) we randomly assigned 322 moderately obese subjects (mean age=52 years; BMI=31kg/m2) to one of three strategies: low-fat, Mediterranean, or low-carbohydrate diet. We conducted the trial in an exclusive workplace (the nuclear research center) with an on-site medical clinic and a cafeteria we could monitor for two years, using daily color-coded food labels. The adherence rate to a study diet was 95% at year 1 and 85% in two years. The results suggested that the Mediterranean and low-carbohydrate diets were more effective in weight loss and resulted in more favorable lipid (low-carbohydrate diet) and glycemic control (Mediterranean diet in particular) outcomes. A significant finding of DIRECT is that diets can induce a marked reduction in measurable carotid wall volume (Circulation 2010). In addition, across a panel of 12 traditional biomarkers and non-traditional adipokines, we identified two distinct patterns: Pattern A, characterized by biomarkers whose dynamics tightly corresponded to changes in body weight dynamics vs. Pattern B, indicated by biomarkers that displayed continued, cumulative improvement throughout the intervention window, despite partial weight regain, suggesting that switching to healthier dietary patterns resulted in a continuous, beneficial response that extended beyond weight loss (Diabetes Care 2012). We addressed cholesterol, and apolipoprotein metabolism (Am J Clin Nutr 2011, Nutrition 2012) and predictors of successful/failed weight loss (J Am Coll Nutr 2009, 2011, Public Health Nutr 2010, Am J Clin Nutr 2010). Plasma leptin reduction, the degree of initial weight loss, and the presence of genetic variations in the LEP gene significantly predicted subsequent long-term weight regain during the intervention window (Int J Obes 2011). The DIRECT trial further contributed data regarding diet and renal function (Diabetes Care 2013) and specific minerals (E Spen Eur E J Clin Nutr Metab 2013). We followed the participants for four additional years after the intervention window finished. The findings suggested that a 2-year intervention window had long-lasting, favorable post-intervention effects, particularly among participants receiving Mediterranean and low-carbohydrate diets. Moreover, such results were present despite a partial weight regain, suggesting that the beneficial, post-intervention window effects were related to and independent of weight loss (peer-reviewed letter, N Engl J Med letter 2013). The results of the DIRECT trial were cited in several most recent international medical guidelines in heart diseases, diabetes, obesity, and nutrition.