C1q Tumor Necrosis Factor α-related Protein Isoform 5 Is Increased in Mitochondrial DNA-depleted Myocytes and Activates AMP-activated Protein Kinase

Depletion of mtDNA in myocytes causes insulin resistance and alters nuclear gene expression that may be involved in rescuing processes against cellular stress. Here we show that the expression of C1q tumor necrosis factor α-related protein isoform 5 (C1QTNF5) is drastically increased following depletion of mtDNA in myocytes. C1QTNF5 is homologous to adiponectin in respect to domain structure, and its expression and secretion from myocytes correlated negatively with the cellular mtDNA content. Similar to adiponectin, C1QTNF5 induced the phosphorylation of AMP-activated protein kinase (AMPK), leading to increased cell surface recruitment of GLUT4 and increased glucose uptake. Treatment of cells with purified recombinant C1QTNF5 increased the phosphorylation of acetyl-CoA carboxylase and stimulated fatty acid oxidation. C1QTNF5-mediated phosphorylation of AMPK or acetyl-CoA carboxylase was unaffected by depletion of adiponectin receptors such as AdipoR1 or AdipoR2, which indicated that adiponectin receptors do not participate in C1QTNF5-induced activation of AMPK. Serum C1QTNF5 levels were significantly higher in obese/diabetic animals (OLETF rats, ob/ob mice, and db/db mice). These results highlight C1QTNF5 as a putative biomarker for mitochondrial dysfunction and a potent activator of AMPK. Depletion of mtDNA in myocytes causes insulin resistance and alters nuclear gene expression that may be involved in rescuing processes against cellular stress. Here we show that the expression of C1q tumor necrosis factor α-related protein isoform 5 (C1QTNF5) is drastically increased following depletion of mtDNA in myocytes. C1QTNF5 is homologous to adiponectin in respect to domain structure, and its expression and secretion from myocytes correlated negatively with the cellular mtDNA content. Similar to adiponectin, C1QTNF5 induced the phosphorylation of AMP-activated protein kinase (AMPK), leading to increased cell surface recruitment of GLUT4 and increased glucose uptake. Treatment of cells with purified recombinant C1QTNF5 increased the phosphorylation of acetyl-CoA carboxylase and stimulated fatty acid oxidation. C1QTNF5-mediated phosphorylation of AMPK or acetyl-CoA carboxylase was unaffected by depletion of adiponectin receptors such as AdipoR1 or AdipoR2, which indicated that adiponectin receptors do not participate in C1QTNF5-induced activation of AMPK. Serum C1QTNF5 levels were significantly higher in obese/diabetic animals (OLETF rats, ob/ob mice, and db/db mice). These results highlight C1QTNF5 as a putative biomarker for mitochondrial dysfunction and a potent activator of AMPK. Impaired mitochondrial function has been implicated in a number of human diseases, including diabetes and obesity (1Wallace D.C. Annu. Rev. Genet. 2005; 39: 359-407Crossref PubMed Scopus (2605) Google Scholar). Previously, we demonstrated that the depletion of mtDNA in myocytes reduces the expression of insulin receptor substrate-1 (IRS-1), 2The abbreviations used are: IRS-1insulin receptor substrate-12-DG2-deoxyglucoseACCacetyl-CoA carboxylaseACPannealing controlled primerAICAR5-aminoimidazole-4-carboxamide-1-β-d-ribofuranosideAMPKAMP-activated protein kinaseC1QTNFC1q tumor necrosis factor α-related proteinCOXcytochrome oxidaseEtBrethidium bromideFBSfetal bovine serumGSTglutathione S-transferaseMAPKmitogen-activated protein kinaseOLETF ratOtsuka Long-Evans Tokushima Fatty ratLETO ratLong-Evans Tokushima Otsuka ratPMplasma membranesiRNAsmall inhibitory RNAqRT-PCRquantitative real time-PCR. which results in insulin resistance and impaired