title: CTRP1 protein enhances fatty acid oxidation via AMP-activated protein kinase (AMPK) activation and acetyl-CoA carboxylase (ACC) inhibition.
abstract: We previously described the adipokine CTRP1, which has up-regulated expression following exposure to the anti-diabetic drug rosiglitazone and increased circulating levels in adiponectin-null mice (Wong, G. W., Krawczyk, S. A., Kitidis-Mitrokostas, C., Revett, T., Gimeno, R., and Lodish, H. F. (2008) Biochem. J. 416, 161-177). Although recombinant CTRP1 lowers blood glucose in mice, its physiological function, mechanisms of action, and roles in metabolic stress remain unknown. Here, we show that circulating levels of CTRP1 are strikingly reduced in diet-induced obese mice. Overexpressing CTRP1 in transgenic mice improved insulin sensitivity and decreased high-fat diet-induced weight gain. Reduced adiposity resulted from enhanced fatty acid oxidation and energy expenditure, effects mediated by AMP-activated protein kinase (AMPK). In skeletal muscle of transgenic mice, AMPKα and its downstream target, acetyl-CoA carboxylase (ACC), were hyperphosphorylated, indicative of AMPK activation and ACC inhibition. Inactivation of ACC promotes mitochondrial fat oxidation. Consistent with the direct effect of CTRP1 on AMPK signaling, recombinant CTRP1 administration acutely stimulated muscle AMPKα and ACC phosphorylation in vivo. In isolated soleus muscle, recombinant CTRP1 activated AMPK signaling to increase fatty acid oxidation ex vivo, an effect abrogated by an AMPK inhibitor. These results provide the first in vivo evidence that CTRP1 is a novel regulator of fatty acid metabolism.
authors.affiliation: Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Peterson
authors.forename: Susan
authors.initials: S
authors.lastname: Aja
authors.forename: Zhikui
authors.initials: Z
authors.lastname: Wei
authors.forename: G William
authors.initials: GW
authors.lastname: Wong
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism*; D054392:Adipokines / Q000235:genetics / Q000378:metabolism*; D050154:Adiposity / Q000235:genetics; D000818:Animals; D004041:Dietary Fats; D004734:Energy Metabolism / Q000502:physiology*; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D010084:Oxidation-Reduction; D015398:Signal Transduction / Q000502:physiology
chemical_list: D054392:Adipokines; C570300:CTRP1 protein, mouse; D004041:Dietary Fats; D005227:Fatty Acids; D009124:Muscle Proteins; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase
references.citation: Biochem Biophys Res Commun. 1999 Apr 2;257(1):79-83
references.pmid: 10092513
references.citation: Cell. 1995 Dec 29;83(7):1263-71
references.pmid: 8548812
references.citation: Nat Med. 2007 Mar;13(3):332-9
references.pmid: 17268472
references.citation: Cell Metab. 2011 Apr 6;13(4):401-412
references.pmid: 21459325
references.citation: J Clin Invest. 2001 Oct;108(8):1167-74
references.pmid: 11602624
references.citation: J Biol Chem. 1978 Jun 25;253(12):4128-36
references.pmid: 659409
references.citation: Biochem Biophys Res Commun. 2009 Oct 16;388(2):360-5
references.pmid: 19666007
references.citation: J Biol Chem. 2011 May 6;286(18):15652-65
references.pmid: 21378161
references.citation: Int J Obes (Lond). 2008 Dec;32 Suppl 7:S13-8
references.pmid: 19136982
references.citation: J Clin Invest. 2006 Jul;116(7):1784-92
references.pmid: 16823476
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10308-13
references.pmid: 15210937
references.citation: Genomics. 2005 Jul;86(1):100-11
references.pmid: 15953544
