IK is essentially involved in ciliogenesis as an upstream regulator of oral-facial-digital syndrome ciliopathy gene, ofd1.

BACKGROUND: The cilia are microtubule-based organelles that protrude from the cell surface. Abnormalities in cilia result in various ciliopathies, including polycystic kidney disease (PKD), Bardet-Biedl syndrome (BBS), and oral-facial-digital syndrome type I (OFD1), which show genetic defects associated with cilia formation. Although an increasing number of human diseases is attributed to ciliary defects, the functions or regulatory mechanisms of several ciliopathy genes remain unclear. Because multi ciliated cells (MCCs) are especially deep in vivo, studying ciliogenesis is challenging. Here, we demonstrate that ik is essential for ciliogenesis in vivo. RESULTS: In the absence of ik, zebrafish embryos showed various ciliopathy phenotypes, such as body curvature, abnormal otoliths, and cyst formation in the kidney. RNA sequencing analysis revealed that ik positively regulated ofd1 expression required for cilium assembly. In fact, depletion of ik resulted in the downregulation of ofd1 expression with ciliary defects, and these ciliary defects in ik mutants were rescued by restoring ofd1 expression. Interestingly, ik affected ciliogenesis particularly in the proximal tubule but not in the distal tubule in the kidney. CONCLUSIONS: This study demonstrates the role of ik in ciliogenesis in vivo for the first time. Loss of ik in zebrafish embryos displays various ciliopathy phenotypes with abnormal ciliary morphology in ciliary tissues. Our findings on the ik-ofd1 axis provide new insights into the biological function of ik in clinical ciliopathy studies in humans.

Adiponectin affects the migration ability of bone marrow-derived mesenchymal stem cells via the regulation of hypoxia inducible factor 1α.

BACKGROUND: Bone marrow (BM) is progressively filled with adipocytes during aging process. Thus, BM adipocytes-derived adiponectin (APN) affects the function of bone marrow-derived mesenchymal stem cells (BMSCs). However, little is known about the effect of APN on migration ability of BMSCs cultured under hypoxic conditions, which is similar to the BM microenvironment. RESULTS: We found that the population and migration ability of BMSCs from APN KO mice was higher than that of WT mice due to increased stability of hypoxia inducible factor 1α (HIF1α). Stem cell factor (SCF)-activated STAT3 stimulated the induction of HIF1α which further stimulated SCF production, indicating that the SCF/STAT3/HIF1α positive loop was highly activated in the absence of APN. It implies that APN negatively regulated this positive loop by stimulating HIF1α degradation via the inactivation of GSK3ß. Furthermore, APN KO BMSCs were highly migratory toward EL-4 lymphoma, and the interaction between CD44 in BMSCs and hyaluronic acid (HA) from EL-4 enhanced the migration of BMSCs. On the other hand, the migrated BMSCs recruited CD8+ T cells into the EL-4 tumor tissue, resulting in the retardation of tumor growth. Additionally, gradually increased APN in BM on the aging process affects migration and related functions of BMSCs, thus aged APN KO mice showed more significant suppression of EL-4 growth than young APN KO mice due to higher migration and recruitment of CD8+ T cells. CONCLUSION: APN deficiency enhances CD44-mediated migration ability of BMSCs in the hypoxic conditions by the SCF/STAT3/HIF1α positive loop and influences the migration ability of BMSCs for a longer time depending on the aging process. Video Abstract.

LY6K depletion modulates TGF-ß and EGF signaling.