glucose utilization (2Park S.Y. Choi G.H. Choi H.I. Ryu J. Jung C.Y. Lee W. J. Biol. Chem. 2005; 280: 9855-9864Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). The signals from mitochondrial stress cause a variety of changes in nuclear gene expressions (3Biswas G. Guha M. Avadhani N.G. Gene. 2005; 354: 132-139Crossref PubMed Scopus (133) Google Scholar). Loss of mitochondrial membrane potential and ATP generation capacity as a result of mitochondrial stress activates some transcription factors that facilitate mitochondrial recovery from cellular stress (4Ryan M.T. Hoogenraad N.J. Annu. Rev. Biochem. 2007; 76: 701-722Crossref PubMed Scopus (477) Google Scholar). In this study, we performed annealing controlled primer (ACP)-based PCR to identify nuclear genes that were differentially expressed in response to changes in mtDNA content, and we identified a gene encoding C1q tumor necrosis factor α-related protein isoform 5 (C1QTNF5) that is drastically increased in mtDNA-depleted myocytes. C1QTNF5 belongs to the C1QTNFα family of proteins that are characterized by a specific domain structure, including an N-terminal signal peptide, a collagen repeat domain, and a C-terminal C1q-like globular domain (5Hayward C. Shu X. Cideciyan A.V. Lennon A. Barran P. Zareparsi S. Sawyer L. Hendry G. Dhillon B. Milam A.H. Luthert P.J. Swaroop A. Hastie N.D. Jacobson S.G. Wright A.F. Hum. Mol. Genet. 2003; 12: 2657-2667Crossref PubMed Scopus (159) Google Scholar). Nuclear DNA-encoded C1QTNF isoforms (C1QTNFs) are thought to be adiponectin paralogs in mammalian cells, because they contain similar modular organizational structure as adiponectin (6Wong G.W. Wang J. Hug C. Tsao T.S. Lodish H.F. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 10302-10307Crossref PubMed Scopus (362) Google Scholar). The globular domain of C1QTNF5 is homologous (∼40%) in amino acid sequence to that of adiponectin (supplemental material 1), which suggests that the two proteins may have similar functions in cellular metabolism. insulin receptor substrate-1 2-deoxyglucose acetyl-CoA carboxylase annealing controlled primer 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside AMP-activated protein kinase C1q tumor necrosis factor α-related protein cytochrome oxidase ethidium bromide fetal bovine serum glutathione S-transferase mitogen-activated protein kinase Otsuka Long-Evans Tokushima Fatty rat Long-Evans Tokushima Otsuka rat plasma membrane small inhibitory RNA quantitative real time-PCR. Adiponectin is an important adipokine, which participates in the regulation of energy metabolism (7Yamauchi T. Kamon J. Minokoshi Y. Ito Y. Waki H. Uchida S. Yamashita S. Noda M. Kita S. Ueki K. Eto K. Akanuma Y. Froguel P. Foufelle F. Ferre P. Carling D. Kimura S. Nagai R. Kahn B.B. Kadowaki T. Nat. Med. 2002; 8: 1288-1295Crossref PubMed Scopus (3537) Google Scholar). Unlike adiponectin, which is expressed exclusively in adipocytes, C1QTNFs are expressed in a wide variety of tissues and appear to have diverse functions (8Tom Tang Y. Hu T. Arterburn M. Boyle B. Bright J.M. Palencia S. Emtage P.C. Funk W.D. Genomics. 2005; 86: 100-111Crossref PubMed Scopus (83) Google Scholar). C1QTNF1, which is expressed by vascular smooth muscle cells, inhibits collagen-induced platelet aggregation (9Lasser G. Guchhait P. Ellsworth J.L. Sheppard P. Lewis K. Bishop P. Cruz M.A. Lopez J.A. Fruebis J. Blood. 