Meteorin-like protein/METRNL/Interleukin-41 ameliorates atopic dermatitis-like inflammation.

BACKGROUND: Meteorin-like protein (METRNL)/Interleukin-41 (IL-41) is a novel immune-secreted cytokine/myokine involved in several inflammatory diseases. However, how METRNL exerts its regulatory properties on skin inflammation remains elusive. This study aims to elucidate the functionality and regulatory mechanism of METRNL in atopic dermatitis (AD). METHODS: METRNL levels were determined in skin and serum samples from patients with AD and subsequently verified in the vitamin D3 analogue MC903-induced AD-like mice model. The cellular target of METRNL activity was identified by multiplex immunostaining, single-cell RNA-seq and RNA-seq. RESULTS: METRNL was significantly upregulated in lesions and serum of patients with dermatitis compared to healthy controls (p <.05). Following repeated MC903 exposure, AD model mice displayed elevated levels of METRNL in both ears and serum. Administration of recombinant murine METRNL protein (rmMETRNL) ameliorated allergic skin inflammation and hallmarks of AD in mice, whereas blocking of METRNL signaling led to the opposite. METRNL enhanced ß-Catenin activation, limited the expression of Th2-related molecules that attract the accumulation of Arginase-1 (Arg1)hi macrophages, dendritic cells, and activated mast cells. CONCLUSIONS: METRNL can bind to KIT receptor and subsequently alleviate the allergic inflammation of AD by inhibiting the expansion of immune cells, and downregulating inflammatory gene expression by regulating the level of active WNT pathway molecule ß-Catenin.

Metrnl: a promising biomarker and therapeutic target for cardiovascular and metabolic diseases.

Modern human society is burdened with the pandemic of cardiovascular and metabolic diseases. Metrnl is a widely distributed secreted protein in the body, involved in regulating glucose and lipid metabolism and maintaining cardiovascular system homeostasis. In this review, we present the predictive and therapeutic roles of Metrnl in various cardiovascular and metabolic diseases, including atherosclerosis, ischemic heart disease, cardiac remodeling, heart failure, hypertension, chemotherapy-induced myocardial injury, diabetes mellitus, and obesity.

Chronic vascular pathogenesis results in the reduced serum Metrnl levels in ischemic stroke patients.

Metrnl is a secreted protein involved in neurite outgrowth, insulin sensitivity, immunoinflammatory responses, blood lipids and endothelial protection. In this study, we investigated the role of Metrnl in ischemic stroke. Fifty-eight ischemic stroke patients (28 inpatient patients within 2 weeks of onset and 30 emergency patients within 24 h of onset) and 20 healthy controls were enrolled. Serum Metrnl was measured by enzyme-linked immunosorbent assay. We showed that serum Metrnl levels were significantly reduced in both inpatient and emergency patient groups compared with the controls. Different pathological causes for ischemic stroke such as large artery atherosclerosis and small artery occlusion exhibited similar reduced serum Metrnl levels. Transient ischemic attack caused by large artery atherosclerosis without brain infarction also had lower serum Metrnl levels. Metrnl was correlated with some metabolic, inflammatory and clotting parameters. Reduced serum Metrnl was associated with the severity of intracranial arterial stenosis and the presence of ischemic stroke. In order to elucidate the mechanisms underlying the reduced serum Metrnl levels, we established animal models of ischemic stroke in normal mice, atherosclerotic apolipoprotein E-knockout mice and Metrnl-knockout mice by middle cerebral artery occlusion (MCAO) using intraluminal filament or electrocoagulation. We demonstrated that serum Metrnl levels were significantly lower in atherosclerosis mice than normal mice, whereas acute ischemic stroke injury in normal mice and atherosclerosis mice did not alter serum Metrnl levels. Metrnl knockout did not affect acute ischemic stroke injury and death. We conclude that reduced serum Metrnl levels are attributed to the chronic vascular pathogenesis before the onset of ischemic stroke. Metrnl is a potential target for prevention of ischemic stroke.

Protective role of the novel cytokine Metrnl/ interleukin-41 in host immunity defense during sepsis by promoting macrophage recruitment and modulating Treg/Th17 immune cell balance.

