Metabolic dysfunction is a risk factor of cardio-cerebrovascular disease, and key molecules that play pivotal roles in its pathogenesis need to be further investigated. As a common risk factor for a variety of metabolic diseases, obesity promotes the imbalance of expression and secretion of a variety of cytokines and eventually leads to the occurrence of metabolic and cardiovascular diseases [1, 2, 3, 4]. Given that improving insulin resistance (IR) represents a critical strategy in the treatment of type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS), novel insulin-sensitizing treatments are needed [5, 6, 7]. Recently, a novel adipokine, subfatin, has been found, which may be involved in the pathophysiology of obesity and IR and therefore have comprehensive effects on atherosclerosis [8]. And it may become a potential biomarker or a therapeutic target of MS.

To date, subfatin has been found to play roles in lipid metabolism, tumor and immunity [9, 10, 11], which are of great clinical interest. However, the current literature is still limited and some findings are controversial. For instance, in the study of patients with newly diagnosed T2DM, contradictory results of both increasing and decreasing serum levels of subfatin were noted, which requires a larger sample size to reduce bias [12, 13, 14].

Given the potential role of subfatin in patients with MS, this article aimed to review the novel findings and profound function of subfatin (Fig. 1).

Fig. 1.

The schematic illustration of subfatin in metabolic syndrome. This review explains the biological functions of subfatin in cardiovascular homeostasis and metabolic syndrome, especially in the terms of glucose and lipid metabolism, insulin resistance, inflammation regulation, and browning of white adipose tissue (BWT).

Adipose tissue is the largest endocrine organ [15], which secrets a variety of adipokines. Jorgensen et al. firstly reported a novel secreted protein termed subfatin which together with meteorin defines a new evolutionary conserved protein family. Li et al. [16] identified subfatin as a novel adipokine. Subfatin is possibly also a neurotrophic factor with therapeutic potential [17].

Subfatin is also named Metrnl (Meteorin-like), cometin [18], or interleukin 39 (IL-39) [19, 20]. The gene of subfatin is located in chromosome 11qE2 in mice and chromosome 17q25.3 in humans, respectively [21]. Bioinformatic analysis shows that the subfatin protein is encoded in human genomes contain 311 amino acids, with an NH2-terminal signal peptide of 45 amino acids and without any transmembrane region, suggesting a mature protein that contains 266 amino acids when secreted (Fig. 2). Studies have shown that its expression was induced by a chronic high-fat diet, inflammation, exercise, cold exposure and other factors.

Fig. 2.

The schematic illustration of human subfatin gene. The subfatin gene is composed of a signal peptide at the N-terminus and a meteorin-like protein at the C-terminus. The secreted subfatin presents two expression modes of autocrine and paracrine in the body.

It is named meteorin-like protein due to the similar sequence to metrn protein [22, 23]. The initial name of Meteorin (Metrn) was a vivid description of its function in transforming glial cells into cells with an elongated tail that look like meteors [24]. Following studies found that subfatin was mainly distributed in white adipose tissue, different from the homologous Metrn that is majorly expressed in the brain, and ubiquitously throughout the whole body. It plays a pivotal role in the browning of white adipose tissue (BWT), and highly enriched in subcutaneous fat. Therefore, Li et al. [16] propose a more appropriate name “subfatin” (refers to subcutaneous fat highly expressed protein) instead of “Meteorin-like”.

We searched the literature from the PubMed database and found that although subfatin protein was first mentioned in 2012, there are still only a handful of studies on it in the past 9 years. Given its involvement in lipid metabolism, oncology and immunity, and without a very specific breakthrough point, most studies are still scattered. Zheng et al. [21] published four successive articles from 2014 to 2016, and had a more in-depth study on the potential of the protein [16, 21, 25, 26].

Based on the available literature, subfatin may improve insulin sensitivity, increase systemic energy expenditure, induce white adipose browning, regulating lipid metabolism and promote anti-inflammatory gene programs in obese/diabetic mice [22, 27].

Both aerobic and resistance exercises improve insulin sensitivity [28]. As is known, exercise promotes the release of metabolism-related proteins through repeated muscle contraction and relaxation in skeletal muscle, which leads to a series of phenotypic adaptations of skeletal muscle and helps to alleviate metabolic disorders [29]. Subfatin is induced into circulation after exercise and in the adipose tissue upon cold exposure. Increased subfatin stimulates energy expenditure, improves glucose tolerance and the expression of genes associated with beige fat thermogenesis and anti-inflammatory cytokines [30]. The serum level of subfatin is independently related to insulin resistance. It affects insulin sensitivity at least via its local autocrine/paracrine action through AMP-activated protein kinase (AMPK) or peroxisome proliferator-activated receptor $\delta$ (PPAR-$\delta$) dependent signaling. Therefore, subfatin can be regarded as a bridge between exercise and thermogenesis, and participates in the molecular mechanism of energy metabolism, involving in maintaining energy homeostasis [31].