2006; 107: 423-430Crossref PubMed Scopus (91) Google Scholar) and activates Akt and MAPK (10Wong G.W. Krawczyk S.A. Kitidis-Mitrokostas C. Revett T. Gimeno R. Lodish H.F. Biochem. J. 2008; 416: 161-177Crossref PubMed Scopus (321) Google Scholar). C1QTNF3 is expressed by chondrocytes, and recombinant C1QTNF3 stimulates cartilage development by activating extracellular signal-regulated kinase (ERK) and Akt signaling pathway (11Akiyama H. Furukawa S. Wakisaka S. Maeda T. FEBS J. 2006; 273: 2257-2263Crossref PubMed Scopus (48) Google Scholar, 12Maeda T. Jikko A. Abe M. Yokohama-Tamaki T. Akiyama H. Furukawa S. Takigawa M. Wakisaka S. J. Cell. Physiol. 2006; 206: 537-544Crossref PubMed Scopus (62) Google Scholar). Recently, it was reported that C1QTNF2 induces the phosphorylation of AMPK in C2C12 myocytes, resulting in increased glycogen accumulation and fatty acid oxidation (6Wong G.W. Wang J. Hug C. Tsao T.S. Lodish H.F. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 10302-10307Crossref PubMed Scopus (362) Google Scholar). However, C1QTNF2 is not present in plasma, which indicates that other C1QTNFs act on muscle and liver cells to regulate metabolism. In this study, we demonstrated that the expression and secretion of C1QTNF5 correlates negatively with mtDNA content in myocytes. Although the C1QTNF5 receptor has yet to be identified, C1QTNF5 exhibits similar biological activities to adiponectin, such as activating AMPK and augmenting glucose uptake and fatty acid oxidation. Serum C1QTNF5 levels were significantly higher in obese/diabetic animals as compared with normal animals. Antibodies for AMPKα, phospho-AMPKα (Thr172), phospho-ACC (Ser79), Akt, and phospho-Akt (Ser473) were purchased from Cell Signaling Technology (Beverly, MA). Antibodies for adiponectin and its receptors (AdipoR1 and AdipoR2) were from Santa Cruz Biotechnology (Santa Cruz, CA). Anti-IRS-1 antibody was from Upstate Biotechnology, Inc. (Lake Placid, NY) and anti-phospho-IRS-1 antibody was from Dr. Pann-Gill Suh (Postech, Pohang, Korea). Oligonucleotide primers were from Bionics (Seoul, Korea). Unless otherwise indicated, all other antibodies and chemicals were from Sigma. The cell lines used in this study were L6 and L6 GLUT4myc rat skeletal myocytes (provided by Dr. Amira Klip, Hospital for Sick Children, Toronto, Canada) (13Kanai F. Nishioka Y. Hayashi H. Kamohara S. Todaka M. Ebina Y. J. Biol. Chem. 1993; 268: 14523-14526Abstract Full Text PDF PubMed Google Scholar). Myocytes were cultured and differentiated as described previously (14Somwar R. Koterski S. Sweeney G. Sciotti R. Djuric S. Berg C. Trevillyan J. Scherer P.E. Rondinone C.M. Klip A. J. Biol. Chem. 2002; 277: 50386-50395Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). For mtDNA depletion, L6 GLUT4myc myocytes were incubated with EtBr (0.2 μg/ml) and uridine (50 μg/ml) for 3 weeks in α-minimum essential medium supplemented with 10% FBS. Under these experimental conditions, mtDNA was depleted to <10% of normal. The removal of EtBr from the medium normalized mtDNA content (>90% of normal) within 7 days. The control parental L6 GLUT4myc myocytes were maintained for the same time period in normal culture medium. The mtDNA content of L6 GLUT4myc myocytes cultured with or without EtBr was monitored routinely by amplifying genomic DNA as described previously (2Park S.Y. Choi G.H. Choi H.I. Ryu J. Jung C.Y. Lee W. J. Biol. Chem. 2005; 280: 9855-9864Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). HEK293 and SK-Hep1 cells were cultured in Dulbecco's modified Eagle's medium with 10% FBS. Human C1QTNF5 full-length cDNA cloned in pcDNA3.1 (Invitrogen) was transfected into HEK293, L6 GLUT4myc, and SK-Hep1 cells using Lipofectamine 2000 (Invitrogen). Differentially expressed genes in control, mtDNA-depleted, and -reverted myocytes were screened by the ACP-based PCR A.H. 2004; PubMed Scopus Google Scholar) using a Korea). The PCR were cloned into and with CA). The identified genes were by using primer The cDNA was normalized with the gene