BACKGROUND: Metrnl play an immunocytokine-like role in several diseases, which is also known as meteorin-like because it is homologous to the neurotrophic factor meteorin (Metrn). Although the expression and function of Metrnl, including neurotrophic, immunomodulatory, and insulin resistance functions in different tissues have been extensively studied, its role in sepsis has remained largely limited. METHODS: The present work analyzed the levels of Metrnl and cytokines in the circulation, such as tumor necrosis factor (TNF-α), interleukin (IL-1)ß, IL-6, IL-8, together with IL-10 among septic adult patients. Clinical information was obtained from such patients, including sofa score, procalcitonin(PCT)count, and C-reactive count (CRP) within 24 h when entering the intensive care unit (ICU). We constructed a sepsis model in Metrnl-deficient or normal wild-type mice using cecal ligation and perforation to study its functions in bacterial burden, survival, cytokine/chemokine generation, peritoneal lavage fluid neutrophils, macrophage and lymphocyte recruitment, and Treg/Th17 immune cell balance after CLP-induced sepsis. RESULTS: The expression of Metrnl was remarkably elevated in the early phase of sepsis clinically. Its serum content in patients dying of sepsis slightly decreased relative to that in survivors. Furthermore, the concentration of Metrnl in septic cases when entering the ICU independently predicted the 28-day mortality. For septic patients who had low serum Metrnl content (≤ 274.40 pg/mL), the death risk increased by 2.3 folds relative to those who had a high serum content. It is reported that Metrnl is probably insufficient among patients dying of sepsis. Additionally, the content of Metrnl in the serum of septic patients when entering the ICU is markedly and negatively related to the levels of TNF-α, IL-1ß, IL-6, IL-8, IL-17, PCT, and Sofa score. Collectively, Metrnl could be a potential therapeutic target for sepsis. A low-lethality non-severe sepsis (NSS) model was constructed, which suggested that Metrnl insufficiency elevated the death rate and reduced bacterial clearance during sepsis. For Metrnl-deficient mice, impaired sepsis immunity defense might be related to decreased macrophage recruitment and Treg/Th17 lymphocyte imbalance. Recombinant Metrnl administered to Metrnl-deficient mice abolished the immunity defense impairment following NSS while protecting the high-lethality severe sepsis (SS) model in wild-type (WT) mice. In addition, Metrnl-induced sepsis prevention was intricately associated with the increased recruitment of peritoneal macrophages and modulation of the Treg/TH17 immune cell balance. Furthermore, CCL3 exposure in Metrnl-deficient mice reduced peritoneal bacterial loads while improving survival during sepsis partially by promoting the recruitment of peritoneal macrophages. Furthermore, Metrnl regulated the polarization of M1 macrophages through the ROS signaling pathway and promoted macrophage phagocytosis, thereby killing Escherichia coli. CONCLUSIONS: The present proof-of-concept work suggests that Metrnl-mediated recruitment of macrophages significantly affects sepsis defense in the host and modulates the Treg/Th17 immune cell balance. Findings in this work shed more light on the development of host-directed treatments that can be used to manipulate host immunity to treat sepsis.

Plasma interleukin-41 serves as a potential diagnostic biomarker for Kawasaki disease.

INTRODUCTION: Kawasaki disease (KD) is a systemic vasculitis that causes abnormalities in the coronary arteries. Interleukin (IL)-41 is a novel immunoregulatory cytokine involved in the pathogenesis of some inflammatory and immune-related diseases. However, the role of IL-41 in KD is unclear. The purpose of this study was to detect the expression of IL-41 in the plasma of children with KD and its relationship with the disease. METHODS: A total of 44 children with KD and 37 healthy controls (HC) were recruited for this study. Plasma concentrations of IL-41 were determined by ELISA. Correlations between plasma IL-41 levels and KD-related clinical parameters were analyzed by Pearson correlation and multivariate linear regression analysis. Receiver operating characteristic curve analysis was used to assess the clinical value of IL-41 in the diagnosis of KD. RESULTS: Our results showed that plasma IL-41 levels were significantly elevated in children with KD compared with HC. Correlation analysis demonstrated that IL-41 levels were positively correlated with D-dimer and N-terminal pro-B-type natriuretic peptide, and negatively correlated with IgM, mean corpuscular hemoglobin concentration, total protein, albumin and pre-albumin. Multivariable linear regression analysis revealed that IgM and mean corpuscular hemoglobin concentrations were associated with IL-41. Receiver operating characteristic curve analysis showed that the area under the curve of IL-41 was 0.7101, with IL-41 providing 88.64 % sensitivity and 54.05 % specificity. CONCLUSION: Our study indicated that plasma IL-41 levels in children with KD were significantly higher than those in HC, and may provide a potential diagnostic biomarker for KD.

