title: In vivo adeno-associated viral vector-mediated genetic engineering of white and brown adipose tissue in adult mice.
abstract: Adipose tissue is pivotal in the regulation of energy homeostasis through the balance of energy storage and expenditure and as an endocrine organ. An inadequate mass and/or alterations in the metabolic and endocrine functions of adipose tissue underlie the development of obesity, insulin resistance, and type 2 diabetes. To fully understand the metabolic and molecular mechanism(s) involved in adipose dysfunction, in vivo genetic modification of adipocytes holds great potential. Here, we demonstrate that adeno-associated viral (AAV) vectors, especially serotypes 8 and 9, mediated efficient transduction of white (WAT) and brown adipose tissue (BAT) in adult lean and obese diabetic mice. The use of short versions of the adipocyte protein 2 or uncoupling protein-1 promoters or micro-RNA target sequences enabled highly specific, long-term AAV-mediated transgene expression in white or brown adipocytes. As proof of concept, delivery of AAV vectors encoding for hexokinase or vascular endothelial growth factor to WAT or BAT resulted in increased glucose uptake or increased vessel density in targeted depots. This method of gene transfer also enabled the secretion of stable high levels of the alkaline phosphatase marker protein into the bloodstream by transduced WAT. Therefore, AAV-mediated genetic engineering of adipose tissue represents a useful tool for the study of adipose pathophysiology and, likely, for the future development of new therapeutic strategies for obesity and diabetes.
authors.affiliation: Center of Animal Biotechnology and Gene Therapy and Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, Bellaterra, and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Barcelona, Spain.
authors.forename: Veronica
authors.initials: V
authors.lastname: Jimenez
authors.forename: Sergio
authors.initials: S
authors.lastname: Muñoz
authors.forename: Estefania
authors.initials: E
authors.lastname: Casana
authors.forename: Cristina
authors.initials: C
authors.lastname: Mallol
authors.forename: Ivet
authors.initials: I
authors.lastname: Elias
authors.forename: Claudia
authors.initials: C
authors.lastname: Jambrina
authors.forename: Albert
authors.initials: A
authors.lastname: Ribera
authors.forename: Tura
authors.initials: T
authors.lastname: Ferre
authors.forename: Sylvie
authors.initials: S
authors.lastname: Franckhauser
authors.forename: Fatima
authors.initials: F
authors.lastname: Bosch
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D000229:Dependovirus; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism / Q000235:genetics; D005818:Genetic Engineering; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016688:Mice, Inbred NOD; D008820:Mice, Obese; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*
references.citation: Diabetes Metab. 2008 Sep;34(4 Pt 1):317-27
references.pmid: 18550411
references.citation: Proteomics. 2010 Sep;10(18):3356-66
references.pmid: 20706982
references.citation: Diabetes. 2012 Jul;61(7):1801-13
references.pmid: 22522611
references.citation: Biochem Soc Trans. 2001 May;29(Pt 2):76-80
references.pmid: 11356131
references.citation: J Biol Chem. 1996 Dec 6;271(49):31533-42
references.pmid: 8940169
references.citation: Gene Ther. 2011 Apr;18(4):403-10
references.pmid: 21150938
references.citation: J Biol Chem. 2001 Sep 7;276(36):34167-74
references.pmid: 11445576
references.citation: Dis Model Mech. 2012 Sep;5(5):569-73
references.pmid: 22915015
references.citation: Neuro Oncol. 2005 Oct;7(4):452-64
references.pmid: 16212810