and used as a on the from of the rat and human C1QTNF5 two primer were as and The PCR with L6 GLUT4myc cDNA was an by of for for and for and a Under these conditions, the and primer DNA of and The were purified with a and expression of specific genes was in a 2000 using PCR and specific primers (supplemental material and the of the PCR The results were using as described previously (2Park S.Y. Choi G.H. Choi H.I. Ryu J. Jung C.Y. Lee W. J. Biol. Chem. 2005; 280: 9855-9864Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). the of full-length rat cDNA was by PCR and cloned into the and of The globular domain of rat C1QTNF5 was by PCR and cloned into the and of These recombinant proteins were expressed in and purified using to the (Invitrogen) the globular domain of human C1QTNF5 (5Hayward C. Shu X. Cideciyan A.V. Lennon A. Barran P. Zareparsi S. Sawyer L. Hendry G. Dhillon B. Milam A.H. Luthert P.J. Swaroop A. Hastie N.D. Jacobson S.G. Wright A.F. Hum. Mol. Genet. 2003; 12: 2657-2667Crossref PubMed Scopus (159) Google Scholar) was from Dr. A. F. Wright The recombinant protein was and purified as described (5Hayward C. Shu X. Cideciyan A.V. Lennon A. Barran P. Zareparsi S. Sawyer L. Hendry G. Dhillon B. Milam A.H. Luthert P.J. Swaroop A. Hastie N.D. Jacobson S.G. Wright A.F. Hum. Mol. Genet. 2003; 12: 2657-2667Crossref PubMed Scopus (159) Google Scholar). the globular domain of human C1QTNF5 an without a The C1QTNF5 gene was by PCR using a primer and a primer and cloned into the and of (Invitrogen). The globular domain of human C1QTNF5 was expressed in and purified with and recombinant proteins were to for the purified protein was in against human C1QTNF5 was in using the purified recombinant globular domain of human were with the protein in The from the was purified by protein and the antibody was by The antibody was specific for the globular domain of human without against or The antibody the globular of rat and the globular of and C1QTNF5 were not by an adiponectin antibody (supplemental material L6 GLUT4myc myocytes were for 5 and with insulin or of recombinant proteins for the were with and in and in by the was for protein levels and with and for 5 protein was by and with the indicated RNA were with from to the of the medium was with α-minimum essential medium 10% and the cells were for of cDNA and for AdipoR1 and were as described R. X. M. M. S. S. Y. Wang Y. A. Sweeney G. 2007; PubMed Scopus Google Scholar). Myocytes were for 5 and with and 5 uptake and the of GLUT4 to the cell surface were as described (2Park S.Y. Choi G.H. Choi H.I. Ryu J. Jung C.Y. Lee W. J. Biol. Chem. 2005; 280: 9855-9864Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). The fatty acid oxidation was as generation from as described previously T. J. Physiol. 2002; PubMed Scopus Google Scholar). were in with the of and with the from and control were by Otsuka and ob/ob were purchased from were in a controlled and in with and and were monitored The animals were weeks and weeks of they were The animals were for to all experimental was from or are expressed as the the of was using the for mtDNA-depleted myocytes were by L6 GLUT4myc myocytes to a of EtBr (0.2 μg/ml) (2Park S.Y. Choi G.H. Choi H.I. Ryu J. Jung C.Y. Lee W. J. Biol. Chem. 2005; 280: 9855-9864Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). in and cytochrome oxidase and in were from the genomic DNA of the cells with EtBr for 3 In nuclear DNA-encoded genes such as and were similar levels in control and cells, that with EtBr depleted cellular mtDNA content without the nuclear DNA In the removal of EtBr from medium normalized mtDNA content within 7 and the changes in mtDNA content have been to a stress signal that