Metrnl deficiency retards skin wound healing in mice by inhibiting AKT/eNOS signaling and angiogenesis.

Meteorin-like (Metrnl) is a novel secreted protein with various biological activities. In this study, we investigated whether and how Metrnl regulated skin wound healing in mice. Global Metrnl gene knockout mice (Metrnl-/-) and endothelial cell-specific Metrnl gene knockout mice (EC-Metrnl-/-) were generated. Eight-mm-diameter full-thickness excisional wound was made on the dorsum of each mouse. The skin wounds were photographed and analyzed. In C57BL/6 mice, we observed that Metrnl expression levels were markedly increased in skin wound tissues. We found that both global and endothelial cell-specific Metrnl gene knockout significantly retarded mouse skin wound healing, and endothelial Metrnl was the key factor affecting wound healing and angiogenesis. The proliferation, migration and tube formation ability of primary human umbilical vein endothelial cells (HUVECs) were inhibited by Metrnl knockdown, but significantly promoted by addition of recombinant Metrnl (10 ng/mL). Metrnl knockdown abolished the proliferation of endothelial cells stimulated by recombinant VEGFA (10 ng/mL) but not by recombinant bFGF (10 ng/mL). We further revealed that Metrnl deficiency impaired VEGFA downstream AKT/eNOS activation in vitro and in vivo. The damaged angiogenetic activity in Metrnl knockdown HUVECs was partly rescued by addition of AKT activator SC79 (10 µM). In conclusion, Metrnl deficiency retards skin wound healing in mice, which is related to impaired endothelial Metrnl-mediated angiogenesis. Metrnl deficiency impairs angiogenesis by inhibiting AKT/eNOS signaling pathway.

Metrnl regulates cognitive dysfunction and hippocampal BDNF levels in D-galactose-induced aging mice.

Aging is one of the main risk factors for cognitive dysfunction. During aging process, the decrease of brain-derived neurotrophic factor (BDNF) and the impairment of astrocyte function contribute to the cognitive impairment. Metrnl, a neurotrophic factor, promotes neural growth, migration and survival, and supports neural function. In this study, we investigated the role of Metrnl in cognitive functions. D-galactose (D-gal)-induced aging model was used to simulate the process of aging. Cognitive impairment was assessed by the Morris water maze test. We showed that Metrnl expression levels were significantly increased in the hippocampus of D-gal-induced aging mice. Metrnl knockout did not affect the cognitive functions in the baseline state, but aggravated the cognitive impairment in the D-gal-induced aging mice. Furthermore, Metrnl knockout significantly reduced hippocampal BDNF, TrkB, and glial fibrillary acidic protein (GFAP) levels in the D-gal-induced aging mice. In the D-gal-induced aging cell model in vitro, Metrnl levels in the hippocampal astrocytes were significantly increased, and Metrnl knockdown and overexpression regulated the BDNF levels in primary hippocampal astrocytes rather than in neurons. We conclude that Metrnl regulates cognitive functions and hippocampal BDNF levels during aging process. As a neurotrophic factor and an endogenous protein, Metrnl is expected to become a new candidate for the treatment or alleviation of aging-related cognitive dysfunction.

Is meteorin-like (Metrnl) a novel biomarker to distinguish patients with obstructive sleep apnea (OSA) and patients with OSA at vascular risk.