BACKGROUND: Lymphocyte antigen 6 complex locus K (LY6K), a glycosylphosphatidylinositol-anchored protein, plays a dynamic role in cancer metastasis. In the current study, we deciphered the effects of LY6K on transforming growth factor-ß (TGF-ß) and epidermal growth factor (EGF) signaling through clathrin- and caveolin-1 (CAV-1)-mediated endocytosis. METHODS: Analysis of the TCGA and GTEx dataset were performed to explore the expression and survival of LY6K in cancer patients. Short interfering RNA (siRNA) was used to knockdown the expression of LY6K in human cervical cancer patients. The effect of lack of LY6K on cell proliferation, migration, and invasion was performed, and RT-qPCR and immunoblotting were performed to identify LY6K-affected TGF-ß and EGF signaling pathways. Additionally, Immunofluorescence (IF) and transmission electron microscope (TEM) were performed to identify the role of LY6K in CAV-1- and Clathrin-mediated endocytosis. RESULTS: Lymphocyte antigen 6 complex locus K expression level is elevated in higher grade cervical cancer patients correlating with poor overall survival, progression-free survival, and disease-free survival. LY6K-depletion in HeLa and SiHa cancer cells suppressed EGF-induced proliferation and TGF-ß-enhanced migration and invasion. Both TGF-ß receptor-I (TßRI) and EGF receptor (EGFR) localized at the plasma membrane regardless of LY6K expression, and LY6K bound TßRI irrespective of the presence of TGF-ß; however, LY6K did not bind EGFR. LY6K-depleted cells showed impaired Smad2 phosphorylation upon TGF-ß treatment and lower proliferation rates following long-term treatment with EGF. We revealed the atypical movement of TßRI and EGFR from plasma membrane upon ligand stimulation in LY6K-depleted cells and an impaired movement of the endocytic proteins clathrin and CAV-1. CONCLUSIONS: Our study demonstrates the key role of LY6K in both clathrin- and CAV-1-mediated endocytic pathways regulated by TGF-ß and EGF, and it suggests a correlation between LY6K overexpression in cervical cancer cells and poor overall survival.

Corrigendum: Increased Melanoma-Associated Antigen C2 Expression Affords Resistance to Apoptotic Deathin Suspension-Cultured Tumor Cells.

This corrects the article on p. 138 in vol. 24, PMID: 33818016.

Adapted suspension tumor cells rewire metabolic pathways for anchorage-independent survival through AKT activation.

Metastatic spread of cancer cells is the main cause of cancer-related death. As cancer cells adapt themselves in a suspended state in the blood stream before penetration and regrowth at distal tissues, understanding their survival strategy in an anchorage-independent condition is important to develop appropriate therapeutics. We have previously generated adapted suspension cells (ASCs) from parental adherent cancer cells to study the characteristics of circulating tumor cells. In this study, we explored metabolic rewiring in MDA-MB-468 ASCs to adapt to suspension growth conditions through extracellular flux analyses and various metabolic assays. We also determined the relationship between AKT activation and metabolic rewiring in ASCs using the AKT inhibitor, MK2206. ASCs reprogramed metabolism to enhance glycolysis and basal oxygen consumption rate. RNA-sequencing analysis revealed the upregulation in the genes related to glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. The changes in the metabolic program led to a remarkable dependency of ASCs on carbohydrates as an energy source for proliferation as compared to parental adherent cells (ADs). AKT activation was observed in ASCs and those generated from pancreatic and other breast cancer cells, and AKT activation inhibition in ASCs decreased glycolysis and oxygen consumption. AKT activation is an important strategy for obtaining energy through the enhancement of glycolysis in ASCs. The regulation of AKT activity and/or glycolysis may provide a strong therapeutic strategy to prevent the metastatic spread of cancer cells.

[Corrigendum] Cryptotanshinone inhibits IgE­mediated degranulation through inhibition of spleen tyrosine kinase and tyrosine­protein kinase phosphorylation in mast cells.

