Nonequilibrium thermodynamic analysis of human bioenergetics in obesity: implications of the second law

• Published in: American journal of physiology: endocrinology and metabolism Vol. 329; no. 2; pp. E191 - E209
• Main Author: Istfan, Nawfal
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.08.2025
• Subjects: 3-Hydroxybutyric Acid - metabolism; Adult; Bioenergetics; Body weight; Constraints; Efficiency; Energy balance; Energy conservation law; Energy conversion; Energy dissipation; Energy expenditure; Energy Metabolism - physiology; Female; Free energy; Humans; Legislation; Male; Mitochondria; Mitochondria - metabolism; Models, Biological; Nonequilibrium thermodynamics; Obesity; Obesity - metabolism; Oxidative Phosphorylation; Phosphorylation; Thermodynamics; metabolic efficiency; entropy production; total energy expenditure; second law of thermodynamics
• DOI: 10.1152/ajpendo.00487.2024
• ISSN: 0193-1849

This article introduces the second law of thermodynamics as an integral component of the study of human energy metabolism. The concepts of efficiency and energy dissipation are unified with the current understanding of energy balance in human subjects. It is important to note that the energy utilized in biological processes constitutes only a fraction of the total energy metabolism. Measurement of this fraction relative to total energy expenditure elucidates the body’s mechanisms for adapting to fuel scarcity and abundance, as exemplified by weight gain and weight loss. The fundamental principle of energy balance, a statement of the first law of thermodynamics, overlooks the second law, resulting in gaps in our knowledge of body weight regulation and obesity. This study develops research tools to implement nonequilibrium thermodynamics in human subjects based on a mitochondrial energy conversion model. A key advancement measures ATP phosphorylation through its relationship to the mitochondrial redox couple, beta-hydroxybutyrate, and acetoacetate. Applying this methodology in humans, utilizing data from a recent study, provides a comprehensive understanding of the impact of the second law. The results demonstrate that oxidative phosphorylation efficiency is approximately 57%, with minor but significant variations among individuals. Four out of 24 healthy subjects exhibited a sufficiently higher efficiency of oxidative phosphorylation and lower free energy dissipation compared to the remaining subjects. Feeding is associated with lower efficiency, a higher rate of free energy dissipation, and a slight reduction in coupling. The amount of energy utilized for useful work represents only one-third of resting energy expenditure. These findings are integrated with the current principle of energy balance to adhere to the constraints of the first and second laws. Based on theoretical modeling, it is demonstrated that interindividual differences and variations in mitochondrial efficiency and energy dissipation during specific metabolic conditions can lead to discrepancies between total energy balance and the balance of the fraction of energy used for useful work. Consequently, the constraints imposed by the second law should be incorporated into the current understanding of energy balance and obesity. NEW & NOTEWORTHY This article introduces the second law of thermodynamics as an integral component of the study of human energy metabolism. The concepts of efficiency and energy dissipation are unified with the current understanding of energy balance in human subjects. It is important to note that the energy utilized in biological processes constitutes only a fraction of the total energy metabolism. Measurement of this fraction relative to total energy expenditure elucidates the body’s mechanisms for adapting to fuel scarcity and abundance, as exemplified by weight gain and weight loss.