to in nuclear gene expression (3Biswas G. Guha M. Avadhani N.G. Gene. 2005; 354: 132-139Crossref PubMed Scopus (133) Google we differentially expressed genes in mtDNA-depleted and -reverted L6 GLUT4myc myocytes using ACP-based The levels of a number of were increased or in mtDNA-depleted myocytes not cloned and of these and we identified a that was drastically increased in mtDNA-depleted myocytes, which sequence to rat C1QTNF5 we that C1QTNF5 was expressed in L6 GLUT4myc myocytes and that expression was increased in mtDNA-depleted myocytes and normalized in myocytes other C1QTNF isoforms were differentially expressed in mtDNA-depleted and -reverted myocytes by and Although were expressed in myocytes, the expression of C1QTNF5 was significantly increased in mtDNA-depleted myocytes and mtDNA content was to the expression of C1QTNF5 to control These results indicated that the of C1QTNF5 correlates with impaired mtDNA and transcription in myocytes. C1QTNF isoforms a putative secretion signal in and in cells have that C1QTNF1, and are (6Wong G.W. Wang J. Hug C. Tsao T.S. Lodish H.F. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 10302-10307Crossref PubMed Scopus (362) Google Scholar). C1QTNF5 was from cells, we transfected HEK293 cells, L6 GLUT4myc myocytes, and SK-Hep1 with an expression encoding full-length human and we protein secretion by C1QTNF5 to the culture medium cell which indicated that expressed C1QTNF5 is from mammalian cells of C1QTNF5 secretion using of cell and culture medium on a transfected cells as as of the C1QTNF5 they the transcription of C1QTNF5 was increased in mtDNA-depleted myocytes and we the secretion of C1QTNF5 was increased in mtDNA-depleted myocytes we the secretion of C1QTNF5 was increased in mtDNA-depleted myocytes as compared with control mtDNA content was to the expression and secretion of C1QTNF5 to control these indicated that C1QTNF5 is a protein and that its expression is negatively correlated with the depletion of cellular mtDNA mitochondrial dysfunction in myocytes. The of C1QTNF5 and its to cellular mtDNA content in myocytes C1QTNF5 in muscle metabolism. the of C1QTNF5 on AMPK because AMPK an important in the energy the regulation of glucose and fatty acid utilization S.A. J. Physiol. 2006; PubMed Scopus Google Scholar). L6 GLUT4myc myocytes were with purified recombinant proteins of full-length or globular domain of rat and the activation of AMPK and insulin signaling such as and Akt was monitored by a control, we myocytes with a which stimulates AMPK and glucose of T. PubMed Scopus Google Scholar). in induced phosphorylation of AMPK as as its of myocytes with or increased the phosphorylation of AMPK and without AMPK and expression similar to of in purified recombinant full-length and the that the globular domain of C1QTNF5 was potent the full-length protein and we the of C1QTNF5 on AMPK phosphorylation using and as recombinant induced a in the phosphorylation of resulting in phosphorylation of In on the phosphorylation of and Akt, insulin a on the phosphorylation of proteins These results that C1QTNF5 is a potent and activator of AMPK and has on and Akt in the insulin signaling pathway in myocytes. Although to be in of a to a protein the structure and function of that control for these we recombinant human C1QTNF5 globular domain and its to the phosphorylation of AMPK and in myocytes. Human and rat C1QTNF5 are in amino acid and within the globular domain, they are Treatment of myocytes with increased the phosphorylation of AMPK and in a on Akt phosphorylation AMPK phosphorylation was induced by of and for to The phosphorylation of and was maintained for to In skeletal with results in the phosphorylation of which in