Following the publication of the above article, an interested reader drew to the authors' attention that they had mentioned that activated PKCδ phosphorylates IKKß in order that IKKß is relocated to the plasma membrane, resulting in the induction of mast cell degranulation; however, four references the authors had included did not seem to support this statement. The authors have re-examined their paper, and realized that the four references the reader mentioned were indeed cited incorrectly, and wish to rectify this error through revising the third paragraph in the Discussion section, the References section, and an associated figure (Fig. 6C) in order to avoid any further misunderstandings on the part of the readership. First, the authors wish to revise the wording of the third and fourth paragraphs of the Discussion, as featured on pp. 1101-1102, to the following (changed text is indicated in bold): 'We showed that CRT exerts anti-AD effect through inhibition of the mast cell degranulation in mast cells. Upon IgE/antigen stimulation, the immunoreceptor tyrosine-based activation motif (ITAM) region of FcεRI receptor which is on the mast cell surface is phosphorylated and the initial signalling protein kinases Lyn and Syk are recruited to the ITAM (28,29). Then, the activated Lyn and Syk leads to phosphorylation of the transmembrane adaptor linker for activation of T cells (LAT). Phosphorylated LAT which is a scaffold for multimolecular signalling complexes and activates PLCγ through phosphorylation. The activated PLCγ hydrolyses phosphatidylinositol biphosphate (PIP2) to generate second signalling molecules IP3 and DAG, which activate PKCs including PKCδ to induce the mast cell degranulation (30,31). On the other hand, cross-linking of FcεRI also activates IKKß, which moves to the lipid raft fractions and phosphorylates synaptosomal-associated protein 23 (SNAP-23) leading to degranulation (7). Since PKCδ phosphorylates IKKα, but not IKKß (32), it is not likely that two signalling pathways are directly connected. In this study, novel function of CRT on phosphorylations of Lyn/Syk kinases in mast cells is elucidated for the first time. Furthermore, it is likely that this inhibitory effect of CRT on Lyn/Syk kinases negatively affected activities of their downstream signalling molecules including PLCγ, PKCδ, and IKKß, which leads to decrease in mast cell degranulation by CRT treatment. Besides the inhibitory effect of CRT on mast cell degranulation, here we provide additional evidence that CRT exerts anti-AD effects through inactivation of MAPK and NF­κB. It has been reported that CRT regulates the activities of MAPK and NF­κB in various cell types. In rhabdomyosarcoma, hepatoma, and breast carcinoma, CRT activates MAPK p38/JNK and suppresses ERK1/2, followed by caspase-independent apoptosis (10,33,34). In chronic myeloid leukaemia cells, CRT enhances TNF­α-induced apoptosis through the activation of MAPK p38 (35). In smooth muscle cells, CRT exerts anti-migration/invasion effect as it inhibits TNF­α/NF­κB signalling pathway (36).' Secondly, the authors wish to make the following changes to the Reference list: New references 30-32 have been inserted to the list, as follows: 30. Ozawa K, Szallasi Z, Kazanietz MG, Blumberg PM, Mischak H, Mushinski JF and Beaven MA: Ca2+-dependent and Ca2+-independent isozymes of protein kinase C mediate exocytosis in antigen-stimulated rat basophilic RBL-2H3 cell. J Biol Chem 268: 1749-1756, 1993. 31. Cho SH, Woo CH, Yoon SB and Kim JH: Protein kinase Cδ functions downstream of Ca2+ mobilization in FcεRI signaling to degranulation in mast cells. J Allergy Clin Immunol 114: 1085-1092, 2004. 32. Yamaguchi T, Miki Y and Yoshida K: Protein kinase Cδ activates IκB-kinase α to induce the p53 tumor suppressor in response to oxidative stress. Cell Signal 19: 2088-2097, 2007. The addition of these new references means that the former references 30-33 have been accordingly renumbered to references 33-36. Finally, the authors have revised Fig. 6C, as it appeared on p. 1102, in order to assist the understanding of the readers, and the corrected version of Fig. 6 appears on the next page. All these corrections have been approved by all the authors, with the exception of the first author, Sumiyasuren Buyanravjikh, who is no longer uncontactable. The authors regret that these errors were included in the paper, even though they did not substantially alter any of the major conclusions reported in the study, are grateful to the Editor for allowing them this opportunity to publish a Corrigendum, and apologize to the readership for any inconvenience caused. [the original article was published in Molecular Medicine Reports 18: 1095­1193, 2018; DOI: 10.3892/mmr.2018.9042].

