title: Molecular, biochemical and functional characterizations of C1q/TNF family members: adipose-tissue-selective expression patterns, regulation by PPAR-gamma agonist, cysteine-mediated oligomerizations, combinatorial associations and metabolic functions.
abstract: The insulin-sensitizing hormone, adiponectin, belongs to the expanding C1q/TNF (tumour necrosis factor) family of proteins. We recently identified a family of adiponectin paralogues designated as CTRP (C1q/TNF-related protein) 1-7, and in the present study describe CTRP10. In the present study, we show that CTRP1, CTRP2, CTRP3, CTRP5 and CTRP7 transcripts are expressed predominantly by adipose tissue. In contrast, placenta and eye expressed the highest levels of CTRP6 and CTRP10 transcripts respectively. Expression levels of CTRP1, CTRP2, CTRP3, CTRP6 and CTRP7 transcripts are up-regulated in 8-week-old obese (ob/ob) mice relative to lean controls. Treatment of mice with a PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) agonist, rosiglitazone, increased the expression of CTRP1 and decreased CTRP6 transcript levels. All CTRPs are secreted glycoproteins when expressed in mammalian cells. CTRP1, CTRP2, CTRP3, CTRP5 and CTRP6 circulate in the blood and are potential endocrine hormones; their serum levels vary according to the sex and genetic background of mice. Importantly, serum levels of CTRP1 and CTRP6 are increased in adiponectin-null mice. Like adiponectin, all secreted CTRP proteins form trimers as their basic structural units. CTRP3, CTRP5, CTRP6 and CTRP10 trimers are further assembled into higher-order oligomeric complexes via disulfide bonding mediated by their N-terminal cysteine residues. Besides forming homo-oligomers, CTRP1/CTRP6, CTRP2/CTRP7 and adiponectin/CTRP2 are secreted as heterotrimers, thus providing a mechanism to potentially generate functionally distinct ligands. Functional characterization of one such family member, CTRP1, showed that it specifically activates Akt and p44/42-MAPK (mitogen-activated protein kinase) signalling pathways in differentiated mouse myotubes. Moreover, injection of recombinant CTRP1 into mice significantly reduced their serum glucose levels. Thus at least CTRP1 may be considered a novel adipokine. In summary, these molecular, biochemical and functional data provide an important framework to further address the physiological functions and mechanisms of the action of this family of secreted glycoproteins in normal and disease states.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. gwwong@jhmi.edu
authors.forename: G William
authors.initials: GW
authors.lastname: Wong
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Krawczyk
authors.forename: Claire
authors.initials: C
authors.lastname: Kitidis-Mitrokostas
authors.forename: Tracy
authors.initials: T
authors.lastname: Revett
authors.forename: Ruth
authors.initials: R
authors.lastname: Gimeno
authors.forename: Harvey F
authors.initials: HF
authors.lastname: Lodish
mesh_terms: D017667:Adipocytes / Q000502:physiology; D052242:Adiponectin / Q000235:genetics / Q000502:physiology*; D000273:Adipose Tissue / Q000502:physiology*; D000818:Animals; D018932:Chemokine CCL2 / Q000502:physiology; D003001:Cloning, Molecular; D003094:Collagen / Q000235:genetics*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D020738:Leptin / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D047495:PPAR gamma / Q000819:agonists / Q000502:physiology*; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology; D011506:Proteins / Q000235:genetics*; D017154:Stromal Cells / Q000502:physiology; D014162:Transfection
chemical_list: D052242:Adiponectin; C512356:C1QTNF1 protein, human; C487851:C1QTNF5 protein, human; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D020738:Leptin; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D011506:Proteins; D003094:Collagen
references.citation: Diabetes. 2002 May;51(5):1319-36
references.pmid: 11978627
references.citation: Biochim Biophys Acta. 2003 Jul 9;1628(1):64-70
references.pmid: 12850274
references.citation: Immunopharmacology. 2000 Aug;49(1-2):159-70