Obesity is associated with chronic inflammation and dysregulation of adipokine secretion and may increase the risk of T2DM and CAD (coronary artery diseases) [32, 33, 34, 35]. Adipose tissue, as the largest endocrine organ of the body [15], participates in homeostasis regulation by releasing adipokines which function in various signaling pathways [36]. Adipokines are considered as potential candidates for the relation of the adipose tissue with systemic glucose and lipids metabolism [13, 26]. Subfatin is a novel adipomyokine that shows high levels of expression in white adipose tissue and barrier tissues. It ameliorates lipid-induced inflammation and IR via AMPK or PPAR-$\delta$-dependent signaling pathways in the skeletal muscle of mice [37, 38]. Therefore, subfatin might be a potential therapeutic target in inflammation and MS by regulating tissue energy homeostasis [30]. The overall regulation mechanism of subfatin was showed in Fig. 3, and the detailed explanation as followed.

Fig. 3.

The signaling mechanism of subfatin in the glucose and lipid metabolism. Subfatin regulates glucose and lipid metabolism through AMPK and PPAR-$\delta$ dependent signal pathways, and finally mediates insulin resistance and inflammation progression through PGC1$\alpha$ and GLUT4, respectively.

Firstly, subfatin promoted eosinophils to infiltrate adipose tissue, induced the expression of eosinophil-specific chemokines in adipocytes, to induce immune cytokines (IL-4/IL-13) to stimulate thermogenesis, and upregulated the expression of pyrogen gene [39, 40, 41]. Secondly, in addition to stimulating thermogenesis, subfatin also promotes inflammatory cytokines that inhibit the phenotype of macrophages.

Subfatin exerts effects through AMPK and PPAR-$\delta$-dependent signaling pathways in skeletal muscle. In addition to its role in maintaining intracellular energy balance, AMPK regulates systemic energy metabolism [37]. AMPK activity decreases in adipose tissue of overweight individuals with IR, which is related to increased oxidative stress and changes in gene expression. PPARs are members of the superfamily of nuclear hormone receptors, including PPAR-$\alpha$, PPAR-$\beta$/$\delta$ and PPAR-$\gamma$[42, 43, 44, 45]. PPARs control the expression of a large number of genes involved in metabolic homeostasis, lipid, glucose and energy metabolism, adipogenesis and inflammation. PPARs regulate a large number of metabolic pathways that are implicated in the pathogenesis of MS such as T2DM, nonalcoholic fatty liver disease and cardiovascular disease [46].

IR represents a core culprit of MS. Molecular and phenotypic changes in adipose tissue, skeletal muscle, and the liver are involved in the development of IR and eventually T2DM [47]. At present, it has been mentioned in the literature that the level of subfatin is related to IR and endothelial dysfunction and ultimately affects the occurrence of MS such as obesity, diabetes, coronary artery disease, and acute ST-segment elevation myocardial infarction.

In conclusion, subfatin is a novel secretory protein identified by emerging bioinformatic techniques, which is induced by exercise and cold stimulation in skeletal muscle and adipocytes, respectively. It promoted white adipose tissue browning, increased thermogenesis of adipose tissue, accelerated decomposition of adipose tissue and improved IR. It may play a pivotal role in the occurrence of MS. Based on this, it is considered that it has the potential to become a therapeutic target for MS. However, the current studies barely reveal the mechanism of its interaction with various signaling pathways. Therefore, it is still far from clinical application. Moreover, the relationship between subfatin and fatty liver has never been studied. This suggests that there is another angle to further expand the influence of subfatin in MS from the correlation between subfatin and fatty liver.

MS, metabolic syndrome; BWT, browning of white adipose tissue; IR, insulin resistance; AMPK, AMP-activated protein kinase; PPAR-$\delta$, peroxisome proliferator-activated receptor $\delta$; T2DM, type 2 diabetes mellitus; CAD, coronary artery diseases; ACS, acute coronary syndrome; CRP, C-reaction protein; STEMI, ST-segment elevation myocardial infarction; Metrn, meteorin; IL, interleukin.

SH and LC conducted the literature manufacture and drafted the manuscript. DL and YL provided technological support and contributed to the project discussion. HC and ZW had contributions to the conceptualization of this study and authentication of the validity of the reported results.

Not applicable.

Thanks to all the peer reviewers for their opinions and suggestions.

This study was supported by the General Project of Fujian Natural Science Foundation (2020J011131), the Science and Technology Innovation Joint Fund Project of Fujian Province (2019Y9044), and the Outstanding Youth funds of the 900th Hospital of Joint Logistic Support Force, PLA (2018Q07) from Fengsui Chen.

The authors declare no conflict of interest.