Loss of splicing factor IK impairs normal skeletal muscle development.

BACKGROUND: IK is a splicing factor that promotes spliceosome activation and contributes to pre-mRNA splicing. Although the molecular mechanism of IK has been previously reported in vitro, the physiological role of IK has not been fully understood in any animal model. Here, we generate an ik knock-out (KO) zebrafish using the CRISPR/Cas9 system to investigate the physiological roles of IK in vivo. RESULTS: The ik KO embryos display severe pleiotropic phenotypes, implying an essential role of IK in embryonic development in vertebrates. RNA-seq analysis reveals downregulation of genes involved in skeletal muscle differentiation in ik KO embryos, and there exist genes having improper pre-mRNA splicing among downregulated genes. The ik KO embryos display impaired neuromuscular junction (NMJ) and fast-twitch muscle development. Depletion of ik reduces myod1 expression and upregulates pax7a, preventing normal fast muscle development in a non-cell-autonomous manner. Moreover, when differentiation is induced in IK-depleted C2C12 myoblasts, myoblasts show a reduced ability to form myotubes. However, inhibition of IK does not influence either muscle cell proliferation or apoptosis in zebrafish and C2C12 cells. CONCLUSION: This study provides that the splicing factor IK contributes to normal skeletal muscle development in vivo and myogenic differentiation in vitro.

Increased Melanoma-Associated Antigen C2 Expression Affords Resistance to Apoptotic Deathin Suspension-Cultured Tumor Cells.

PURPOSE: Melanoma-associated antigen C2 (MAGEC2) is an oncogene associated with various types of cancers. However, the biological function of MAGEC2 in circulating tumor cells remains unclear. In this study, we investigated the role of MAGEC2 using adapted suspension cells (ASCs), which were previously developed to study circulating tumor cells (CTCs). METHODS: Differential gene expression in adherent cells (ADs) and ASCs was examined using RNA-seq analysis. MAGEC2 expression was assessed using reverse transcription quantitative polymerase chain reaction (RT-qPCR), immunoblotting, and ChIP-seq analysis. Depletion of MAGEC2 expression was performed using siRNA. MAGEC2-depleted ADs and ASCs were used to investigate changes in the proliferation rate and cell cycle. Then, the protein levels of signal transducer and activator of transcription 3 (STAT3), phosphorylated STAT3, and downstream of STAT3 were measured using control and MAGEC2-depleted ADs and ASCs. In ASCs, the direct effect of active STAT3 inhibition with Stattic, a STAT3 inhibitor, was assessed in terms of proliferation and apoptosis. Finally, an Annexin V/7-AAD assay was performed to determine the percentage of apoptotic cells in the Stattic-treated cells. RESULTS: MAGEC2 was highly expressed in ASCs when compared with ADs. Depletion of MAGEC2 reduced the proliferation rate and viability of ASCs. To elucidate the underlying mechanism, the level of STAT3 was examined owing to its oncogenic properties. Tyrosine-phosphorylated active STAT3 was highly expressed in ASCs and decreased in MAGEC2-depleted ASCs. Furthermore, on treating ASCs with Stattic, an active STAT3 inhibitor, the cells were markedly sensitive to intrinsic pathway-mediated apoptosis. CONCLUSIONS: High MAGEC2 expression may play an important role in the survival of ASCs by maintaining the expression of activated STAT3 to prevent apoptotic cell death.

Deubiquitinase USP47-stabilized splicing factor IK regulates the splicing of ATM pre-mRNA.

