Abstract Basal metabolic rate (BMR) represents the minimum energy expenditure required to maintain vital physiological functions at rest. Over the past decade, research has moved beyond classic calorimetric measurements to integrate molecular biology, organ-level bioenergetics, and artificial intelligence. This review synthesizes recent advances in BMR research, including the identification of novel metabolic regulators, the role of mitochondrial dynamics, the impact of circadian and epigenetic factors, and the development of wearable and imaging-based estimation technologies. We also discuss future directions such as single-cell metabolic profiling and personalized metabolic phenotyping.

1. Introduction Basal metabolic rate accounts for 60–75% of total daily energy expenditure in sedentary individuals and is a critical determinant of body weight regulation, metabolic health, and aging. Traditionally measured by indirect calorimetry under standardized conditions, BMR has been recognized as a highly heritable trait (40–60%) with substantial inter-individual variation not fully explained by differences in fat-free mass, sex, or age (Speakman et al., 2021). Recent technological and conceptual breakthroughs are reshaping our understanding of the mechanisms that set and modulate BMR.

2. Novel molecular regulators of BMR Recent genome-wide association studies (GWAS) have identified over 100 loci associated with BMR, many of which map to genes involved in mitochondrial function, ion transport, and thyroid hormone signaling (Loos & Yeo, 2022). Among these,UCP1variants continue to attract attention for their role in brown adipose tissue (BAT) thermogenesis. However, human BAT activity is now known to contribute only 1–5% to BMR in most adults, shifting interest toward non-shivering thermogenesis in skeletal muscle mediated by sarcolipin and SERCA uncoupling (Bal et al., 2021).

A landmark study by van der Lans et al. (2023) demonstrated that cold-induced activation of BAT increases resting energy expenditure by only ~2–3% in lean individuals, whereas muscle-based futile calcium cycling can elevate BMR by up to 15–20% in cold-acclimated subjects. This finding challenges the long-held assumption that BAT is the primary driver of adaptive thermogenesis in humans.

3. Mitochondrial dynamics and BMR Mitochondrial efficiency—the proportion of oxygen consumed that is coupled to ATP synthesis—is emerging as a key determinant of BMR. Using high-resolution respirometry on human muscle biopsies, Larsen et al. (2022) showed that individuals with higher BMR exhibit greater mitochondrial proton leak, resulting in lower ATP production per oxygen molecule. This uncoupling is regulated by mitochondrial dynamics: fusion-fission balance and cristae remodeling directly influence the activity of uncoupling proteins and the adenine nucleotide translocator (ANT).

Single-cell transcriptomic studies have further revealed that BMR variability may originate from heterogeneity in mitochondrial content and oxidative capacity across fiber types. Type I fibers, which are more abundant in endurance athletes, have higher mitochondrial density but also greater proton leak, paradoxically increasing BMR while improving metabolic flexibility (Miotto et al., 2023).

4. Circadian and epigenetic modulation BMR is not constant over 24 hours; it exhibits a circadian rhythm with a nadir in the early morning and a peak in the late afternoon. A recent controlled inpatient study by Poggiogalle et al. (2024) used continuous whole-room calorimetry to demonstrate that the amplitude of the BMR rhythm is reduced in shift workers and individuals with insulin resistance, independent of sleep and activity. This desynchrony is associated with altered expression of core clock genes (CLOCK,BMAL1) in adipose tissue and skeletal muscle.

Epigenetic modifications also contribute to BMR regulation. DNA methylation patterns at thePPARGC1A(PGC-1α) promoter predict resting metabolic rate in both lean and obese individuals (Rönn et al., 2022). Furthermore, histone acetylation at theUCP3locus in skeletal muscle is increased after exercise training, leading to sustained elevations in BMR that persist even after training cessation (McGee & Hargreaves, 2023).

5. Technological breakthroughs in BMR estimation Traditional indirect calorimetry, while accurate, is expensive and impractical for large-scale or field studies. Recent advances include:

6. Clinical implications Accurate BMR assessment is critical for managing obesity, cachexia, and metabolic syndrome. New BMR prediction equations incorporating fat-free mass, organ size (measured by MRI), and ethnicity are outperforming the Harris-Benedict and Mifflin-St Jeor formulas by 10–15% in validation cohorts (Hasson et al., 2024). In clinical practice, personalized BMR-guided dietary prescriptions have shown improved weight loss maintenance in a randomized trial compared to standard energy deficit approaches (Camacho et al., 2023).

Moreover, drugs targeting mitochondrial uncoupling—such as controlled-release niclosamide and BAM15—are entering phase II trials for obesity, aiming to increase BMR without affecting heart rate or blood pressure (Feng et al., 2024). These agents mimic the metabolic effects of cold exposure and exercise by inducing mild mitochondrial uncoupling in skeletal muscle and liver.

7. Future perspectives The next frontier in BMR research lies in single-cell and spatial metabolomics. By mapping metabolic flux at the cellular level within different organs, researchers hope to identify “metabolic hotspots” that disproportionately influence whole-body BMR. Organ-specific BMR contributions, currently estimated from allometric scaling, could be directly measured using positron emission tomography (PET) with ¹¹C-acetate or ¹⁸F-FDG under resting conditions.

Artificial intelligence will increasingly integrate genomic, proteomic, and continuous physiological data to predict BMR trajectories across the lifespan. Longitudinal studies that combine wearable sensors with periodic metabolic chamber assessments are needed to understand how BMR changes during aging, menopause, and pharmacological interventions.

Finally, the interaction between BMR and the gut microbiome warrants deeper investigation. Recent work suggests that specific bacterial taxa (e.g.,Akkermansia muciniphilaandPrevotella) are associated with higher resting energy expenditure, possibly via short-chain fatty acid production and modulation of intestinal serotonin synthesis (Depommier et al., 2023).

8. Conclusion Basal metabolic rate is no longer viewed as a static, unchangeable parameter. Advances in molecular biology, circadian physiology, and portable measurement technologies are revealing BMR as a dynamic, modifiable trait with profound implications for metabolic health. As we move toward personalized medicine, integrating BMR into routine clinical assessment will require continued innovation in both mechanistic understanding and practical measurement tools.

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