stimulates GLUT4 to the plasma membrane Lee 2006; PubMed Scopus Google Scholar). Similar to induced the phosphorylation of MAPK within of The phosphorylation of and MAPK was significantly by of cells with an of AMPK and These results that stimulates the phosphorylation of and MAPK the activation of and that and MAPK are of AMPK in the of full-length human C1QTNF5 on we transfected myocytes with an expression for full-length human C1QTNF5 in the of was into the medium. The of drastically increased the phosphorylation of and MAPK on the phosphorylation of or Akt the full-length and globular domain of human C1QTNF5 induced the phosphorylation of and MAPK of the insulin signaling the phosphorylation of AMPK by the cellular of or adiponectin glucose uptake and fatty acid oxidation in skeletal muscle S.A. J. Physiol. 2006; PubMed Scopus Google Scholar, D. Biochem. Sci. 2004; Full Text Full Text PDF PubMed Scopus Google we C1QTNF5 increased glucose uptake and fatty acid oxidation in L6 GLUT4myc myocytes. the globular of and significantly increased uptake to a similar as insulin and Similar to its on AMPK was potent full-length C1QTNF5 in glucose uptake. The of C1QTNF5 on glucose uptake was to the activation of because C1QTNF5-mediated AMPK phosphorylation was of and Akt phosphorylation and C1QTNF5 the recruitment of a glucose specific to muscle and from to the in the globular domain of similar to significantly increased the cell surface of GLUT4myc by was of with and In with and GLUT4 These results that the globular domain of C1QTNF5 stimulates the recruitment of GLUT4 to the the activation of glucose uptake in myocytes. The activation of AMPK in muscle the phosphorylation of leading to fatty acid and a in of fatty Tsao T.S. C. Lodish H.F. Proc. Natl. Acad. Sci. U.S.A. 2002; PubMed Scopus Google Scholar). Treatment of myocytes with the globular domain of human C1QTNF5 significantly increased fatty acid oxidation in myocytes, as by oxidation C1QTNF5-induced phosphorylation and and oxidation were by of C1QTNF5-induced fatty acid oxidation was to the activation of AMPK. the adiponectin receptors AdipoR1 and were involved in C1QTNF5-mediated AMPK we the of C1QTNF5 on myocytes transfected with that AdipoR1 and not and that the expression of AdipoR1 or was significantly in myocytes transfected with or not with a of AdipoR1 or by specific on the C1QTNF5-induced phosphorylation of AMPK and and which indicated that AdipoR1 and are not involved in the C1QTNF5-mediated activation of AMPK. These results that is a C1QTNF5 receptor in myocytes, the and of which the and of we serum C1QTNF5 levels in of such as rats, ob/ob mice, and db/db The rat is a of insulin resistance and diabetes K. T. S. T. Full Text PDF PubMed Scopus Google Scholar). impaired glucose by a in plasma insulin weeks of weeks of and impaired glucose as compared with control (supplemental material mtDNA content was significantly in skeletal muscle of and serum C1QTNF5 levels were significantly higher in as compared with to be a serum C1QTNF5 levels and mtDNA content in skeletal muscle in these results in other of we serum C1QTNF5 levels in db/db and ob/ob weeks of In of these characterized of were significantly higher levels of serum C1QTNF5 in These results that serum C1QTNF5 levels may be correlated with impaired glucose insulin and in C1QTNF5 is a acid protein that are to all C1QTNFα family as an N-terminal signal peptide, a collagen repeat domain, and a C-terminal C1q-like globular domain (6Wong G.W. Wang J. Hug C. Tsao T.S. Lodish H.F. Proc. Natl. Acad. Sci. U.S.A. 2004; 101: 10302-10307Crossref PubMed Scopus (362) Google Scholar). In this study, we the expression and biological function of C1QTNF5 in muscle metabolism. we that and the globular domain of C1QTNF5 in activates AMPK in myocytes. AMPK is a in the regulation of energy S.A. J. Physiol. 