IK depletion leads to an aberrant mitotic entry because of chromosomal misalignment through the enhancement of Aurora B activity at the interphase. Here, we demonstrate that IK, a spliceosomal component, plays a crucial role in the proper splicing of the ATM pre-mRNA among other genes related with the DNA Damage Response (DDR). Intron 1 in the ATM pre-mRNA, having lengths <200 bp, was not spliced in the IK-depleted cells and led to a deficiency of the ATM protein. Subsequently, the IK depletion-induced ATM protein deficiency impaired the ability to repair the damaged DNA. Because the absence of SMU1 results in IK degradation, the mechanism underlying IK degradation was exploited. IK was ubiquitinated in the absence of SMU1 and then subjected to proteolysis through the 26S proteasome. To prevent the proteolytic degradation of IK, a deubiquitinating enzyme, USP47, directly interacted with IK and stabilized it through deubiquitination. Collectively, our results suggest that IK is required for proper splicing of the ATM pre-mRNA and USP47 contributes toward the stabilization of IK.

Silent mating-type information regulation 2 homolog 1 overexpression is an important strategy for the survival of adapted suspension tumor cells.

Characterization of circulating tumor cells (CTC) is important to prevent death caused by the metastatic spread of cancer cells because CTC are associated with distal metastasis and poor prognosis of breast cancer. We have previously developed suspension cells (SC) using breast cancer cell lines and demonstrated their high metastatic potential. As survival of CTC is highly variable from a few hours to decades, herein we cultured SC for an extended time and named them adapted suspension cells (ASC). Silent mating-type information regulation 2 homolog 1 (SIRT1) expression increased in ASC, which protected the cells from apoptosis. High SIRT1 expression was responsible for the suppression of nuclear factor kappa B (NF-κB) activity and downregulation of reactive oxygen species (ROS) in ASC. As the inhibition of NF-κB and ROS production in SIRT1-depleted ASC contributed to the development of resistance to apoptotic cell death, maintenance of a low ROS level and NF-κB activity in ASC is a crucial function of SIRT1. Thus, SIRT1 overexpression may play an important role in growth adaptation of SC because SIRT1 expression is increased in long-term rather than in short-term cultures.

Erratum: Eupatolide inhibits the TGF-ß1-induced migration of breast cancer cells via downregulation of SMAD3 phosphorylation and transcriptional repression of ALK5.

[This corrects the article DOI: 10.3892/ol.2017.6957.].

Cryptotanshinone inhibits IgE­mediated degranulation through inhibition of spleen tyrosine kinase and tyrosine­protein kinase phosphorylation in mast cells.

Atopic dermatitis (AD) is a type of chronic skin inflammation and one of the most common relapsing allergic diseases, which presents with a severe rash and itchy skin lesions. The pathogenesis of AD is primarily associated with hyper­activated mast cells, which makes them an effective treatment target. After cross­linking the antigen/immunoglobulin (Ig) E complex binds to its high affinity receptor FcεRl on the surface of mast cells. The cells subsequently secrete excessive pro­inflammatory mediators, including histamine and cytokines, which lead to pruritus and immune cell infiltration in the skin lesions. The present study screened natural compounds that have an inhibitory effect on IgE/antigen­mediated secretory activity. It was revealed that cryptotanshinone (CRT), a natural compound extracted from Salvia miltiorrhiza Bunge, had inhibitory effects on the IgE/antigen complex. The underlying mechanism by which CRT exerted an anti­allergy/inflammatory function was investigated using rat basophilic leukaemia (RBL) cells for degranulation assays and a 1­chloro­2,4­dinitrobenzene (DNCB)­induced AD Balb/c mouse model for in vivo study. CRT effectively mitigated the secretion of pro­inflammatory cytokines, including tumor necrosis factor­α and interleukin 1ß, as well as immune cell infiltration into skin lesions in a mouse model of AD­like skin disease induced by dinitrochlorobenzene. The inhibitory effect of CRT on IgE­mediated mast cell degranulation was mediated by the inhibition of tyrosine kinase­dependent degranulation signalling pathways involving spleen tyrosine kinase and Lyn. The present study revealed CRT as an inhibitor of mast cell degranulation. Therefore, CRT may be considered for development as a therapeutic drug to treat IgE­mediated skin diseases.

