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Review
. 2023 Sep 8;12(18):2240.
doi: 10.3390/cells12182240.

Myoglobin in Brown Adipose Tissue: A Multifaceted Player in Thermogenesis

Mostafa A Aboouf  1   2   3 , Thomas A Gorr  1 , Nadia M Hamdy  3 , Max Gassmann  1   2 , Markus Thiersch  1   2
Affiliations
Review

Myoglobin in Brown Adipose Tissue: A Multifaceted Player in Thermogenesis

Mostafa A Aboouf et al. Cells. .

Abstract

Brown adipose tissue (BAT) plays an important role in energy homeostasis by generating heat from chemical energy via uncoupled oxidative phosphorylation. Besides its high mitochondrial content and its exclusive expression of the uncoupling protein 1, another key feature of BAT is the high expression of myoglobin (MB), a heme-containing protein that typically binds oxygen, thereby facilitating the diffusion of the gas from cell membranes to mitochondria of muscle cells. In addition, MB also modulates nitric oxide (NO•) pools and can bind C16 and C18 fatty acids, which indicates a role in lipid metabolism. Recent studies in humans and mice implicated MB present in BAT in the regulation of lipid droplet morphology and fatty acid shuttling and composition, as well as mitochondrial oxidative metabolism. These functions suggest that MB plays an essential role in BAT energy metabolism and thermogenesis. In this review, we will discuss in detail the possible physiological roles played by MB in BAT thermogenesis along with the potential underlying molecular mechanisms and focus on the question of how BAT-MB expression is regulated and, in turn, how this globin regulates mitochondrial, lipid, and NO• metabolism. Finally, we present potential MB-mediated approaches to augment energy metabolism, which ultimately could help tackle different metabolic disorders.