2006; PubMed Scopus Google Scholar). is by an in the cellular of to ATP S.A. J. Physiol. 2006; PubMed Scopus Google Scholar, D. Biochem. Sci. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). of skeletal muscle to an AMPK stimulates an in glucose uptake J. Physiol. 273: PubMed Google of an AMPK the of J. M. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). AMPK glucose uptake by the recruitment of GLUT4 to the and GLUT4 expression J. Physiol. 273: PubMed Google Scholar, PubMed Scopus Google Scholar). In this study, we demonstrated for the time that of myocytes with recombinant C1QTNF5 induces AMPK phosphorylation and glucose uptake the of GLUT4 to the C1QTNF5 not the phosphorylation of and Akt in the insulin signaling which indicates that glucose uptake and GLUT4 of the activation of AMPK. C1QTNF5 stimulated phosphorylation and fatty acid oxidation the phosphorylation of AMPK in myocytes. AMPK an important in metabolism in skeletal The activation of AMPK induces the phosphorylation of and a of fatty acid oxidation J. Physiol. 273: PubMed Google Scholar, D. A. J. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the of levels of fatty with GLUT4 and are with the development of insulin resistance J. PubMed Scopus Google Scholar). The that C1QTNF5 is involved in glucose uptake and fatty acid oxidation its potential as a and insulin C1QTNF5 induced the phosphorylation of MAPK the activation of AMPK. In skeletal the phosphorylation of which in stimulates GLUT4 to the Lee 2006; PubMed Scopus Google Scholar). of MAPK results in the phosphorylation of receptor and it induces the of receptor with its resulting in the activation of fatty acid oxidation Lee 2006; PubMed Scopus Google Scholar). has been that MAPK and by activating glucose uptake and fatty acid are which adiponectin insulin in skeletal muscle cells T. Kamon J. Ito Y. A. T. Kita S. T. M. K. M. K. T. Uchida S. S. Waki H. Y. Y. Froguel P. K. S. K. T. T. Nagai R. Kadowaki T. 2003; PubMed Scopus Google Scholar). results that C1QTNF5 activates glucose uptake and fatty acid oxidation the phosphorylation of MAPK and similar to and of the of this study is that adiponectin receptors were not involved in C1QTNF5-induced AMPK activation in myocytes. are two adiponectin AdipoR1 and T. Kamon J. Ito Y. A. T. Kita S. T. M. K. M. K. T. Uchida S. S. Waki H. Y. Y. Froguel P. K. S. K. T. T. Nagai R. Kadowaki T. 2003; PubMed Scopus Google Scholar). AdipoR1 is expressed in skeletal muscle and exhibits for the globular domain of adiponectin, is expressed in liver and has a higher for full-length In with a X. R. X. Y. A. Wang Y. Sweeney G. J. Mol. 2005; PubMed Scopus Google AdipoR1 and were expressed in L6 GLUT4myc myocytes, and AdipoR1 was the receptor for adiponectin in myocytes. we not changes in the C1QTNF5-induced phosphorylation of AMPK and in cells in which the expression of AdipoR1 or AdipoR1 was significantly by These results that the activation of AMPK by C1QTNF5 is of AdipoR1 and is that the globular domain of C1QTNF5 was a potent activator of AMPK the full-length which has characterized that AdipoR1 in muscle T. Kamon J. Ito Y. A. T. Kita S. T. M. K. M. K. T. Uchida S. S. Waki H. Y. Y. Froguel P. K. S. K. T. T. Nagai R. Kadowaki T. 2003; PubMed Scopus Google Scholar). is that the C1QTNF5 receptor in myocytes has a domain structure that is similar to The of the putative C1QTNF5 receptor and other proteins is an for are to Dr. Amira Klip Hospital for Sick Children, Toronto, Canada) for L6 GLUT4myc myocytes. with

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