Glycoprotein Non-Metastatic Protein B (GPNMB): The Missing Link Between Lysosomes and Obesity

Abstract

As a result of an unhealthy diet and limited physical activity, obesity has become a widespread pandemic worldwide and is an important predictor for the development of cardiovascular disease. Obesity is often characterized by a pro-inflammatory environment in white adipose tissue (WAT), mainly due to increased macrophage infiltration. These immune cells boost their lipid concentrations by accumulating the content of dying adipocytes. As the lysosome is highly involved in lipid handling, the progressive lipid accumulation may result in lysosomal stress and a metabolic shift. Recent studies have identified glycoprotein non-metastatic melanoma protein B (GPNMB) as a novel marker of inflammatory diseases. GPNMB is a type I transmembrane protein on the cell surface of various cell types, such as macrophages, dendritic cells, osteoblasts, and microglia, from which it can be proteolytically cleaved into a soluble molecule. It is induced by lysosomal stress via microphthalmia-associated transcription factor and thus has been found to be upregulated in many lysosomal storage disorders. In addition, a clear connection between GPNMB and obesity was recently established. GPNMB was shown to have protective and anti-inflammatory effects in most cases, preventing the progression of obesity-related metabolic disorders. In contrast, soluble GPNMB likely has the opposite effect and promotes lipogenesis in WAT. This review aims to summarize and clarify the role of GPNMB in the progression of obesity and to highlight its potential use as a biomarker for lipid-associated disorders.

Key words

adipose tissue macrophages - glycoprotein non-metastatic melanoma protein B - lipid-associated disorders - lysosomal storage disorders - osteoactivin

Introduction

Obesity can be described as a disproportionate accumulation or organization of body fat and has become an increasingly important health problem worldwide, referred to as the obesity pandemic [1]. Obesity is usually assessed by measuring height and weight to calculate the body mass index (BMI, kg/m²). Recently, however, it has emerged that this parameter is not an efficient predictor of mortality risk and should be replaced by the estimation of percent body fat despite the complexity and high financial cost of assessment [2].

Obesity contributes to chronic diseases, including type 2 diabetes (T2D), hepatic steatosis and steatohepatitis, cardiovascular disease, stroke, dyslipidemia, hypertension, and different types of cancers [3] [4]. Moreover, progressive caloric pressure on white adipose tissue (WAT) results in low-grade but persistent inflammation, called “metaflammation”, associated with increased macrophage infiltration responsible for the clearance of dysfunctional and dying adipocytes [5] [6]. Adipocytes and infiltrating immune cells can produce and release a plethora of chemokines and cytokines that mediate systemic inflammation in obese patients [7]. This continuous inflammatory status in WAT also leads to a metabolic switch from a storage to an inflammatory phenotype, causing ectopic lipid deposition in secondary tissues such as the liver or muscle, which in turn results in deregulated systemic insulin signaling [8].

Adipose tissue macrophages (ATMs) play a central role in the development and progression of inflammation in WAT. In fact, inhibition or silencing of various mediators produced by these immune cells was shown to be sufficient to ameliorate the multiple pathological consequences of obesity [9] [10]. By investigating the molecular mechanism of this polarization switch in macrophages, inositol-requiring enzyme 1a and peroxisome proliferator-activated receptor gamma were identified as important regulators in this process, as they create an inflammatory environment [11] [12]. To reduce WAT inflammation and adipocyte hypertrophy, caloric restriction is widely used as a treatment strategy. However, this therapy paradoxically increases the number of ATMs and the expression of related cytokines in humans and mice [13] [14] [15] [16]. In addition, various pharmacological approaches have been used in an attempt to reduce obesity. For instance, melatonin, a powerful antioxidant, has been demonstrated to reduce obesity-related problems by lowering inflammatory adipokines such as interleukin-6 (IL-6), monocyte chemoattractant protein-1, leptin, and tumor necrosis factor-α [17]. The numerous beneficial effects of glucagon-like peptide-1 (GLP-1) render this hormone an interesting candidate for the development of pharmacotherapies to treat obesity, diabetes, and neurodegenerative disorders [18]. In fact, a weekly dose of the GLP-1R agonist semaglutide was associated with a sustained reduction in body weight [19]. In mice, semaglutide reduced adipocyte hypertrophy and macrophage infiltration and activated adipocyte browning and mitochondrial biogenesis to promote weight loss [20].