Keywords: brown adipose tissue; energy metabolism; fatty acid metabolism; lipid shuttling; metabolic disorders; mitochondrial oxidative metabolism; myoglobin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Typical gas binding-related functions of MB in muscle cells. (1) MB acts as a temporary store or reservoir for O2 storage, especially in breath-holding diving mammals. (2) MB buffers short phases of exercise-induced increases in O2 flux by supplying it to the mitochondria of myocytes via facilitated diffusion [5,6,7]. (3) MB impacts the homeostasis of important mediators of cell signaling. Reactive oxygen species (ROS) generated from mitochondria are rapidly detoxified/scavenged by MB. Under normoxic conditions, oxygenated MB (MBO2) scavenges nitric oxide (NO•), thus preventing its inhibitory effect on cytochrome c oxidase and allowing for sustained mitochondrial respiration. Under hypoxic conditions, deoxy MB (MB) produces (NO•) that works dually to stimulate vasodilation (i.e., bring more blood and O2) as well as to inhibit cytochrome c oxidase and thus mitochondrial respiration to spare the limited O2 in the cell for other metabolic processes [47,48]. The figure was created with Biorender.com.
Figure 2
Figure 2
Fatty acid metabolism in BAT. (A) Active BAT is located in interscapular and cervical–supraclavicular sites in mice [70] and humans [71,72,73], respectively. Brown adipocytes are characterized by the presence of multiple small lipid droplets (plurilocular phenotype) and a high content of mitochondria, unlike white adipocytes which have one large lipid droplet (unilocular appearance) and far fewer mitochondria [74]. Moreover, only the mitochondria of brown adipocytes express the uncoupling protein 1 (UCP1). UCP1 is located at the inner mitochondrial membrane and facilitates the runback of protons along their gradients without the formation of ATP but with the dissipation of heat instead [75,76]. Free fatty acids (FAs), bound to UCP1, are essential for this uncoupling activity [65,66]. (B) Fatty acids (Fas) are released from very low-density lipoproteins (VLDLs) carried in the bloodstream by the action of the endothelial lipoprotein lipase (LPL) on the triglycerides contained within VLDLs. Fatty acid transporter proteins 1 and 4 (FATP1 and 4) as well as cluster of differentiation 36 (CD36) take up Fas into brown adipocytes. Proper fat storage into smaller and numerous lipid droplets is achieved via the activity of the following lipid droplet membrane proteins genes: the lipolytic regulator cell death-inducing DNA fragmentation factor- a-like effector A (CIDEA) and the fat-specific protein 27 (FSP27 or CIDEC), which ultimately increase the surface area of lipid droplets by storing FAs within numerous small lipid droplets (i.e., increasing surface area of energy expenditure by providing lipids more efficiently to mitochondria). The levels of the saturated free FAs (SFAs) determine UCP1 expression and thermogenic activity. The second mechanism determining FA abundance in brown adipocytes is de novo synthesis (lipogenesis) via the following enzymes: fatty acid synthase (FASN), elongation of very long chain fatty acid 3 (ELOVL3), and stearoyl-CoA desaturase1 (SCD1). FA-binding proteins (FABP) aid in binding FAs and hence prevent lipotoxicity. Regarding FA oxidation: FAs are converted into fatty acyl-CoA via the action of fatty acyl-CoA synthetase-1 (FACS1), then converted to acylcarnitine via the action of carnitine palmitoyltransferase-1 (CPT1). Acylcarnitine is transported to the mitochondrial matrix by carnitine/acylcarnitine translocase (CACT), followed by reconversion to fatty acyl CoA via the action of carnitine palmitoyltransferase-2 (CPT2) before being oxidized in presence of O2 [77]. The figure was created with BioRender.com.
Figure 3
Figure 3
Illustrative scheme of proposed roles of MB in regulating lipid and mitochondrial metabolism in BAT. MB enhances mitochondrial respiration, positively stimulates expression of oxidative phosphorylation proteins (OXPHOS) and upregulates abundance of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and peroxisome proliferator activated receptor α (PPARα). MB expression was also associated with enhanced expression of the thermogenic marker uncoupling protein 1 (UCP1). MB aids in proper fat storage into smaller and numerous lipid droplets by upregulating expression of lipid droplet membrane proteins: the lipolytic regulator cell death-inducing DNA fragmentation factor- a-like effector A (CIDEA), fat-specific protein 27 (FSP27 or CIDEC), ultimately increasing surface area of energy expenditure. MB promotes shuttling of C16:0 palmitate fatty acid (FA) from diglycerides (DG) to the cytosolic pools (represented by free FAs). The increased levels of the saturated free FAs might be the reason behind stimulating UCP1 expression and uncoupling activity. Lack of MB was correlated with increased abundance of enzymes controlling de novo synthesis of FAs (lipogenesis): fatty acid synthase (FASN), elongation of very long chain fatty acid 3 (ELOVL3) and stearoyl-CoA desaturase1 (SCD1), probably as compensatory mechanism to increased long chain (limited) FA oxidation seen in absence of MB. Conversely, MB has no impact on expression of FA binding proteins (FABP) or on regulators of FA oxidation: acyl-CoA synthetase-1 (FACS-1/ACSL1), carnitine palmitoyltransferase-1 B isoform (CPT1B), carnitine/acylcarnitine translocase (CACT) and carnitine palmitoyltransferase-2 (CPT2). Figure created by BioRender.com.
Figure 4
Figure 4
Oxy- vs. deoxy-MB roles in BAT metabolism. Oxygenated myoglobin (oxy-MB) can bind and shuttle fatty acids (FAs), enhance mitochondrial respiration, stimulate the expression of oxidative phosphorylation proteins (OXPHOS), and upregulate the abundance of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and peroxisome proliferator-activated receptor α (PPARα). MB expression was also associated with an enhanced thermogenic marker uncoupling protein 1 (UCP1) expression. MB aids in proper fat storage into smaller and numerous lipid droplets by upregulating the expression of lipid droplet membrane proteins: the lipolytic regulator cell death-inducing DNA fragmentation factor- a-like effector A (CIDEA), fat-specific protein 27 (FSP27 or CIDEC), ultimately increasing surface area of energy expenditure. MB promotes the shuttling of C16:0 palmitate FA from diglycerides to the cytosolic pools (represented by free FAs) by stimulating protein kinase A (PKA)-dependent lipolysis. The increased levels of the saturated free FA might be the reason behind the stimulated UCP1 expression and uncoupling activity. Lack of MB, in turn, was correlated with an increased abundance of enzymes controlling de novo synthesis of FA (lipogenesis). MB expression in brown adipocytes is under the transcriptional control of nuclear respiratory factor-1 (Nrf1) and is upregulated during cold. On the other hand, deoxygenated Mb can generate NO• from nitrite (NO2−) when O2 partial pressure drops. A sufficient degree of hypoxia is likely to occur under conditions of increased O2 demand and O2 flux, as seen in thermogenically activated BAT under conditions of β3-adrenergic stimulation or cold. NO• can induce mitochondrial biogenesis by impacting PGC1a and NRF1 transcription. NO• can also regulate hypoxia-inducible factor-1 (HIF-1) and increase cGMP levels, ultimately regulating genes and pathways that support thermogenesis and brown adipocyte function. Hence, MB might impact brown adipocyte phenotype and activity through its O2 and FA-sensing qualities. Figure was created with BioRender.com.
Figure 5
Figure 5
Myoglobin in silico interaction network analysis. (A) STRING protein–protein interaction (PPI) network with 11 proteins; with no clustering, the network is shown as it is. HP: Haptoglobin-related protein, Haptoglobin; CYB5A: Cytochrome b5 type a; Cytochrome b5; MT-CYB: Cytochrome b; Component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex) that is part of the mitochondrial respiratory chain; TG: Thyroglobulin; CYCS: Cytochrome c, somatic, Cytochrome c; CKMT2: Creatine kinase S-type, mitochondrial; NGB: Neuroglobin; TNNI3: Troponin I, cardiac muscle, Troponin I is the inhibitory subunit of troponin; ALB: Serum albumin; CKM: Creatine kinase, m-type. (B) Molecular Interaction Database IntACT Version 1.0.3. Physical association is indicated as a cyan blue line for ANK1; Ankyrin-R and HSPB2; Heat shock protein beta-2. Association between proteins denoted as a dotted line for CORT; Cortistatin and PPP1CA; Serine/threonine-protein phosphatase PP1-alpha catalytic subunit, from heart atrium. (C) BioGRID4.4 database 14 interaction network. Green-colored nodes for chemical compounds; however, the blue ones are proteins, and the yellow line denotes the physical vs. blue lines chemical associations.
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This research was funded by the Swiss National Science Foundation 31003A_175637 (M.G).
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