Decoding Metabolic Adaptation: Caloric Restriction’s Impact on Organ Size in the CALERIE 2 Trial

Highlight

– Caloric restriction (CR) over 24 months reduces adipose tissue, skeletal muscle, and estimated heart mass in healthy adults.
– Sleeping energy expenditure declines beyond expectations from weight loss alone, reflecting metabolic adaptation.
– MRI-derived models that incorporate organ-specific changes detect greater metabolic adaptation than models based solely on body mass.
– Advanced imaging techniques provide critical insights into organ-specific contributions to energy metabolism during CR.

Introduction

Caloric restriction (CR) — a sustained reduction in caloric intake without malnutrition — has been demonstrated to extend lifespan and improve healthspan across numerous species. While preclinical studies reveal mechanisms that could underlie these benefits, translating these findings to humans remains challenging due to complex physiological adaptations, especially in energy metabolism and expenditure. Weight loss induced by CR includes reductions in adipose tissue, fat-free tissue, and bone mass, with variation influenced by factors like initial body composition and sex. Fat-free mass comprises organs and tissues with markedly differing metabolic rates, such as brain, liver, kidneys, and skeletal muscle. The degree to which changes in organ size contribute to metabolic adaptation — the reduction in energy expenditure beyond that predicted by mass loss — remains to be fully elucidated. The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) Phase 2 trial uniquely offers long-term controlled data on CR in healthy, normal-weight adults, enabling an examination of organ-specific changes via magnetic resonance imaging (MRI) and their contributions to alterations in energy expenditure.

Study Design and Participants

This ancillary analysis was conducted within the CALERIE 2 randomized controlled trial framework, enrolling 42 healthy adults aged 21-50 years with body mass indices (BMI) between 22.0 and 28.0 kg/m² from Pennington Biomedical Research Center. Participants were randomized 2:1 to a caloric restriction group targeting 25% energy intake reduction for 24 months (with 12 months of weight loss followed by 12 months of weight maintenance) or an ad libitum (AL) control group maintaining regular intake. Adherence criteria ensured participants with >5% body mass loss in the CR group and <5% mass change in the AL group were analyzed. The rigorous protocol included serial assessments of body composition and energy expenditure.

Methods

Participants underwent comprehensive assessments, including dual-energy X-ray absorptiometry (DXA) for total fat and fat-free mass, and whole-body MRI for detailed organ and tissue volumetrics (brain, liver, kidneys, skeletal muscle, adipose tissue, residual lean tissue). Given limitations in cardiac-gated MRI sequences, heart mass was estimated from trunk lean mass measured by DXA using validated equations. Energy expenditure, specifically sleeping energy expenditure (SleepEE), was precisely measured via whole-room indirect calorimetry during monitored sleep periods to minimize physical activity confounding.

Four predictive models for SleepEE were developed at baseline: (1) using age, sex, body mass; (2) using DXA-derived fat mass and fat-free mass; (3) using MRI-derived organ and tissue mass from previous coefficients (MRI-ELIA); and (4) a regression model built from study data based on MRI measures (MRI-REGRESSION). Metabolic adaptation was quantified as the difference between measured SleepEE changes and those predicted by body composition, controlling for baseline prediction error.

Key Findings

Body mass decreased significantly in the CR group by ~13% at 12 and 24 months versus slight increases in the AL group. MRI data revealed significant reductions in adipose tissue, skeletal muscle mass, and estimated heart mass in the CR group over time; kidneys remained unchanged. Residual lean tissue mass also declined at 24 months. Liver mass showed near-significant reduction at 12 months.

SleepEE decreased significantly in the CR group at both time points, with reductions exceeding predictions from models based solely on body mass, DXA composition, or MRI-derived tissue mass, indicating metabolic adaptation. At 12 months, all models confirmed metabolic adaptation; at 24 months, only DXA and MRI-based models detected persistently reduced SleepEE beyond expectations.

MRI-based prediction models explained up to 76% of SleepEE variance at baseline (versus about 70% for body mass or DXA models). MRI models consistently identified greater metabolic adaptation magnitudes than simpler models. However, no statistically significant differences in metabolic adaptation existed among prediction models except at 12 months, where MRI-regression models detected significantly greater adaptation than body mass-based models.

Furthermore, analysis revealed a significant interaction showing progressively greater metabolic adaptation with increased precision of tissue assessment in CR but not AL participants, underscoring the importance of detailed organ and tissue metrics in understanding energy expenditure changes during CR.

Discussion

This detailed ancillary analysis of the CALERIE 2 trial provides key insights into the physiological adaptations to prolonged CR in healthy adults. Findings confirm that CR induces preferential losses in adipose tissue and skeletal muscle coupled with organ-specific size decreases, particularly in the heart and trends in liver mass, contributing to metabolic adaptation — a reduction in energy expenditure exceeding that predicted by weight loss alone.

MRI-derived organ and tissue mass assessments augmented the ability to detect metabolic adaptation compared to body mass or DXA-based metrics, highlighting the significant metabolic heterogeneity of different tissues. Notably, metabolically active organs like brain, liver, and kidneys, despite their relatively stable mass, play a disproportionate role in resting energy expenditure. The persistence of metabolic adaptation at 24 months as revealed by MRI and DXA models suggests sustained physiological recalibrations in response to prolonged caloric deficits.

However, the study reveals complexities: despite improved baseline predictive power with MRI metrics, physiological and behavioral factors unmeasured in the study likely influence energy expenditure adaptations. The lack of incremental benefit beyond DXA in explaining metabolic adaptation with MRI suggests limits due to cohort homogeneity and estimation methods, notably for heart mass approximations.

Limitations include the relatively small, healthy, and normal-weight sample limiting generalizability to other populations such as obese or metabolically compromised individuals who may experience different organ size and metabolic responses to CR. Advances in imaging, including cardiac-gated MRI, may refine assessments of organ contributions to energy metabolism. Finally, updated, human-specific tissue metabolic rates are needed to enhance predictive accuracy.

Conclusion

The study robustly demonstrates significant CR-induced reductions in organ and tissue mass alongside metabolic adaptation in energy expenditure. Incorporating advanced imaging of organ size refines understanding of the physiological basis for metabolic adaptation during sustained CR and emphasizes the metabolic significance of organ-specific tissue changes. These findings underscore the complexity of energy metabolism adaptations to CR and support the utility of high-resolution body composition analysis to inform clinical and translational research aimed at optimizing CR’s health benefits.

References

Falkenhain K, Redman LM, Chen W, Martin CK, Ravussin E, Shen W. Effect of caloric restriction on organ size and its contribution to metabolic adaptation: an ancillary analysis of CALERIE 2. Sci Rep. 2025 Aug 19;15(1):30374. doi: 10.1038/s41598-024-83762-0. PMID: 40830369; PMCID: PMC12365256.