rein M, Bril N, Serfaty D, Kenigsbuch S, Chassidim Y, Sarusy B, Dicker D, Thiery J, Ceglarek U, Stumvoll M, Blüher M, Stampfer MJ, Rudich A, Shai I. Intrahepatic fat, abdominal adipose tissues, and metabolic state; magnetic resonance imaging study. Diabetes Metab Res Rev. 2017; Epub ahead of print.


Gepner Y, Golan R, Harman-Boehm I, Henkin Y, Schwarzfuchs D, Shelef I, Durst R, Leitersdorf E, Spitzen S, Blag S, Shemesh E, Witkow S, Tangi-Rosental O, Chassidim Y, Liberty I, Sarusi B, Ben-Avraham S, Kovsan J, Bolotin A, Helander A, Ceglarek U, Stumvoll M, Blüher M, Thiery J, Rudich A, Stampfer MJ, Shai I. Effects of Initiating Moderate Alcohol Intake on Cardiometabolic Risk in Adults With Type 2 Diabetes: A 2-Year Randomized, Controlled Trial. Ann Intern Med. 2015;163:569-79.


Gepner Y, Bril N, Shelef I, Schwarzfuchs D, Serfaty D, Rein M, Cohen N, Shemesh E, Tangi-Rosental O, Sarusi B, Goshen E, Kenigsbuch S, Chassidim Y, Golan R, Witkow S, Henkin Y, Stampfer MJ, Rudich A, Shai I. Higher visceral adiposity is associated with an enhanced early thermogenic response to carbohydrate-rich food. Clin Nutr. 2015;35:422-7.


Golan R, Shelef I, Rudich A, Gepner Y, Shemesh E, Chassidim Y, Harman-Boehm I, Henkin Y, Schwarzfuchs D, Ben Avraham S, Witkow S, Tangi-Rosental O. Liberty I. Sarusi B. Stampfer MJ. Shai I. Abdominal superficial subcutaneous fat – a putative distinct protective fat sub-depot in type 2 diabetes. Diabetes Care. 2012;35:640-7.


Blüher M, Rudich A, Klöting N, Golan R, Henkin Y, Rubin E, Schwarzfuchs D, Gepner Y, Stampfer MJ, Fiedler M, Thiery J, Stumvoll M, Shai I. Two Patterns of Adipokine and Other Biomarker Dynamics in a Long-Term Weight Loss Intervention. Diabetes Care. 2012;35:342-9.


Erez G, Tirosh A, Rudich A, Meiner V, Schwarzfuchs D, Sharon D, Shpitzen S, Bluher M, Stumvoll M, Thiery M, Fiedler G, Friedlander Y, Leiterstdorf E, Shai I. Phenotypic and genetic variation in leptin as determinants of weight regain. Int J Obes. 2011;35:785-92.


Shai I, Spence DJ, Schwarzfuchs D, Henkin Y, Parraga G, Rudich A, Fenster A, Mallett C, Cohen NL, Tirosh A, Bolotin A, Thiery J, Fiedler GM, Blüher M, Stumvoll M, Stampfer MJ. Dietary intervention to reverse carotid atherosclerosis. Circulation. 2010;121:1200-8.


Schwarzfuchs D, Golan R, Shai I. Four-year follow-up after two-year dietary interventions. N Engl J Med. 2012;367:1373-4.


Tirosh A*, Shai I*, Afek A, Dubnov‑Raz G, Ayalon N, Gordon B, Derazne E, Tzur D, Shamis A, Vinker S, Rudich A. Adolescent Body Mass Index Trajectory and Risk of Diabetes versus Coronary Disease. N Engl J Med. 2011;364:1315-25.


Shai I, Schwarzfuchs D, Henkin Y, Shahar D, Witkow S, Greenberg I, Golan R, Fraser D, Bolotin A, Vardi H, Tangi O, Zuk R, Sarusi B, Brickner D, Schwartz Z, Sheiner E, Marko R, Katorza E, Thiery J, Fiedler M, Blüher M, Stumvoll M, Stampfer J. Weight Loss with Low-Carbohydrate, Mediterranean, or Low-Fat Diets. N Engl J Med. 2008;359:229-41.


Tirosh A *, Shai I*, Manova DT, Israeli E, Pereg D, Shochat T, Kochba I, Rudich A. Normal fasting plasma glucose levels and type 2 diabetes in young adult men. N Engl J Med. 2005;353:1454-62.

 

PROJECT TEAM

 PhD students: Ehud Rinott, Hila Zelicha, Alon Kaplan, Gal Tsaban, Anat Yaskolka Meir