references.citation: FASEB J. 2009 Jan;23(1):241-58
references.pmid: 18787108
references.citation: Gene. 1991 Dec 15;108(2):193-9
references.pmid: 1660837
references.citation: J Clin Invest. 2010 Dec;120(12):4342-52
references.pmid: 21041950
references.citation: Trends Immunol. 2004 Oct;25(10):551-61
references.pmid: 15364058
references.citation: Nature. 2003 Jun 12;423(6941):762-9
references.pmid: 12802337
references.citation: Biochem J. 2008 Dec 1;416(2):161-77
references.pmid: 18783346
references.citation: Science. 2011 Jun 17;332(6036):1433-5
references.pmid: 21680840
references.citation: J Biol Chem. 2006 Jun 16;281(24):16391-400
references.pmid: 16621799
references.citation: Nat Med. 2004 May;10(5):524-9
references.pmid: 15077108
references.citation: J Biol Chem. 2002 Sep 20;277(38):34658-61
references.pmid: 12151381
references.citation: Cell Metab. 2007 Jul;6(1):55-68
references.pmid: 17618856
references.citation: Nature. 2005 Jul 21;436(7049):356-62
references.pmid: 16034410
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10302-7
references.pmid: 15231994
references.citation: Am J Physiol Endocrinol Metab. 2001 Aug;281(2):E335-40
references.pmid: 11440910
references.citation: J Biol Chem. 2002 Jul 19;277(29):25863-6
references.pmid: 12032136
references.citation: J Biol Chem. 2006 Feb 3;281(5):2654-60
references.pmid: 16326714
references.citation: J Biol Chem. 1994 Sep 2;269(35):22162-8
references.pmid: 7915280
references.citation: Endocr J. 2008 Jul;55(3):515-22
references.pmid: 18446001
references.citation: J Biol Chem. 2002 May 31;277(22):19521-9
references.pmid: 11912203
references.citation: J Biol Chem. 2006 Mar 31;281(13):8748-55
references.pmid: 16431926
references.citation: Am J Physiol. 1997 Dec;273(6):E1107-12
references.pmid: 9435525
references.citation: Nature. 1994 Dec 1;372(6505):425-32
references.pmid: 7984236
references.citation: J Biol Chem. 2010 Dec 17;285(51):39691-701
references.pmid: 20952387
references.citation: J Mol Evol. 2005 Sep;61(3):372-80
references.pmid: 16044242
references.citation: Am J Physiol. 1999 Mar;276(3):E409-26
references.pmid: 10070005
references.citation: Nature. 1997 Jun 26;387(6636):903-8
references.pmid: 9202122
references.citation: Ann N Y Acad Sci. 2010 Nov;1212:E1-E19
references.pmid: 21276002
references.citation: Biochem Soc Trans. 1995 Aug;23(3):481-5
references.pmid: 8566378
references.citation: Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):2005-10
references.pmid: 11172066
references.citation: Nat Med. 2002 Nov;8(11):1288-95
references.pmid: 12368907
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16309-13
references.pmid: 12456889
references.citation: Diabetes. 2006 Jan;55(1):141-7
references.pmid: 16380487
references.citation: Biochem J. 2008 Dec 1;416(2):e7-9
references.pmid: 18990088
references.citation: Cell Metab. 2005 Jan;1(1):15-25
references.pmid: 16054041
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3329-35
references.pmid: 14985505
references.citation: Nat Med. 2002 Jul;8(7):731-7
references.pmid: 12068289
references.citation: Cell. 1977 May;11(1):223-32
references.pmid: 194704
references.citation: Cancer Res. 2008 Mar 1;68(5):1407-16
references.pmid: 18316604
references.citation: Biochem J. 2000 Feb 1;345 Pt 3:437-43
references.pmid: 10642499
references.citation: FEBS Lett. 1994 Oct 10;353(1):33-6
references.pmid: 7926017
references.citation: Diabetes. 2006 Jun;55(6):1537-45
references.pmid: 16731815
references.citation: Nature. 2001 Jan 18;409(6818):307-12
references.pmid: 11201732