PURPOSE: Metrnl, a newly discovered adipokine with significant expression in white adipose tissue, promotes energy expenditure and contributes to the development of cardiovascular disorders. Endocan is a surrogate marker for endothelial dysfunction and is linked to cardiovascular risk factors. Higher cardiovascular morbidity and mortality have been linked to obstructive sleep apnea (OSA). In this study, we investigated the potential of serum Metrnl and endocan as biomarkers to identify patients with OSA who are at increased cardiovascular risk and differentiate them from healthy controls. METHODS: The study included the evaluation of serum levels of endocan and Metrnl in individuals with OSA and healthy controls. All participants underwent full polysomnography to evaluate their sleep, and carotid intima-media thickness (CIMT) was measured in each of them. RESULTS: Patients with OSA (n = 117) had considerably lower levels of Metrnl and significantly higher levels of endocan than controls (n = 59). Once confounding factors were taken into account, both Metrnl and endocan were effective predictors of OSA. Additionally, the severity of OSA, as determined by the apnea-hypopnea index (AHI), was linked to Metrnl and endocan levels. The study also found a significant and independent inverse association between CIMT and Metrnl, along with a positive association with endocan after making multiple adjustments. Furthermore, there was a significant and independent connection between CIMT and AHI. CONCLUSION: Based on these findings, Metrnl and endocan have the potential to be valuable markers for identifying patients with OSA who are at increased risk of early vascular damage.

Elevated levels of Metrnl in rheumatoid arthritis: Association with disease activity.

BACKGROUND: Meteorin-like (Metrnl) is a novel adipokine that is highly expressed in white adipose tissues. Whether Metrnl plays a role in rheumatoid arthritis (RA) remains unclear. In this study, sera from 159 RA patients, 28 osteoarthritis (OA) patients, and 50 healthy individuals were included. The serum levels of Metrnl were measured using an enzyme-linked immunosorbent assay. Clinical parameters, including disease activity score 28 (DAS28), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), antibodies to cyclic citrulline peptide (anti-CCP), inflammatory cytokines, and blood biochemical indices were collected. RESULTS: Metrnl levels were higher in RA patients compared to OA patients and controls. In the RA group, serum Metrnl levels were positively correlated with DAS28, RF, and CRP levels. However, in the RA group, serum Metrnl levels were not correlated with ESR, anti-CCP, immunoglobulins, and blood biochemical indices. CONCLUSION: This study showed that Metrnl is involved in the pathogenesis of RA. Increase in serum Metrnl levels is closely related to RA activity.

Meteorin-like protein (Metrnl): A metabolic syndrome biomarker and an exercise mediator.

Metrnl is a secreted protein able to activate different intracellular signaling pathways in adipocytes, macrophages, myocytes and cardiomyocytes with physiological effects of the browning of white adipose tissue (BWT), insulin sensitivity, inflammation inhibition, skeletal muscle regeneration and heart protection. Shown to be regulated by obesity, diabetes, caloric restriction, weight loss and heart diseases, Metrnl is definitely involved in metabolic turbulences, and may play roles in metabolic syndrome (MetS). However, due to the conflicting data yielded, Metrnl is still far from clinical application as a diagnostic and/or a therapeutic agent or even a therapeutic target in MetS-related diseases such as type 2 diabetes (T2D) and obesity. Nevertheless, blood Metrnl levels as well as Metrnl as a cardiokine have been reported to play cardioprotective roles against heart diseases. Considering the established metabolic and anti-inflammatory hallmarks, exercise-induced Metrnl (as a myokine) is regarded as an exercise mediator in improving obesity-induced complications such as insulin resistance, T2D and inflammation. Besides, due to its healing role in muscle damage, Metrnl is also a potential therapeutic candidate to enhance regeneration with ageing or other inflammatory myopathies like Duchenne muscular dystrophy (DMD). Therefore, there are still many exercise-related questions unanswered on Metrnl, such as Metrnl-mediated fat browning in humans, exercise effects on heart Metrnl production and secretion and the effects of other exercise-induced skeletal muscle stressors like hypoxia and oxidative in Metrnl production other than exercise-induced muscle damage.

