- Background —We aimed to assess whether distinct lifestyle strategies can differentially affect specific body adipose depots. Methods —We performed an eighteen-month randomized controlled trial among 278 sedentary adults with abdominal obesity (75%) or dyslipidemia in an isolated workplace with a monitored provided lunch. Participants were randomized to iso-caloric low-fat (LF) or Mediterranean/low-carbohydrate (MED/LC) diet+28g walnuts/day with/without added moderate physical activity (PA;80% aerobic; supervised/free gym membership). Overall primary outcome was body fat re-distribution, and the main specific endpoint was visceral adipose tissue (VAT). We further followed the dynamics of different fat depots [deep/superficial subcutaneous (D/SSAT), liver, pericardial, muscle, pancreas and renal-sinus] by magnetic-resonance-imaging. Results —Of 278 participants (age=48y; 89%men, body-mass-index=30.8kg/m 2 ), 86% completed the trial, with good adherence. The LF group preferentially decreased reported fat intake (-21.0% vs. -11.5% for the MED/LC; P + groups significantly increased the metabolic-equivalents (METs)/week vs. the PA - groups (19.0 vs. 2.1;P=0.009). Whereas final moderate weight loss was indifferent, exercise attenuated the waist circumference rebound with the greatest effect in MED/LC PA+ group (P 2 ;95%CI:(-14.8 to -0.45) compared with PA - ]. The MED/LC diet was superior to LF in decreasing intra-hepatic, intra-pericardial and pancreatic fats (P Conclusions —Moderate weight loss alone inadequately reflects the significant lifestyle effects on atherogenic and diabetogenic fat depots. The MED/LC diet mobilizes specific ectopic fat depots, and exercise has an independent contribution to VAT loss. Fat depots exhibit diverse responsiveness and are differentially related to cardiometabolic markers. Distinct lifestyle protocols may uniquely induce fat mobilization from specific anatomical sites. Clinical Trial Registration —URL: http://www.clinicaltrials.gov. Unique identifier: NCT01530724.