references.citation: Eur J Biochem. 1996 May 1;237(3):660-7
references.pmid: 8647110
references.citation: Nat Rev Genet. 2011 May;12(5):341-55
references.pmid: 21499295
references.citation: N Engl J Med. 2009 Apr 9;360(15):1509-17
references.pmid: 19357406
references.citation: Biochem Biophys Res Commun. 1993 Jul 15;194(1):338-46
references.pmid: 8392839
references.citation: Curr Pharm Des. 2008;14(12):1225-30
references.pmid: 18473870
references.citation: RNA. 2005 Sep;11(9):1461-70
references.pmid: 16043497
references.citation: J Lipid Res. 2001 Mar;42(3):460-6
references.pmid: 11254759
references.citation: Diabetes. 2013 Mar;62(3):864-74
references.pmid: 23321074
references.citation: Hum Gene Ther. 2012 Dec;23(12):1237-46
references.pmid: 22909060
references.citation: Gene Ther. 2005 Jan;12(1):48-58
references.pmid: 15470480
references.citation: Gene Ther. 2011 Feb;18(2):128-34
references.pmid: 20844567
references.citation: Biochem J. 1998 Jul 15;333 ( Pt 2):243-6
references.pmid: 9657961
references.citation: Gene Ther. 2010 Apr;17(4):503-10
references.pmid: 19956269
references.citation: Hum Gene Ther. 1997 Jan 20;8(2):215-27
references.pmid: 9017425
references.citation: Best Pract Res Clin Endocrinol Metab. 2005 Dec;19(4):605-23
references.pmid: 16311220
references.citation: Diabetologia. 2010 Nov;53(11):2417-30
references.pmid: 20623219
references.citation: Obesity (Silver Spring). 2012 Jan;20(1):101-11
references.pmid: 21779095
references.citation: Transgenic Res. 2006 Oct;15(5):647-53
references.pmid: 16952017
references.citation: J Biol Chem. 1993 Apr 5;268(10):6823-6
references.pmid: 8463205
references.citation: Am J Physiol. 1998 May;274(5):R1460-7
references.pmid: 9612415
references.citation: Am J Physiol Endocrinol Metab. 2008 Aug;295(2):E514-8
references.pmid: 18559984
references.citation: J Cell Sci. 1994 Jan;107 ( Pt 1):313-9
references.pmid: 8175918
references.citation: Biochim Biophys Acta. 2005 Oct 15;1731(1):1-12
references.pmid: 16150499
references.citation: Am J Physiol Endocrinol Metab. 2004 Sep;287(3):E574-82
references.pmid: 15126244
references.citation: Cell Metab. 2013 Jan 8;17(1):61-72
references.pmid: 23312284
references.citation: Diabetes. 2002 Mar;51(3):624-30
references.pmid: 11872659
references.citation: Mol Cell Biol. 1992 Mar;12(3):1202-8
references.pmid: 1545801
references.citation: N Engl J Med. 2009 Apr 9;360(15):1500-8
references.pmid: 19357405
references.citation: J Clin Invest. 2013 Jul 1;123(8):3254-3271
references.pmid: 23863627
references.citation: Hum Gene Ther. 2006 Sep;17(9):921-8
references.pmid: 16972760
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Diabetes. 2013 May;62(5):1718-29
references.pmid: 23378612
references.citation: J Med Toxicol. 2012 Jun;8(2):145-52
references.pmid: 22351299
references.citation: N Engl J Med. 1991 Sep 26;325(13):938-48
references.pmid: 1881419
references.citation: Blood. 2011 Jun 16;117(24):6459-68
references.pmid: 21474674
references.citation: J Lipid Res. 2000 Jul;41(7):1082-6
references.pmid: 10884289
references.citation: Proc Natl Acad Sci U S A. 1990 Dec;87(24):9590-4
references.pmid: 2263614
references.citation: Mol Ther. 2008 May;16(5):931-41
references.pmid: 18388926
references.citation: Exp Cell Res. 1987 Jan;168(1):218-32
references.pmid: 2877896
references.citation: Bioessays. 2002 Apr;24(4):382-8
references.pmid: 11948624
references.citation: Diabetes. 2013 Feb;62(2):551-60
references.pmid: 23099863
references.citation: Mol Ther. 2008 Jun;16(6):1073-80
references.pmid: 18414476
references.citation: Mol Ther. 2004 Mar;9(3):337-46
references.pmid: 15006600
references.citation: Cardiovasc Res. 2010 Apr 1;86(1):12-9
references.pmid: 19812043