Tissue losses and metabolic adaptations both contribute to the reduction in resting metabolic rate following weight loss

The study addresses why resting metabolic rate (RMR) decreases during weight loss, a key factor in attenuated total daily energy expenditure that can hinder continued weight loss and promote regain. Traditional assumptions attribute RMR preservation primarily to maintaining fat-free mass (FFM), yet FFM is heterogeneous and losses during weight loss typically occur in skeletal muscle rather than highly metabolic organs. Even after accounting for tissue losses, RMR often declines more than expected, indicating metabolic adaptations—reductions in the metabolic activity of remaining tissues—linked to changes in hormones such as leptin and thyroid hormones. The purpose was to quantify the unique contributions of organ/tissue losses versus metabolic adaptations to RMR reduction during prolonged weight loss and to examine their inter-relationships using data from the CALERIE randomized trial in non-obese adults.

Prior work shows RMR reductions are a consistent component of reduced total daily energy expenditure during weight loss. While FFM strongly relates to RMR, its heterogeneous composition means losing skeletal muscle (lower specific metabolic rate) affects RMR differently than losing high-metabolic-rate organs. Studies have reported that only a fraction of RMR decline is explained by tissue loss, with substantial unexplained reductions attributed to adaptive thermogenesis/metabolic adaptations, associated with declines in leptin and thyroid hormones. Other investigations variably report RMR changes normalized to FFM, but often without organ-specific resolution. Evidence from severe energy deficits and bariatric/intensive weight loss contexts suggests metabolic adaptations scale with adipose loss and hormonal changes, though no gold standard exists for direct measurement of metabolic adaptations.

Design: Secondary analysis of the CALERIE randomized clinical trial prescribing 25% energy intake reduction over 2 years in non-obese adults. This analysis used data at baseline, 6 months, and 12 months, focusing on the calorie restriction group with complete baseline and 12-month data; controls were excluded. Participants: Adults aged 20–50 years with BMI 22–27.9 kg/m²; exclusions included prior eating disorders, significant health issues, recent major weight loss, certain medications. Intervention: Free-living caloric restriction without mandated diet composition or activity; adherence supported via counseling and tools. Assessments: Body weight measured every 3 months; body composition by DXA (baseline, 6, 12 months); RMR by indirect calorimetry (baseline, 6, 12 months); metabolic hormones (insulin, leptin, triiodothyronine [T3], IGF-1) at baseline and 12 months. Calculations: Organ/tissue masses (skeletal muscle from extremity lean mass; adipose from fat mass; bone from BMC; brain from skull area; inner organs [heart, liver, kidneys] from trunk lean-derived estimates; residual mass by difference) were combined with published tissue-specific metabolic rates to compute component metabolic rates and summed to a predicted RMR. Changes in predicted RMR reflected tissue loss contributions; metabolic adaptations were defined as measured RMR change minus predicted RMR change. Statistics: Analyses in R 4.0.3. Paired t-tests (Holm-Bonferroni) assessed changes over time. Linear regression and Pearson correlations examined associations between tissue changes and RMR outcomes. Participants were stratified into quartiles by skeletal muscle and adipose losses; generalized linear models adjusted for age, sex, body weight, height, initial BMI, and body fat percentage compared RMR and adaptation contributions across quartiles. Significance set at p<0.05.