Effects of meteorin-like hormone on endocrine function of hypothalamo-hypophysial system and peripheral uncoupling proteins in rats.

BACKGROUND: Meteorin-like hormone (Metrnl) is a peptide secreted from the adipose tissue and modulates the whole-body energy metabolism. Metrnl release into the circulation is influenced by obesity, cold exposure, and exercise. Thyroid hormones also exert many of their effects on metabolism through uncoupling proteins (UCPs). This study aimed to determine effect of Metrnl on hypothalamo-hypophysier-thyroid axis and energy metabolism and reveal the possible involvement of UCPs in this process. METHODS AND RESULTS: Fourty male Sprague-Dawley rats were divided into 4 groups with 10 animals in each group: control, sham, 10 and 100 nM Metrnl. Hypothalamus, muscle, white adipose tissue (WAT) and brown adipose tissue (BAT) samples were collected to detect thyrotropin-releasing hormone (TRH), and UCP1 and UCP3 protein levels by western blot analysis. Serum thyroid-stimulating hormone (TSH), triiodothyronine (T3) and thyroxine (T4) hormone levels were determined by enzyme-linked immunosorbent assay. Central infusion of Metrnl caused significant increase in serum TSH, T3 and T4 levels compared to control (p < 0.05). After Metrnl treatment, there were significant increases in TRH in hypothalamus tissue, UCP1 in WAT and BAT; and UCP3 protein in the muscle tissue (p < 0.05). CONCLUSIONS: The findings that Metrnl induced increases in the peripheral UCPs and hypothalamus-pituitary-thyroid axis hormones implicate a role for this hormone in body energy homeostasis through UCP-mediated mechanisms.

Elevated serum Meteorin-like levels in patients with hyperthyroidism.

BACKGROUND: Meteorin-like (Metrnl) is a newly discovered adipomyokine that regulates systemic energy homeostasis. Both thyroid hormones and Metrnl increase energy expenditure and induce browning of adipose tissue. Thus, the aim of this study was to investigate serum Metrnl levels in hyperthyroid patients and the association of serum Metrnl levels with hyperthyroidism. METHODS: The study included 88 patients with newly diagnosed untreated overt hyperthyroidism and 100 age- and sex- matched healthy controls. Serum Metrnl levels were determined using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS: Serum Metrnl levels were significantly elevated in patients with hyperthyroidism compared with controls. Linear regression analyses indicated that serum Metrnl levels were independently associated with FT3 (ß = 0.324, P = 0.001), FT4 (ß = 0.293, P = 0.001), and TSH (ß = -0.234, P = 0.006) after full adjustment. Additionally, further logistic regression analyses revealed that the highest Metrnl tertile was significantly associated with hyperthyroidism compared with the lowest tertile (P for trend < 0.001). The relationship remained significant even after adjusting for potential confounders. Meanwhile, each one-unit increase in circulating Metrnl was independently associated with hyperthyroidism (OR 1.021, 95%CI 1.007-1.036, P < 0.01). CONCLUSION: Serum Metrnl levels were elevated in patients with hyperthyroidism and were independently associated with hyperthyroidism.

Decreased serum interleukin-41/Metrnl levels in patients with Graves' disease.

BACKGROUND: Interleukin (IL)-41, also known as Metrnl, is a novel immunomodulatory cytokine, which is involved in the pathogenesis of many inflammatory and metabolic diseases, but its role in thyroid autoimmune diseases is not clear. The aim of this study was to evaluate the serum IL-41 levels in patients with Graves' disease (GD) and its relationship with GD. METHODS: This study included a total of 49 GD patients and 47 age- and sex-matched healthy individuals. All baseline data were obtained by physical examination. Free triiodothyronine 3 (FT3), free triiodothyronine 4 (FT4), thyroid-stimulating hormone (TSH), anti-thyroglobulin antibodies (TgAb), thyroid peroxidase antibody (TPOAb), and thyrotropin receptor antibody (TRAb) levels in plasma of GD patients were measured by chemiluminescence. The high-sensitivity C-reactive protein (CRP) and white blood cell count (WBC) were detected using automated biochemical analyzer. Serum IL-41 levels were measured by enzyme-linked immunosorbent assay. RESULTS: Serum IL-41 levels in patients with GD were significantly lower than those in healthy controls (201.0 vs. 260.8 pg/mL, p < 0.05). There was a significant positive correlation between IL-41 level and CRP (r = 0.2947, p = 0.0385) and WBC (r = 0.4104, p = 0.0034) in GD patients. CRP was positively correlated with TRAb (r = 0.2874, p = 0.0452) and TSH (r = 0.3651, p = 0.0099) levels in GD patients. CONCLUSIONS: This study demonstrates that GD patients have decreased serum IL-41 levels, and IL-41 plays a potential role in abnormal immune response of GD patients.