references.pmid: 10904115
references.citation: J Biol Chem. 2002 Jul 19;277(29):25863-6
references.pmid: 12032136
references.citation: FEBS Lett. 2007 Mar 6;581(5):809-14
references.pmid: 17292892
references.citation: J Biol Chem. 1995 Nov 10;270(45):26746-9
references.pmid: 7592907
references.citation: Am J Physiol. 1992 Jun;262(6 Pt 2):R1025-32
references.pmid: 1621856
references.citation: Blood. 1998 Nov 15;92(10):3829-40
references.pmid: 9808576
references.citation: Endocrinology. 2004 Jul;145(7):3258-64
references.pmid: 15059949
references.citation: Diabetologia. 2001 Jan;44(1):3-15
references.pmid: 11206408
references.citation: Biochem Biophys Res Commun. 1999 Apr 2;257(1):79-83
references.pmid: 10092513
references.citation: Science. 2005 Jan 21;307(5708):370-3
references.pmid: 15662000
references.citation: Diabetes. 2002 Oct;51(10):2968-74
references.pmid: 12351435
references.citation: Diabetes. 2001 Sep;50(9):2094-9
references.pmid: 11522676
references.citation: Diabetes. 2006 Dec;55 Suppl 2:S145-54
references.pmid: 17130638
references.citation: Trends Immunol. 2004 Oct;25(10):551-61
references.pmid: 15364058
references.citation: Blood. 2006 Jan 15;107(2):423-30
references.pmid: 16195328
references.citation: EMBO J. 1989 Jul;8(7):1939-46
references.pmid: 2551668
references.citation: J Biol Chem. 2003 Mar 14;278(11):9073-85
references.pmid: 12496257
references.citation: J Virol. 2006 Sep;80(17):8705-17
references.pmid: 16912318
references.citation: Stem Cells. 2006 Feb;24(2):376-85
references.pmid: 16322640
references.citation: Endocr J. 2005 Aug;52(4):427-33
references.pmid: 16127210
references.citation: J Biol Chem. 2002 Sep 20;277(38):34658-61
references.pmid: 12151381
references.citation: J Biol Chem. 1991 May 5;266(13):8626-33
references.pmid: 2022673
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10302-7
references.pmid: 15231994
references.citation: J Biol Chem. 2006 Feb 3;281(5):2654-60
references.pmid: 16326714
references.citation: FEBS J. 2006 May;273(10):2257-63
references.pmid: 16650001
references.citation: J Biol Chem. 2004 Mar 26;279(13):12152-62
references.pmid: 14699128
references.citation: Biopolymers. 2001 Apr 15;58(5):459-64
references.pmid: 11241217
references.citation: Anal Biochem. 2000 Apr 10;280(1):20-8
references.pmid: 10805516
references.citation: J Biol Chem. 2003 Dec 12;278(50):50810-7
references.pmid: 14522956
references.citation: Mol Cell Biol. 2006 Dec;26(24):9327-37
references.pmid: 17030622
references.citation: J Biol Chem. 2002 Aug 16;277(33):29359-62
references.pmid: 12087086
references.citation: Mol Cell Biol. 1993 Mar;13(3):1516-21
references.pmid: 8441393
references.citation: JAMA. 2003 Apr 9;289(14):1799-804
references.pmid: 12684358
references.citation: Nat Med. 2001 Aug;7(8):947-53
references.pmid: 11479628
references.citation: Trends Pharmacol Sci. 2004 Jun;25(6):331-6
references.pmid: 15165749
references.citation: Curr Biol. 1998 Mar 12;8(6):335-8
references.pmid: 9512423
references.citation: Cell Metab. 2007 Apr;5(4):237-52
references.pmid: 17403369
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16309-13
references.pmid: 12456889
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):2005-10
references.pmid: 11172066
references.citation: Nat Med. 2001 Aug;7(8):941-6
references.pmid: 11479627
references.citation: Biochem Biophys Res Commun. 1996 Apr 16;221(2):286-9
references.pmid: 8619847
references.citation: J Biol Chem. 1996 May 3;271(18):10697-703
references.pmid: 8631877
references.citation: Eat Weight Disord. 2000 Sep;5(3):132-42
references.pmid: 11082792
references.citation: Diabetes. 2000 Dec;49(12):2063-9
references.pmid: 11118008
references.citation: J Biol Chem. 1992 Jan 5;267(1):473-8
references.pmid: 1730610
references.citation: Nat Med. 2002 Jul;8(7):731-7
references.pmid: 12068289
references.citation: Hum Mol Genet. 2003 Oct 15;12(20):2657-67
references.pmid: 12944416
references.citation: Diabetologia. 2005 May;48(5):892-9
references.pmid: 15830179
references.citation: Endocr Rev. 2006 Dec;27(7):762-78
references.pmid: 17056740