Oncoprotein CIP2A promotes the disassembly of primary cilia and inhibits glycolytic metabolism.

In most mammalian cells, the primary cilium is a microtubule-enriched protrusion of the plasma membrane and acts as a key coordinator of signaling pathways during development and tissue homeostasis. The primary cilium is generated from the basal body, and cancerous inhibitor of protein phosphatase 2A (CIP2A), the overexpression of which stabilizes c-MYC to support the malignant growth of tumor cells, is localized in the centrosome. Here, we show that CIP2A overexpression induces primary cilia disassembly through the activation of Aurora A kinase, and CIP2A depletion increases ciliated cells and cilia length in retinal pigment epithelium (RPE1) cells. CIP2A depletion also shifts metabolism toward the glycolytic pathway by altering the expression of metabolic genes related to glycolysis. However, glycolytic activation in CIP2A-depleted cells does not depend on cilia assembly, even though enhanced cilia assembly alone activates glycolytic metabolism. Collectively, these data suggest that CIP2A promotes primary cilia disassembly and that CIP2A depletion induces metabolic reprogramming independent of primary cilia.

Eupatolide inhibits the TGF-ß1-induced migration of breast cancer cells via downregulation of SMAD3 phosphorylation and transcriptional repression of ALK5.

The epithelial-mesenchymal transition (EMT) is a hallmark of cancer metastasis, and the associated molecular signaling pathways are regarded as therapeutic targets for cancer treatment. Thus, suppressing EMT with a natural chemical compound may be of therapeutic benefit. Eupatolide is a natural chemical compound extracted from the medicinal plant Inula britannica, which is used in Eastern Asia to treat bronchitis, disorders of the digestive system and inflammation. Besides the anti-inflammatory function of eupatolide, the present study found that eupatolide suppressed the migration and invasion of breast cancer cells, which was associated with the downregulation of vimentin in MDA-MB-231 cells and the upregulation of E-cadherin in MCF-7 cells. Treatment with eupatolide also significantly inhibited the migration and invasion of breast cancer cells that had been stimulated with transforming growth factor-ß1 (TGF-ß1). Eupatolide also suppressed TGF-ß1-induced EMT via downregulation of mothers against decapentaplegic homolog 3 (SMAD3) phosphorylation and transcriptional repression of TGF-ß receptor 1 (ALK5). In addition to this canonical pathway, the non-canonical protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways were also inhibited by eupatolide treatment. In summary, the results suggest that eupatolide suppresses the migration and invasion of breast cancer cells by blocking the canonical ALK5-SMAD3 signaling pathway and the non-canonical ERK and AKT signaling pathways.

Von Hippel-Lindau regulates interleukin-32ß stability in ovarian cancer cells.

Hypoxia-induced interleukin-32ß (IL-32ß) shifts the metabolic program to the enhanced glycolytic pathway. In the present study, the underlying mechanism by which hypoxia-induced IL-32ß stability is regulated was investigated in ovarian cancer cells. IL-32ß expression increased under hypoxic conditions in ovarian cancer cells as it did in breast cancer cells. The amount of IL-32ß was regulated by post-translational control rather than by transcriptional activation. Under normoxic conditions, IL-32ß was continuously eliminated through ubiquitin-dependent degradation by the von-Hippel Lindau (VHL) E3 ligase complex. Oxygen deficiency or reactive oxygen species (ROS) disrupted the interaction between IL-32ß and VHL, leading to the accumulation of the cytokine. The fact that IL-32ß is regulated by the energy-consuming ubiquitination system implies that it plays an important role in oxidative stress. We found that IL-32ß reduced protein kinase Cδ (PKCδ)-induced apoptosis under oxidative stress. This implies that the hypoxia- and ROS-stabilized IL-32ß contributes to sustain survival against PKCδ-induced apoptosis.

