A muscle protein at work in brown adipose tissue
How is a muscle protein related to energy production in brown adipose tissue (BAT)? And could this be a possible starting point in the fight against obesity? A team of researchers led by John Heiker from the Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of Helmholtz Munich and the Medical Faculty of the University of Leipzig investigated how the protein myoglobin (MB), best known for its function as an oxygen transporter in muscle, impacts BAT metabolism and thermogenesis in vitro and in vivo. Their results are now published in the journal Clinical and Translational Medicine.
Brown adipose tissue is a metabolically active organ that transfers energy from fat into heat. Heat production from BAT is activated whenever the organism needs extra heat, e.g. during cold-exposure, postnatally, during entry into a febrile state or during arousal from hibernation. Its main function is to maintain body temperature. For a long time, it was assumed that this tissue regresses with increasing age and is completely lost by the time a person reaches adulthood. But this view was refuted and the capacity to produce brown adipose tissue has been shown in adulthood.
The rediscovery of functional BAT in adults provides new perspectives for the treatment of obesity and obesity-associated diseases. In fact, the recruitment and activation of BAT results in an increased energy consumption via thermogenesis (heat development), and thus represents a promising therapeutic approach to combat obesity and treat associated diseases.
Myoglobin: The role of a muscle protein
Thermogenesis of BAT occurs in numerous mitochondria, the energy suppliers of our cells. Biochemically, the energy expenditure occurs by uncoupling oxidative phosphorylation from ATP synthesis to dissipate energy as heat. This process requires a continuous flux of oxygen and lipids to BAT mitochondria. But who is taking care of this task in our BAT?
According to textbooks, it has long been known that the muscle protein myoglobin is highly expressed in cardiac and skeletal muscles. Its key role: to store and promote the transport of oxygen from the cell membrane to mitochondria under conditions of high oxygen demand. However, in the last years, additional roles have been attributed to MB. Evidence suggests for example that it plays a role in thermogenesis of BAT, as the muscle protein is expressed to a high extent in this tissue. Researchers led by John Heiker took a closer look at this assumption and investigated how MB impacts BAT metabolism and thermogenesis.
An important regulatory element for thermogenesis
First author Lisa Christen and her colleagues were able to show that the substantial expression of MB in BAT controls not only brown adipocyte mitochondrial respiration but also the response to adrenergic activation, which plays a major role in increased energy consumption. In line with these findings, they found that whole-body MB knockout in vivo impaired thermoregulation and BAT activation in mice.
In a second step, the team then investigated how MB acts in BAT, based on recent reports of MB’s fundamental property to bind lipids and other metabolites. The researches succeeded in demonstrating for the first time, that it is indeed MB interaction with lipids that is fundamental to improve metabolic activity in brown adipocytes. Furthermore, analysis of MB expression in white adipose tissue samples of patients from the Leipzig Obesity BioBank (LOBB), headed by HI-MAG Director Matthias Blüher, revealed MB as a marker of thermogenic adipocytes in humans.
“Based on ours and others recent work, it may be time to rewrite or expand the textbooks on this classical muscle protein” suggests Juliane Weiner, co-senior author of the study.
Together, these results demonstrate for the first time the functional relevance of myoglobin’s lipid-binding properties and establish MB as an important regulatory element of the thermogenic capacity in brown adipocytes. These findings are of central importance as, only with a good understanding of the molecular mechanisms that control the function of BAT, appropriate therapies against obesity and associated diseases can be developed.
Christen L, Broghammer H, Rapöhn I, et al. Myoglobin-mediated lipid shuttling increases adrenergic activation of brown and white adipocyte metabolism and is as a marker of thermogenic adipocytes in humans. Clin Transl Med. 2022; 12:e1108. https://doi.org/10.1002/ctm2.1108
This work was funded by grants of the Deutsche Forschungsgemeinschaft SFB1052 "Obesity Mechanisms" (B1 to M.B., B4 to N.K. and C7 to J.T.H) as well as funding from the Free State of Saxony and Helmholtz Munich.