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Cross‐talk muscle and brown adipose tissue: Voluntary physical activity, aerobic training, time and temperature

2022; Wiley; Volume: 600; Issue: 17 Linguagem: Inglês

10.1113/jp283342

1469-7793

Ana Paula Azevêdo Macêdo, Gabriel Calheiros Antunes, Renan Fudoli Lins Vieira, Robson Damasceno de Lima,

Muscle metabolism and nutrition

Through physical exercise, signalling molecules called exerkines are released, which exert their effects through endocrine, paracrine and/or autocrine pathways. The term exerkine was first mentioned in 2016, although the concept of humoral factors mediating the beneficial effects of physical exercise has been known for over 100 years. Exerkines are released by a multitude of organs and cells, including skeletal muscle (myokines), heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (batokines) and neurons (neurokins). These molecules improve cardiovascular, metabolic, immunological and neurological health, presenting potential treatment for cardiovascular diseases, type 2 diabetes mellitus and obesity, and may also promote longevity (Chow et al., 2022). In this context, the recent study by Kim et al. (2022) published in The Journal of Physiology investigated the role of a physical training program (voluntary running) on ​​the modulation of the expression of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) by exerkines, reporting on tissue cross-talk muscle and adipose tissue (Fig. 1). Kim et al. (2022) divided C57BL/6 male mice (8 weeks of age) randomly into control and exercise groups for 4 weeks to assess whether exercise training affects the expression of UCP1 in brown adipocytes through the release of different blood factors. The exercise group performed spontaneous physical activity every day for 4 weeks. The distance walked daily was recorded using an activity wheel running counting machine. All groups were maintained under a 12/12 h light/dark photocycle, with a humidity of 60 ± 5% and a temperature of 23 ± 5°C, until the conclusion of the experiment. Physical exercise promoted thermogenesis through increased expression of peroxisome proliferator-activated coactivator-1 receptor-1 (PGC-1α) and UCP1, together with BAT activation, resulting in reduced body weight and fat percentage at room temperature. The correlation of the increase in UCP1 expression during aerobic exercise occurred as a result of the high oxygen consumption rate and free fatty acid mobilization (Gaspar et al., 2021). Similarly, Kim et al. (2022) demonstrated that aerobic exercise stimulates signal transduction by activating AMP-activated protein kinase (AMPK), identified as a sensor of intracellular energy stress in skeletal muscle, liver and adipose tissue (Kim et al., 2022). It was hypothesized that factors released on AMPK activation in skeletal muscle might induce UCP1 expression in brown adipocytes. Therefore, after 4 weeks of physical training, serum from the exercised animal was incubated in fully differentiated brown adipocytes to investigate whether blood factors altered during physical exercise can directly modulate UCP1 expression in brown adipocytes. Furthermore, another analysis was performed with the conditioned medium of C2C12 myotubes treated with an AMPK agonist (AICAR; 5-aminoimidazole-4-carboxamide ribonucleotide) that mimics the condition of aerobic exercise. The results show that aerobic exercise-induced skeletal muscle AMPK significantly affects UCP1 expression in brown adipocytes. In addition to these results, C2C12 myotubes treated with AICAR released large amounts of interleukin-6 and decreased monocyte chemoattractant protein-1 (Bae, 2018). Based on these promising results, there is much to be investigated about the effects of an aerobic exercise model as represented by Kim et al. (2022) for voluntary running with respect to demonstrating the cross-talk of skeletal muscle with other tissues. This area is an innovative point in the work because, following the same line of reasoning, Bae (2018) showed that aerobic training performed for 8 weeks with a gradual increase in intensity in obese mice increased the protein content of phospho-AMPK, AMPK activity and PGC-1α in the gastrocnemius of the trained obese group compared to obese animals. Bae (2018) evaluated meteorin-like protein (Metrnl) in white adipose tissue and muscle, noting increases in both tissues. This result is a result of the role played by Metrnl in controlling insulin sensitivity in adipocytes through the peroxisome proliferator-activated receptor γ pathway in muscle, which can be influenced by PGC-1α causing its increase. Thus, we can infer that the results reported by Kim et al. (2022) can be extended to aerobic training and, from that, new arguments arise about the effectiveness of aerobic training compared to voluntary activity, considering how much the variables time and intensity of physical training can impact the results. Although a previous study by Kim et al. (2022) justified that voluntary wheel running was more effective than treadmill exercise in reducing body weight and fat content of mice, more investigations are necessary because weight and body fat reduction may not reflect all of the beneficial aspects of the molecular changes that occur through aerobic exercise with respect to the process of weight loss and obesity in different tissues. In addition, well-stipulated protocols regarding the duration of the experimental period and programmed training on a mechanical treadmill that control essential variables such as intensity, time and inclination, as well as the training schedule and the zeitgeber of the animal, can influence the physiological and molecular parameters. Another vital aspect is temperature. When it comes to the browning of adipocytes, temperature is an essential factor because the cold stimulates this process, in addition to impacting the animal's performance with respect to physical activity (Kim et al., 2022). Furthermore, the thermal biology of mice is different from that of humans, and conditions of 30°C can trigger immune system activation (Škop et al., 2020). The study by Kim et al. (2022) was carried out at a temperature of 23 ± 5°C. A temperature variation of 5°C can influence the results because the metabolic response at 18°C will probably be different from that at 28°C (Kim et al., 2022). The suggestion for future studies is to control temperature and minimize variation. In addition, as discussed by Kim et al. (2022), raising the housing temperature of mice from room temperature to 27 to 30°C (thermoneutrality) is translatable between humans and mice. However, the thermal biology of mice is fundamentally different from that of humans, and conditions of 30°C may activate the immune system. In conclusion, the study by Kim et al. (2022) addresses important points of muscle and adipose tissue cross-talk. In addition, the study contributes to demonstrating the impact of physical exercise in voluntary running with respect to showing the positive effects obtained in weight loss and the metabolic profile. It also enables a better understanding of the mechanisms involved regarding the results found in cell cultures and the metabolic response of animals. However, the aerobic training protocol and temperature control are points worthy of consideration in future studies. In addition, new studies that analyse the impact of the activity on obese animals should be designed, aiming to show whether there are positive effects on metabolic health in the context of obesity. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. The authors declare that they have no competing interests. All authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. The present work received financial support from the São Paulo Research Foundation (FAPESP; process numbers 2020/15679-2, 2020/14320-0 and 2021/13847-8). We thank Dr José Rodrigo Pauli for his writing support.