Other studies focused on discovering the non-inflammatory role of immune cells induced in obesity. Under conditions of increased adiposity, secreted factors from WAT trigger a program of lysosome biogenesis in ATMs to buffer the huge amount of lipids from adipocytes [21]. Unexpectedly, ATMs from obese mice do not polarize toward one of the classical M1 or M2 phenotypes. The authors, therefore, hypothesized that these are not qualitative changes in the expression profile of ATMs, but that these cells increase in number and, thus, no clear polarization was observed [21]. Obesity reprograms ATMs into a pro-inflammatory metabolically activated state that is transcriptionally, mechanistically, and functionally distinct from M1- or M2-like phenotypes [22]. A unique pleiotropic phenotype in WAT health has been attributed to these macrophages, which varies between beneficial (removal of dead adipocytes) and deleterious (release of pro-inflammatory cytokines) determined by the duration of high-fat diet feeding, at least in mice [23]. Single-cell RNAseq studies have recently identified a new macrophage subset induced during obesity, termed lipid-associated macrophages, characterized by the expression of triggering receptors expressed on myeloid cells 2 [24]. These cells appear to activate an expression profile that involves phagocytosis, lipid catabolism, and lysosomal pathways, which is a common phenotype of macrophages in different inflamed tissues such as the liver, brain, and atherosclerotic plaques [24] [25] [26] [27].

In the last 10 years, the search for new genes that are differentially regulated in the WAT of obese mice has substantially increased. The discovery that glycoprotein non-metastatic melanoma protein B (GPNMB) is highly expressed in the WAT of obese animals [28], opened the way for many studies on this protein. This review aims to emphasize the importance of GPNMB in the context of ATMs, lysosomal function, and obesity.

Structure, function, and regulation of glycoprotein non-metastatic melanoma protein B

GPNMB was first identified in 1995 in a screen using high and low metastatic human melanoma cell lines [29]. It is a type I transmembrane glycoprotein, also known as osteoactivin or dendritic cell heparan sulfate proteoglycan integrin-dependent ligand [30] [31]. GPNMB was detected in a range of cell types, including osteoblasts and osteoclasts in bone, melanocytes, keratinocytes, microglia in the central nervous system, as well as macrophages and dendritic cells [31]. It was found to be increased in a variety of inflammatory diseases such as colitis, renal diseases, different types of cancers, and neurodegenerative disorders [32] [33]. In addition, GPNMB was associated with other disorders, such as senescence [34], vitiligo [35], glaucoma [35], myocardial infarction [37], and atherosclerosis [38]. Mutations in Gpnmb cause hypopigmented lesions and pigmentary glaucoma in mouse models [39] [40] [41] and recessive and semi-dominant amyloidosis cutis dyschromica in humans [42] [43].

The human Gpnmb gene, located at chromosome 7p15, encodes for 2 alternative splicing isoforms of 572 and 260 amino acids [44]. Mouse Gpnmb codes for a protein of 574 amino acids and shares 70.16% sequence identity with the human protein [45] [46]. In its extracellular domain, GPNMB contains an N-terminal signal peptide (SP), an integrin-binding RGD motif and a polycystic kidney disease domain, a single-pass transmembrane domain, as well as an immunoreceptor tyrosine-based activation-like motif and a lysosomal targeting di-leucine motif in the cytoplasmic tail ([Fig. 1a, b]) [47] [48]. The protein has 12 potential N-glycosylation sites, described in numerous cell types [49] [50] [51]. It is predominantly located in endosomal/lysosomal compartments, where it promotes the recruitment of light chain 3 (LC3/Atg8) to the phagosome for lysosomal fusion ([Fig. 1c]) [52] [53] [54] [55]. In addition to phagocytosis, GPNMB was also associated with efferocytosis, the clearance of apoptotic and necrotic cells primarily by macrophages [56]. IL-6, under the control of the phosphorylated-signal transducer and activator of transcription 3 (pSTAT3), was shown to be a positive regulator of this progress [57]. Although Gpnmb-deficient bone marrow-derived macrophages can initiate phagocytosis, they are unable to digest the cargo content, as pSTAT3 activation is not sustained over time. Moreover, this impairment does not allow macrophages to correctly switch from an inflammatory to a restorative phenotype, underscoring the link between GPNMB, phagocytosis, and tissue repair [57].