Myokine-mediated exercise effects: the role of myokine meteorin-like hormone (Metrnl).

Meterorin-like hormone (Metrnl), as a novel secreted factor, has been shown to be involved in physiological and pathophysiological processes. The behaviour of Metrnl in metabolic conditions like type 2 diabetes is conflicting. Metrnl-mediated (treatment with Metrnl) auto/paracrine actions in skeletal muscle are glucose uptake, fat oxidation and muscle regeneration. Exercise-induced Metrnl actions are increased fat oxidation in both skeletal muscle and adipose tissue, the control of inflammation in adipose tissue (metainflammation), and the regulation of muscle regeneration. Based on the current knowledge, Metrnl as a myokine can establish the muscle-fat crosstalk; however, the ability of Metrnl as a myokine to create other crosstalks remains unclear yet. Additionally, given the considerable anti-inflammatory roles of Metrnl in muscle regeneration, it could be a potential therapeutic candidate for muscle-related inflammatory diseases and ageing skeletal muscle which need to be addressed in the future studies.

Potential emerging roles of the novel adipokines adipolin/CTRP12 and meteorin-like/METRNL in obesity-osteoarthritis interplay.

BACKGROUND: Several insights into obesity-osteoarthritis (OA) relationship have been recently highlighted. Adipolin and metrnl are new adipokines also secreted by chondrocytes. However, their role in OA, and obesity-OA interplay hasn't been elucidated. Therefore, this study was designed to investigate the circulating as well as synovial fluid (SF) levels of adipolin and metrnl in osteoarthritic-patients compared to non-osteoarthritic subjects, and to study their association with OA-severity, dyslipidemia and insulin resistance (IR). METHODS: Patients with osteoarthritis and obesity (n = 30), and subjects with obesity not suffering OA (n = 25) were enrolled in the current study. Circulating and SF-levels of adipolin, metrnl, and insulin, as well as SF-levels of matrix-metalloproteinase-13 (MMP-13) were measured by ELISA. Knee-radiographs using X-ray were done to determine OA-severity, and investigate its association with adipokines' levels. RESULTS: Serum and SF-adipolin levels showed tendency to be lower in OA-patients compared to non-OA-subjects; serum: 0.64 [0.45-0.85] and 0.73 [0.62-0.78] ng/ml, p = 0.174, and SF: 0.53 [0.34-0.69] and 0.63 [0.44-0.74] ng/ml, p = 0.353, respectively. Additionally, serum adipolin showed negative-association with SF-MMP-13. However, when stratifying OA-patients into various severity grades, serum adipolin levels did not show a significant difference between them. Regarding serum metrnl, it was significantly lower in OA-patients compared to non-OA-subjects; 19.68 [10.40-53.40] and 48.83 [20.80-86.60] pg/ml, respectively, p = 0.018. Surprisingly, SF-metrnl levels were higher in OA-patients compared to non-OA-subjects; 912 [367-1524] and 315 [125-484] pg/ml, respectively, p = 0.007. SF-metrnl showed positive-association with insulin resistance, and negative-association with SF-MMP-13. Moreover, higher serum metrnl levels were found to be slightly associated with lower likelihood of OA in subjects with obesity; OR = 0.978, CI (0.960- 0.996), p = 0.02, and its levels were also found to be relatively lower in grade-4 compared to the less severe OAgrades. CONCLUSIONS: Metrnl, and to a lesser extent adipolin seem to be interrelated with OA. Different in-context regulatory mechanisms for metrnl production from various tissues are strongly suggested. Importantly, the findings of the current study shed lights on metrnl as a potential novel mediator and therapeutic target to consider in obesity-OA interplay.

