The dynamic nature of resting metabolic rate

Assessment of resting metabolic rate — the amount of energy that the body needs to function while resting — is considered a cornerstone of personalized nutrition.¹ And with the advent of portable calorimeters for human use, measurements of metabolic rate are likely to become more common in clinical practice over the years to come. However, as nutritionists move towards this goal, they will probably need to account for the fact that resting metabolic rate is not as static as it was once presumed. Intra-subject variability in resting metabolic rate is often attributed to physiological regulation, but the dynamics and the mechanisms of this regulation are still under investigation.

New insights into this topic can be found in several of the articles published in Temperature. Daanen and Van Marken Lichtenbelt² discuss the contribution of nonshivering thermogenesis to the metabolic rate of adult humans. Until recently, nonshivering thermogenesis was thought to be an exclusive feature of subjects that have a well-defined depot of brown fat, such as small mammals and newborn humans. However, this view started to change when brown adipocytes were found scatted in the supraclavicular white fat of adult humans. The available evidence indicates that, in adult humans, nonshivering thermogenesis is activated before shivering in response to mild cold, and can account for an increase of 10–20% in metabolic rate. This contribution may vary depending on genetic background and environmental factors. The influence of the environment might be related to adipocyte browning, the process by which white adipocytes can be transformed into thermogenic brown adipocytes. A protein known as ‘PR domain zinc finger protein 16’ (Prdm16) has been shown to play a major role in this process, being capable of activating the full genetic program of thermogenic brown adipocytes.³ Brown adipocyte differentiation also seems to be under the control of peroxisome proliferator-activated receptor-γ (PPAR-γ).⁴

Of particular relevance to nutritional sciences is the increasing body of evidence indicating that nonshivering thermogenesis can be governed by non-thermal factors, including metabolic signals. Motivated by the potential use of vagal nerve stimulation as a treatment for obesity, Madden et al.⁵ investigated how non-thermal sensory fibers of the vagus nerve can modulate nonshivering thermogenesis in experimental rats. The results revealed that vagal afferents suppress brown fat activity via a neural reflex involving glutamatergic activation of neurons in the nucleus of the solitary tract and subsequent GABAergic inhibition of sympathetic premotor neurons in the rostral raphe pallidus. Mohammed et al.⁶ have also shown the importance of non-thermal signals in the control of brown fat thermogenesis in rats, but, in that case, a cross-talk was found between fasting-stimulated orexigenic neurons and brown fat. In another study, Miko et al.⁷ have described alarin as an atypical orexigenic peptide: whereas typical orexigenic peptides increase appetite and suppress metabolic rate, alarin increases both appetite and metabolic rate. Drugs are also non-thermal factors of relevance in assessments of resting metabolic rate, and, in this context, amphetamines deserve attention.⁸

To make matters even more interesting, it has been recently discovered that nonshivering thermogenesis displays an ultradian rhythmicity that may be independent of sensory inputs. This topic is covered in an authoritative review by Blessing and Ootsuka,⁹ which presents a fresh approach for studying integrative physiology, in addition to providing a historical account of the authors’ discovery. Such an approach consists of analyzing physiological data at the individual level, as opposed to the more conventional analysis of group averages. Using this approach, the authors discovered that the brown fat temperature of unanesthetized rats increases suddenly, for no apparent reason, every 1–2 hours in both the light and dark phases of the day. These ultradian bursts in brown fat thermogenesis do not seem to reflect a thermoregulatory reflex, but rather a brain-initiated anticipatory behavior. Indeed, the ultradian bursts in brown fat thermogenesis start concurrently with exploratory behavior, and typically precede feeding episodes by 15 min. The onset of these bursts is coupled with the appearance of theta electroencephalographic waves in the hippocampus, which is seen by many as an indication that the animal is directing its attention towards the external environment.

This is an exciting time for those interested in brown fat thermogenesis! I look forward to seeing how this field of research, once relevant only to those interested in thermoregulation, becomes more and more integrated with other biomedical disciplines.