Fig. 1 GPNMB structure and localization. (a) Model of human GPNMB. The structure of the protein was predicted using the BIOZENTRUM SWISS-MODEL tool [62]. (b) Schematic model of the GPNMB structure, including N-glycosylation sites and cleavage site for AD-AM10. SP, signal peptide; RGD, RGD motif; PKD, polycystic kidney disease domain; TMD, transmembrane domain; ITAM, immunoreceptor tyrosine-based activation-like motif; DL, di-leucin motif. (c) Gpnmb expression is regulated by melanogenesis associated transcription factor (MITF) and transcription factor EB (TFEB). It localizes to the endo/lysosomal com-partment, where it recruits LC3/Atg8 for phagosome fusion. This image was created with Bio-render.com (accessed on September 22nd 2023). [rerif]

Although the precise mechanisms driving this process are unknown, a disintegrin and metalloproteinase 10, a proteolytic enzyme belonging to the matrix metalloproteinase (MMP) family, contributes to GPNMB extracellular domain shedding [58]. This soluble form (sGPNMB) can bind to a variety of receptors, including Na⁺/K⁺-ATPase, CD44, epidermal growth factor receptor, vascular endothelial growth factor receptor, and other molecules such as integrins, heparin, and syndecan-4 [31] [59]. In addition, GPNMB signaling increases extracellular signal-regulated kinase and protein kinase B phosphorylation in many disease models [60] [61] [62] [63]. GPNMB is tightly transcriptionally regulated, with melanogenesis-associated transcription factor (MITF) as one of the major players. MITF overexpression increased GPNMB expression by binding and activating its promoter in both human and animal cells [55] [64] [65]. In addition, transcription factor EB was identified as a regulator of GPNMB expression [34].

Endo/lysosomal localization of glycoprotein non-metastatic melanoma protein B and its role in lysosomal storage diseases

Since GPNMB is localized to endo/lysosomes, studies focused on understanding its role in the biology of these organelles and its link to macrophages, one of the cell types that primarily utilize lysosomal degradation to generate energy in response to the nutritional status of the cell. The link between GPNMB and lysosomal function is supported by many in vitro studies. Numerous inducers of lysosomal stress, such as HEPES, sucrose, chloroquine, bafilomycin, concanamycin A, or palmitate, increase GPNMB expression in macrophage cell lines [28] [66]. Moreover, the lysosomal/endocytic marker lysosomal associated membrane protein 2 was reported to co-localize with GPNMB in osteoclasts [55]. GPNMB is essential for the recruitment of the autophagy protein LC3/Atg8 to the surface of autophagosomes and subsequent acidification and fusion with lysosomes [54], highlighting its close association with this organelle.

The accumulation of lysosomal macromolecules and the resulting stress condition may be due to a genetic deficiency of lysosomal enzymes, leading to lysosomal storage disorders (LSDs). Tissue macrophages are among the primary storage cells involved in LSDs because they contribute to the cleavage of various substrates. Biomarkers such as chitotriosidase (CHIT1) and chemokine (C-C motif) ligand 18 (CCL18) have been identified in patients with LSD but cannot be used in mouse models because CHIT1 is not expressed in phagocytes [67] and a CCL18 homolog is absent in rodents [68]. The urgent need to find a new marker for this group of diseases led to the discovery of GPNMB. Van Ejik and colleagues were among the first to demonstrate an increase in GPNMB in Gaucher disease spleen and, in particular, in Gaucher cells, the lipid-laden macrophages characteristic of this pathology, accompanied by several hundred-fold increase in circulating sGPNMB concentrations [69]. These discoveries paved the way for many other studies that underscored the importance of GPNMB in Gaucher disease [70] [71] [72] [73] and other LSDs [74] [75] [76] and, like CHIT1 and CCL18, confirmed its strong association with LSDs and lipid-laden macrophages.

Further findings provided important insights into the possible molecular mechanisms underlying the increase in GPNMB in LSDs. Another important player during lysosomal stress is the mammalian target of rapamycin complex 1 (mTORC1), a protein localized to the surface of lysosomes and implicated in the control of autophagy [77] [78]. In several models of impaired lysosomal function, mTORC1 was downregulated, and Mitf, the main transcription factor regulating Gpnmb expression, was upregulated [28] [79]. Moreover, lysosomal Ca²⁺ release, as a consequence of organelle stress, was shown to induce nuclear translocation and activation of transcription factor EB, another important transcription factor for Gpnmb [80].