The blooming intersection of subfatin and metabolic syndrome.

Metabolic Syndrome (MS) remains the leading cause of mortality and morbidity globally. Adipose tissue releases adipokines that play key roles in metabolic and cardio-cerebro-vascular homeostasis. Subfatin, induced after exercise or upon cold exposure in adipose tissue, is a novel secreted protein homologous to Metrn, a neutrophic factor with angiogenic properties. The protein was proved to be of great significance in the browning of white adipose tissue (BWT) and insulin resistance (IR). It affected insulin sensitivity at least via its local autocrine/paracrine action through AMP-activated protein kinase (AMPK) or peroxisome proliferator-activated receptor δ (PPAR-δ) dependent signaling. Subfatin blocked the release of inflammatory mediators, improved intracellular insulin signal transduction and reversed IR. It also improved glucose tolerance and played a key role in metabolism and cardiovascular and cerebrovascular homeostasis. It was reported that the level of serum subfatin was significantly correlated with the occurrence and severity of coronary heart disease, which might be a new target for the treatment of coronary heart disease. In addition, exercise increased the level of subfatin in circulation and adipose tissue, promoted energy consumption, improved glucose and lipid metabolism, increased the heat production of brown fat, and strengthened the anti-inflammatory mechanism. Given its role in metabolic disorders, subfatin is considered as a candidate biomarker of MS. However, the clinical significance of subfatin remains largely unclear. The purpose of this article is to review the research on the effect of subfatin on MS in recent years.

Metrnl deficiency decreases blood HDL cholesterol and increases blood triglyceride.

Dyslipidemia is a risk factor for cardiovascular diseases and type 2 diabetes. Several adipokines play important roles in modulation of blood lipids. Metrnl is a recently identified adipokine, and adipose Metrnl participates in regulation of blood triglyceride (TG). In this study, we generated Metrnl global, intestine-specific and liver-specific knockout mice, and explored the effects of Metrnl on serum lipid parameters. Global knockout of Metrnl had no effects on serum lipid parameters under normal chow diet, but increased blood TG by 14%, and decreased total cholesterol (TC) by 16% and high density lipoprotein cholesterol (HDL-C) by 24% under high fat diet. Nevertheless, intestine-specific knockout of Metrnl did not alter the serum lipids parameters under normal chow diet or high fat diet. Notably, liver-specific knockout of Metrnl decreased HDL-C by 24%, TC by 20% and low density lipoprotein cholesterol (LDL-C) by 16% without alterations of blood TG and nonesterified fatty acids (NEFA) under high fat diet. But deficiency of Metrnl in liver did not change VLDL secretion and expression of lipid synthetic and metabolic genes. We conclude that tissue-specific Metrnl controls different components of blood lipids. In addition to modulation of blood TG by adipose Metrnl, blood HDL-C is regulated by liver Metrnl.

Aggravated ulcerative colitis caused by intestinal Metrnl deficiency is associated with reduced autophagy in epithelial cells.

Metrnl is a newly identified secreted protein highly expressed in the intestinal epithelium. This study aimed to explore the role and mechanism of intestinal epithelial Metrnl in ulcerative colitis. Metrnl-/- (intestinal epithelial cell-specific Metrnl knockout) mice did not display any phenotypes of colitis under basal conditions. However, under administration of 3% dextran sodium sulfate (DSS) drinking water, colitis was more severe in Metrnl-/- mice than in WT mice, as indicated by comparisons of body weight loss, the presence of occult or gross blood per rectum, stool consistency, shrinkage in the colon, intestinal damage, and serum levels of inflammatory factors. DSS-induced colitis activated autophagy in the colon. This activation was partially inhibited by intestinal epithelial Metrnl deficiency, as indicated by a decrease in Beclin-1 and LC3-II/I and an increase in p62 in DSS-treated Metrnl-/- mice compared with WT mice. These phenomena were further confirmed by observation of autophagosomes and immunofluorescence staining for LC3 in epithelial cells. The autophagy-related AMPK-mTOR-p70S6K pathway was also activated in DSS-induced colitis, and this pathway was partially blocked by intestinal epithelial Metrnl deficiency, as indicated by a decrease in AMPK phosphorylation and an increase in mTOR and p70S6K phosphorylation in DSS-treated Metrnl-/- mice compared with WT mice. Therefore, Metrnl deficiency deteriorated ulcerative colitis at least partially through inhibition of autophagy via the AMPK-mTOR-p70S6K pathway, suggesting that Metrnl is a therapeutic target for ulcerative colitis.