- Sample: 109 participants (77 women, 32 men). Baseline characteristics included mean age 37.8 ± 7.4 years and BMI 25.0 ± 1.7 kg/m². - Weight loss: −7.3 ± 0.2 kg by 6 months (p<0.001) and an additional −0.7 ± 0.2 kg from 6 to 12 months (total −8.0 ± 0.3 kg, p<0.001). - Tissue changes to 12 months: Skeletal muscle −1.0 ± 0.8 kg (p<0.001 to 6 months; stable thereafter), adipose tissue −7.2 ± 3.1 kg (p<0.001), minimal/no change in brain and inner organs; bone/residual mass changes small. - RMR: Measured RMR decreased by 101 ± 12 kcal/d (−7.6%, p<0.001) by 6 months with no further decline to 12 months; predicted RMR decreased by 60 ± 3 kcal/d (−4.2%, p<0.001). Metabolic adaptations accounted for an additional −40 ± 11 kcal/d on average. Overall, 60% of RMR reduction was explained by tissue losses and 40% by metabolic adaptations. - Inter-individual variability: 83% experienced RMR reduction; among reducers, decreases were 0–100 kcal/d in 27%, 100–200 in 33%, 200–300 in 21%, and >300 in 2%. In 61%, metabolic adaptations contributed more than tissue changes; 33% had positive metabolic adaptations (increased RMR despite tissue loss). - Associations: Skeletal muscle loss was not significantly related to measured RMR change (r=0.14, p=0.16) nor metabolic adaptations (p=0.36). Adipose loss correlated with measured RMR change (≈17 kcal/kg; r=0.42, p<0.001) and with metabolic adaptations (≈12 kcal/kg; r=0.31, p<0.001). In quartile analyses, greater skeletal muscle loss did not translate to larger total RMR reductions; tissue losses explained nearly all RMR change in the highest muscle-loss quartile (≈94.4%), whereas metabolic adaptations contributed more when skeletal muscle loss was smaller. For adipose loss quartiles, tissue-related RMR reductions and total measured RMR reductions decreased as adipose loss decreased; metabolic adaptations contribution fell from 50.4% (Q1) to 5.5% (Q4), with a positive association of adaptations with adipose loss (β≈11.9 kcal/kg, p<0.001). - Hormones: Significant decreases in leptin (−59.9 ± 2.2%), T3 (−14.3 ± 2.0%), and insulin (−14.3 ± 4.6%) (all p<0.001); IGF-1 unchanged. Metabolic adaptations correlated with changes in leptin (r=0.27, p<0.01), T3 (r=0.19, p<0.05), and insulin (r=0.25, p<0.01).

The findings demonstrate that reductions in RMR during 12 months of caloric restriction result from both loss of energy-expending tissues and metabolic adaptations, directly addressing the study question. While tissue losses explained about 60% of the RMR decrease, metabolic adaptations accounted for the remaining 40%, with considerable individual variability. Contrary to common belief, skeletal muscle loss, despite being the principal lean tissue lost, did not significantly predict RMR reductions. Instead, adipose tissue loss was more closely linked to both the magnitude of RMR decline and the extent of metabolic adaptations, aligning with prior observations that adaptive thermogenesis scales with fat loss and is associated with reductions in leptin and thyroid hormone. The organ/tissue-specific modeling clarified why overall FFM changes can obscure contributions to RMR: skeletal muscle has a much lower specific metabolic rate than vital organs, so its loss contributes relatively less to RMR decline. The observed hormonal correlations support the interpretation that adaptive downregulation of energy expenditure accompanies fat loss. These insights suggest that preserving or countering metabolic adaptations may be as important as limiting tissue loss for maintaining RMR during weight loss, and that individual variability necessitates personalized strategies.

RMR decreases by roughly 7% (~100 kcal/d) with ~11% weight loss over 12 months of caloric restriction in non-obese adults. Approximately 60% of the RMR reduction is explained by losses of energy-expending tissues, while ~40% reflects metabolic adaptations. Skeletal muscle loss was not a primary driver of RMR decline, whereas adipose tissue loss was positively associated with both RMR reductions and the magnitude of metabolic adaptations. Given the high inter-individual variability in the relative contributions of tissue loss and adaptations, future research should test whether preserving specific tissues versus attenuating their adaptive metabolic downregulation differentially supports RMR preservation and weight maintenance, and should explore personalized interventions targeting the predominant cause of RMR reduction in each individual.

- Population: Non-obese adults (BMI 22–27.9 kg/m²); generalizability to individuals with obesity or other populations may be limited. - Intervention control: Free-living caloric restriction without strict diet composition or physical activity control may introduce behavioral variability. - Measurement of metabolic adaptations: No gold standard exists; adaptations inferred as the difference between measured and predicted RMR using modeled organ/tissue masses and published metabolic rates. - Organ mass estimation: Inner organ masses estimated from DXA-derived proxies (e.g., trunk lean) rather than direct imaging (e.g., MRI), potentially introducing estimation error. - Hormone timing: Metabolic hormones measured only at baseline and 12 months, limiting temporal resolution of hormonal-adaptation dynamics. - Attrition and data completeness: Analysis included only participants with complete baseline and 12-month data; later time points had higher attrition and were not analyzed.