Glycoprotein non-metastatic melanoma protein B and obesity

Across several models of obesity, expansion of WAT induces a program of lysosome biogenesis in ATMs associated with lipid catabolism but not a classic inflammatory phenotype [21], arguing that the increase in the inflammatory profile of WAT associated with obesity derives primarily from quantitative increases in immune cell populations. Thus, in addition to genetic defects, lysosomal lipid accumulation is also triggered when the amount of fat exceeds the storage capacity of the adipocytes, which eventually undergo apoptosis and recruit macrophages. When the WAT is no longer able to process lipids properly, they may accumulate in ectopic tissues, such as the liver or skeletal muscle.

Since the reports that GPNMB is drastically induced in WAT of several obese animal models [28] [81] [82], many studies have focused on describing the role of this protein in obesity and associated metabolic disorders ([Fig. 2]). GPNMB was identified as a negative regulator of macrophage inflammatory responses and only reparative, anti-inflammatory M2-like macrophages activated by TGFβ retain full-length GPNMB on their surface [83]. Pro-inflammatory macrophages activated by interferon γ and lipopolysaccharide secrete sGPNMB [83]. sGPNMB, which is abundantly produced by hypertrophied adipocytes, was also suggested to reduce the inflammatory capacity of macrophages by inhibiting nuclear factor-κB signaling mainly through binding to CD44. Thus, chronic WAT inflammation was severely exacerbated in high-fat diet-fed Gpnmb-deficient mice, accompanied by a pronounced increase in crown-like structures [84]. These data emphasize the critical function of GPNMB in macrophage activation and the subsequent inflammatory response in obese WAT.

Fig. 2 Overview of the role of GPNMB in macrophage function and obesity. (a) Membrane bound GPNMB is retained on the surface of anti-inflammatory macrophages, whereas soluble (s)GPNMB is released by pro-inflammatory cells. (b) Obesity induces the production of sGPNMB by adipocytes, which lowers the inflammatory capacity of macrophages by interacting with CD44 on the cell surface and inhibiting the function of NF-kB. (c) To reduce oxidative stress, lipid accumulation, and fibrosis in the liver, obese adipocytes release sGPNMB, which interacts with calnexin on Kupffer and stellate cells. (d) In obese WAT, the hepatokine sGPNMB activates SREBP1c to promote lipogenesis by binding to CD44 on adipocytes. This image was created with Biorender.com (accessed on September 24th 2023). [rerif]

The phenomenon that GPNMB plays an essential role in decreasing WAT inflammation during obesity by reducing the number of ATMs was absent when GPNMB was over-expressed in adipocytes and macrophages of mutant mice [81]. Whether the discrepancy in the observed phenotype is due to the different high-fat diet (coconut oil [81] versus lard [83]) remains elusive.

In fact, only palmitic acid present in lard is able to trigger insulin resistance [85] and GPNMB expression [28], leading to a stronger effect on WAT of obese mice. However, both diets were very effective in inducing liver steatosis. Furthermore, both studies showed that sGPNMB secreted by adipocytes from obese mice was responsible for decreased oxidative stress, fat deposition, and fibrosis in the liver by interacting with calnexin on Kupffer and stellate cells. However, sGPNMB was also described as a hepatokine that activates SREBP1c and thus lipogenesis in obese WAT by binding CD44 on adipocytes, resulting in a positive correlation between sGPNMB and BMI [86]. These findings indicate that GPNMB is a strong risk factor for obesity.

GPNMB was also linked to T2D, one of the diseases potentially associated with obesity. Numerous sequelae, such as acute renal injury, cardiovascular disease, muscle failure, ocular pathologies, and cognitive dysfunction, frequently accompany the development of T2D. Indeed, GPNMB was found to be increased in many of these T2D-associated disorders [87] [88] [89], once more emphasizing the important role of this protein as a biomarker in obesity and its related conditions.

Conclusions

This review highlights GPNMB as a key player in lysosomal dysfunction and obesity and its potential as a biomarker for the identification and progression of these diseases. In particular, the studies described underscore the binomial role of the two forms of GPNMB in preventing or aggravating obesity and its related disorders. However, the exact mechanism by which GPNMB modulates obesity and obesity-associated metabolic disorders remains controversial and requires further investigation.

Funding Information

City of Graz — Add-on Funding to SFB F73

Amt der Steiermärkischen Landesregierung — http://dx.doi.org/10.13039/501100009818; Add-on Funding to SFB F73

Austrian Science Fund — http://dx.doi.org/10.13039/501100002428; DK-MCD W1226

Medizinische Universität Graz — http://dx.doi.org/10.13039/501100010109; PhD program Molecular Medicine

Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 03 August 2023
Received: 25 September 2023

Accepted: 06 October 2023

Article published online:
13 November 2023