Non-shivering thermogenesis is mediated by brown and beige adipocytes, which are uncoupling-protein 1 (Ucp1) expressing cells that can convert chemical energy into heat.1 These thermogenic adipocytes are activated through beta-adrenergic signaling, and their highly dynamic metabolism allows for quick adaptation to temperature changes. Christen et al. now show that myoglobin (Mb) contributes to mitochondrial respiration and adrenergic response in thermogenic adipocytes (Figure 1).2 Mb is a single polypeptide chain of 154 amino acids with an iron ion containing heme group that allows for reversible oxygen binding. For decades, Mb was thought to be exclusively present in cardiac and skeletal muscle, where its main functions were storing oxygen and aiding oxygen diffusion. Newer work has shown that Mb binds fatty acids and has a proposed role as fatty acid transporter, affecting triglyceride metabolism in muscle.3 It was discovered that Mb is also present in brown adipose tissue (BAT) and up-regulated during cold exposure.4 Christen et al. investigated the still unknown mechanism and physiological relevance of Mb in BAT and demonstrates that Mb enhances thermogenic activity of adipocytes and differentially expressed in humans. They find that Mb transcription and protein levels increase after brown adipocyte differentiation and cold-induced BAT activation, confirming the results from the existing literature on BAT Mb.5, 6 Beta-adrenergic stimulation did not increase Mb expression level, but instead Mb expression was under transcriptional control of Nuclear Respiratory Factor-1 (Nrf1). Mb levels amplified the adrenergic response of the cell, as overexpression of Mb increased lipolysis and mitochondrial respiration after treatment with adrenergic agent forskolin. Focusing on the underlying mechanism of Mb, the authors show that fatty acid binding to Mb was essential for the observed increase in respiration. They also show increased cold sensitivity and decreased cold-induced Ucp1 expression in a global Mb transgenic knock-out mouse model. Finally, Christen et al. explored the gene expression of Mb in human fat depots and found differential expression in obesity and higher expression in thermogenic adipocytes overall. The two major features of thermogenic adipocytes are high levels of mitochondria and high lipid content or flux. It is known that global deficiency of Mb in mice results in a BAT phenotype,5 but the cell-intrinsic role remained unclear. Christen et al. now find that increasing Mb levels in thermogenic adipocytes resulted in higher mitochondrial respiration and increased lipid droplet numbers. To add another level of complexity, oxygenated Mb can bind non-esterified fatty acids and plays a role in lipid metabolism3 and has been suggested to participate in the BAT phenotype.5 Christen et al. show that fatty acids bind to Mb and, in a proof-of-concept experiment, demonstrate that a non-lipid binding mutant of Mb was unable to increase respiration in cultured thermogenic adipocytes. This suggests that Mb acts as a lipid chaperone and shuttle, similar to fatty acid binding proteins, and thus, delivers fatty acids to mitochondria for Ucp1 activation and beta-oxidation. Notably, the expression of Mb in BAT is induced upon cold exposure but seems to be independent of canonical adrenergic stimulation. There is accumulating evidence that adrenergic signaling is not the only activation mechanism of thermogenesis. Extracellular purine signaling and intracellular lipolysis provide signals that are associated with cold-induced or endocrine activation.7, 8 It is possible that these adrenergic independent signals also drive Mb expression. In addition to cold, it will be interesting to establish if other environmental cues mobilize thermogenic Mb, like certain dietary regimen, exercise, or obesity. As Mb is found in circulation, albeit mostly under conditions of tissue damage, revisiting the systemic effects of Mb might be of interest. Especially, as other fatty acid bainding proteins, such as FABP4 have recently been implicated as lipolysis-induced endocrine hormones that regulate systemic metabolism.9 Cold adaptation is a complex physiologic process that also includes mechanisms beyond non-shivering thermogenesis. Christen et al. use mice globally deficient in Mb, which display cold sensitivity. Considering the cellular results, the authors argue that the cold sensitivity is a result of impaired non-shivering thermogenesis. However, there are examples in the literature where mice are cold resistant in the absence of non-shivering thermogenesis.10 Especially as Mb is abundantly present in skeletal and cardiac muscle, the KO phenotype could be partially caused by impaired shivering thermogenesis, heart malfunction, or any other pathophysiological consequence of Mb loss elsewhere. To further disentangle the cold sensitivity phenotype, mouse models with (inducible) cell type-specific deletion of Mb will be insightful. To the best of our knowledge, Christen et al. are the first to study the presence of Mb in human adipose depots. Their data are limited to levels of Mb gene expression but nevertheless show remarkable patterns. Lean patients have higher Mb expression in visceral adipose tissue compared to subcutaneous adipose tissue, whereas obese patient show the reverse. In addition, Mb was associated with high Ucp1 expression. While these findings are too preliminary to draw strong conclusions about the role of Mb in human adipocytes, they point towards a positive association between Mb expression and metabolic health. Strategies to enhance Mb function, mitochondrial function and lipid turnover should have a beneficial effect on body weight and metabolic health. In conclusion, the study by Christen et al. suggests roles for Mb beyond the dogma, giving a fresh, fiery breath to a classic molecule. A.B. was supported by the DFG Priority Program 2306 (BA 4925/2-1) and the ERC Starting Grant PROTEOFIT. The authors apologize to colleagues whose work they could not cite due to space limitations. The authors declare no competing financial interests related to this work. DFG Priority Program 2306, Grant Number: BA 4925/2-1; ERC Starting Grant PROTEOFIT.
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Mar 20, 2024
Alana Aragón-Herrera + 15
