Ebbeling · JAMA 2012 · randomized 3-way crossover trial · n=21

Effects of dietary composition on energy expenditure during weight-loss maintenance.

Cited 433 times in the scientific literature.

Level 2 - randomized trial

Individual randomized crossover trial

PubMed 22735432 · doi:10.1001/jama.2012.6607 · record verified 2026-08-29

What was done

Twenty-one overweight and obese young adults who achieved 10% to 15% weight loss on a run-in diet were randomized to consume three isocaloric diets for 4 weeks each in a controlled 3-way crossover design: a low-fat diet (60% carbohydrate, 20% fat, 20% protein), a low-glycemic index diet (40% carbohydrate, 40% fat, 20% protein), and a very low-carbohydrate diet (10% carbohydrate, 60% fat, 30% protein). The primary outcome was resting energy expenditure (REE), with secondary outcomes including total energy expenditure (TEE), hormone levels, and metabolic syndrome components.

What was found

Compared to pre-weight-loss baseline, the decrease in REE was greatest on the low-fat diet (-205 kcal/d; 95% CI, -265 to -144), intermediate on the low-glycemic index diet (-166 kcal/d; 95% CI, -227 to -106), and smallest on the very low-carbohydrate diet (-138 kcal/d; 95% CI, -198 to -77; overall P = .03, P for trend = .009). The decrease in TEE followed the same pattern: -423 kcal/d (95% CI, -606 to -239) for low-fat, -297 kcal/d (95% CI, -479 to -115) for low-glycemic index, and -97 kcal/d (95% CI, -281 to 86) for very low-carbohydrate (overall P = .003, P for trend < .001). Significant differences were observed across diets for leptin (P < .001), 24-hour urinary cortisol (P = .005), peripheral insulin sensitivity (P = .02), hepatic insulin sensitivity (P = .03), HDL cholesterol (P < .001), non-HDL cholesterol (P < .001), triglycerides (P < .001), plasminogen activator inhibitor 1 (P for trend = .04), and C-reactive protein (P for trend = .05), with no consistent overall favorable pattern across all markers.

Why it matters

This study demonstrates that the macronutrient composition of an isocaloric diet alters energy expenditure during weight maintenance, challenging the model that all calories have an identical metabolic impact.

Limits

The study had a small sample size (n = 21) and short intervention periods (4 weeks per diet). It examined only young adults, and while the very low-carbohydrate diet best preserved energy expenditure, secondary endocrine and cardiovascular markers showed mixed effects rather than a uniform clinical benefit.

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