B11 - Identification of molecular classifiers and casual drivers determining the personal response to dietary intervention trials

Project B11 will combine multidisciplinary expertise of large-scale interventional studies, molecular epidemiology and bioinformatics to identify and validate molecular classifiers related to the short and long-term outcomes of dietary interventions including weight reduction and obesity sequelae on an individual level. This will help to distinguish between patients likely profiting from dietary interventions and those requiring other types of interventions such as drug treatment. Going beyond associative relationships, we aim to establish comprehensive causal mechanistic chains of dietary intervention, induced molecular response, resulting weight reduction, and finally, long-term clinical outcomes (obesity sequelae). These causal chains provide new strategies for therapy surveillance and new therapy targets.

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, Tuohy K, von Bergen M, Krajmalnik-Brown R, Heinig U, Zelicha H, Tsaban G, Rinott E, Kaplan A, Aharoni A, Zeibich L, Chang D, Dirks B, Diotallevi C, Arapitsas P, Vrhovsek U, Ceglarek U, Haange SB, Rolle-Kampczyk U, Engelmann B, Lapidot M, Colt M, Sun Q, Shai I. The Metabolomic-Gut-Clinical Axis of Mankai Plant-Derived Dietary Polyphenols. Nutrients. 2021 May 30;13(6):1866.

Yaskolka Meir A, Keller M, Müller L, Bernhart SH, Tsaban G, Zelicha H, Rinott E, Kaplan A, Gepner Y, Shelef I, Schwarzfuchs D, Ceglarek U, Stadler P, Blüher M, Stumvoll M, Kovacs P, Shai I. Effects of lifestyle interventions on epigenetic signatures of liver fat: CENTRAL randomized controlled trial. Liver Int. 2021 May 3.

Rinott E, Youngster I, Meir AY, Tsaban G, Kaplan A, Zelicha H, Rubin E, Koren O, Shai I. Autologous fecal microbiota transplantation can retain the metabolic achievements of dietary interventions. Eur J Intern Med. 2021 Apr 18:S0953-6205(21)00110-2.

Meir A Y, Keller Maria, Bernhart S H, Rinott E, Tsaban G, Zelicha H, Kaplan A, Schwarzfuchs D, Shelef I, Gepner Y, Li J, Lin Y, Blüher M, Ceglarek U, Stumvoll M, Stadler P F, Stampfer M J, Kovacs P, Liang L, Shai I. Lifestyle weight‑loss intervention may attenuate methylation aging: the CENTRAL MRI randomized controlled trial. Clin Epigenetics. 2021 Mar 4;13(1):48.

Yaskolka Meir A, Rinott E, Tsaban G, Zelicha H, Kaplan A, Rosen P, Shelef I, Youngster I, Shalev A, Blüher M, Ceglarek U, Stumvoll M, Tuohy K, Diotallevi C, Vrhovsek U, Hu F, Stampfer M, Shai I. Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial. Gut. 2021 Jan 18:gutjnl-2020-323106.

Rinott E,Youngster I, Meir AY, Tsaban G, Zelicha H, Kaplan A, Knights D,Tuohy K, Fava F, Scholz MU, Ziv O, Reuven E, Tirosh A, Rudich A, Blüher M, Stumvoll M, Ceglarek U, Clement K, Koren O, Wang DD, Hu FB, Stampfer MJ, Shai I. Effects of Diet-Modulated Autologous Fecal Microbiota Transplantation on Weight Regain. Gastroenterology. 2021 Jan;160(1):158-173.e10.

Keller M, Yaskolka Meir A, Bernhart SH, Gepner Y, Shelef I, Schwarzfuchs D, Tsaban G, Zelicha H, Hopp L, Müller L, Rohde K, Böttcher Y, Stadler PF, Stumvoll M, Blüher M, Kovacs P, Shai I. DNA methylation signature in blood mirrors successful weight-loss during lifestyle interventions: the CENTRAL trial. Genome Med. 2020 Nov 16;12(1):97.

Sela I, Yaskolka Meir A, Brandis A, Krajmalnik-Brown R, Zeibich L, Chang D, Dirks B, Tsaban G, Kaplan A, Rinott E, Zelicha H, Arinos S, Ceglarek U, Isermann B, Lapidot M, Green R, Shai I. Wolffia globosa-Mankai Plant-Based Protein Contains Bioactive Vitamin B 12 and Is Well Absorbed in Humans. Nutrients . 2020 Oct 8;12(10):3067.

Levakov G, Kaplan A, Yaskolka Meir A, Rinott E, Tsaban G, Zelicha H, Meiran N, Shelef I, Shai I, Avidan G. Neural correlates of future weight loss reveal a possible role for brain-gastric interactions. Neuroimage. 2020 Sep 23;224:117403.

Zelicha H, Kaplan A, Yaskolka Meir A, Tsaban G, Rinott E, Shelef I, Tirosh A, Brikner D, Pupkin E, Qi L, Thiery J, Stumvoll M, Kloting N, von Bergen M, Ceglarek U, Blüher M, Stampfer MJ, Shai I. The Effect of Wolffia globosa Mankai, a Green Aquatic Plant, on Postprandial Glycemic Response: A Randomized Crossover Controlled Trial. Diabetes Care. 2019 Jul;42(7):1162-1169

Gepner Y, Shelef I, Komy O, Cohen N, Schwarzfuchs D, Bril N, Rein M, Serfaty D, Kenigsbuch S, Zelicha H, Yaskolka Meir A, Tene L, Bilitzky A, Tsaban G, Chassidim Y, Sarusy B, Ceglarek U, Thiery J, Stumvoll M, Blüher M, Stampfer MJ, Rudich A, Shai I. The beneficial effects of Mediterranean diet over low-fat diet may be mediated by decreasing hepatic fat Content. EBioMedicine. 2019 May 29. pii: S2352-3964(19)30358-5.

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 U, Burkhardt 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.