Involvement of the secreted protein Metrnl in human diseases.

Metrnl, a secreted protein expressed in white adipose tissue, has been identified as a novel adipokine. It is also highly expressed in barrier tissues, including the skin, intestinal and respiratory tract epithelium in both mice and humans. Research shows that its expression is upregulated by inflammation, chronic high-fat diets, exercise, cold exposure, etc., and it plays important roles in promoting neurite extension, enhancing white fat browning, improving insulin sensitivity, modulating lipid metabolism and regulating inflammatory response, the latter implying Metrnl is a new cytokine. These studies suggest that Metrnl could be a promising biomarker and a potential therapeutic target for the related diseases. For proving this, clinical studies need to be performed to bridge the gap between bench and bedside. In this paper, we summarize the progress in recent clinical research on Metrnl. Most of these clinical studies are designed to confirm the relationship between circulating Metrnl and metabolic or cardiovascular disease (type 2 diabetes and coronary heart disease), or immune inflammation-related diseases, such as colitis, psoriasis and arthritis. Although blood Metrnl seems to fluctuate and are affected by many factors, such as drugs, physical exercise, and cold exposure, these clinical studies provide reliable clues that Metrnl is associated with coronary heart disease, inflammation-related diseases, etc. Nevertheless, the roles of Metrnl in some diseases such as nervous system diseases remain unclear, and its putative involvement should be further clarified. These studies could promote the application of Metrnl in clinic as a new therapeutic target.

Is Metrnl an Adipokine Involved in the Anti-inflammatory Response to Acute Exacerbations of COPD?

PURPOSE: Chronic obstructive pulmonary disease (COPD) is a common lung disease characterized by airflow limitation and systemic inflammation. Recently, there has been growing interest in adipose tissue-mediated inflammation in the pathogenesis of COPD. The aim of our study was to determine the relationships between a new adipocytokine, meteorin-like protein (Metrnl), and acute exacerbations of COPD, smoking, and comorbidities. MATERIALS AND METHODS: The study included 313 patients aged 40-65 years in four groups: Group 1: ex-smokers (≥ 20 pack-years) with COPD hospitalized for COPD exacerbation (n = 133), Group 2: current-smokers (≥ 20 pack-years) without COPD (n = 60), Group 3: ex-smokers (≥ 20 pack-years) without COPD (n = 60), and Group 4: never-smokers without COPD (n = 60). Peripheral venous blood samples (5 cc) were collected from all participants. Plasma Metrnl levels were measured using commercial enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: Mean Metrnl levels were 28.45 ± 11.27 ng/ml in Group 1, 24.34 ± 4.38 ng/ml in Group 2, 18.84 ± 3.8 ng/ml in Group 3, and 19.44 ± 3.92 ng/ml in Group 4. Group 1 had significantly higher mean Metrnl level compared to the other groups (p = 0.006, p = 0.001, p = 0.001). Metrnl level was also significantly higher in Group 2 when compared with Groups 3 and 4 (p = 0.001, p = 0.005). Group 1 patients with diabetes mellitus and coronary artery disease showed significantly lower Metrnl levels compared to other patients in the group (p = 0.001, p = 0.001). CONCLUSION: The high Metrnl level in COPD exacerbations and active smoking may be important in balancing the inflammatory response. However, plasma Metrnl levels were found to be lower in COPD patients with comorbidities.