Neuronatin Is Associated with an Anti-Inflammatory Role in the White Adipose Tissue.

Neuronatin (NNAT) is known to regulate ion channels during brain development and plays a role in maintaining the structure of the nervous system. A previous in silico analysis showed that Nnat was overexpressed in the adipose tissue of an obese rodent model relative to the wild type. Therefore, the aim of the present study was to investigate the function of Nnat in the adipose tissue. Because obesity is known to systemically induce low-grade inflammation, the Nnat expression level was examined in the adipose tissue obtained from C57BL/6 mice administered lipopolysaccharide (LPS). Unexpectedly, the Nnat expression level decreased in the white adipose tissue after LPS administration. To determine the role of NNAT in inflammation, 3T3-L1 cells overexpressing Nnat were treated with LPS. The level of the p65 subunit of nuclear factor-kappa B (NF-κB) and the activity of NF-κB luciferase decreased following LPS treatment. These results indicate that NNAT plays an anti-inflammatory role in the adipose tissue.

Circulating CTRP1 Levels in Type 2 Diabetes and Their Association with FGF21.

The goal of this study was to investigate whether circulating C1q/TNF-α-related protein 1 (CTRP1) levels are associated with diabetes. In addition, relationships between CTRP1 and other diabetes-related cytokines were elucidated, including adiponectin and fibroblast growth factor 21 (FGF21). A total of 178 subjects (78 men and 100 women) aged 29-70 years (mean age, 46.1 years) were randomly selected. The sera from a normal glucose tolerance group (n = 68) and a prediabetes/type 2 diabetes group (n = 110) were collected; then, circulating levels of CTRP1, adiponectin, and FGF21 were determined via enzyme-linked immunosorbent assay in all sera. Subjects with either prediabetes or diabetes exhibited higher circulating CTRP1 levels than healthy subjects. Sera analysis revealed that CTRP1 was positively correlated with age, body mass index, fasting blood glucose, and circulating FGF21 levels. However, CTRP1 was negatively correlated with total cholesterol and total circulating adiponectin levels in univariate analysis. In addition, multivariate analysis found that CTRP1 was independently associated with age, fasting blood glucose, and circulating FGF21 levels. CTRP1 was correlated with homeostasis model assessment-ß (HOMA-ß), but no correlation was observed with HOMA-insulin resistance. In conclusion, circulating CTRP1 levels are increased in subjects with type 2 diabetes and are positively associated with circulating FGF21 levels.

CTRP1 protects against diet-induced hyperglycemia by enhancing glycolysis and fatty acid oxidation.

Complement-C1q/tumor necrosis factor-α related protein 1 (CTRP1) is a 35-kDa glycoprotein that is secreted from various tissues. Although CTRP1 is highly increased in patients with type II diabetes and obesity, the metabolic roles of CTRP1 remain largely unknown. To unveil the physiological roles of CTRP1 in vivo, CTRP1 transgenic (TG) mice were challenged by a high-fat diet (HFD) and a high-sucrose drink (HS). Homeostatic model assessment-estimated insulin resistance values were decreased in HFD- or HS-fed CTRP1 TG mice compared with wild-type control mice. In this context, CTRP1 stimulated glucose uptake through the glucose transporter GLUT4 translocation to the plasma membrane and also increased glucose consumption by stimulating glycolysis. To analyze the roles of CTRP1 in lipid metabolism, acetyl-CoA carboxylase (ACC) and hormone-sensitive lipase levels were determined in CTRP1 TG mice, and the effect of CTRP1 on fatty acid oxidation was assessed in C2C12 myotubes. CTRP1 was found to inhibit ACC by phosphorylation and to stimulate fatty acid oxidation in C2C12 myotubes. Taken together, CTRP1 performs active catabolic roles in vivo. Therefore, CTRP1 seems to perform a defensive function against nutritional challenges.