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Molecular and Cellular Biology, August 2009, p. 4467-4483, Vol. 29, No. 16
0270-7306/09/$08.00+0 doi:10.1128/MCB.00192-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Hypoxia-Inducible Factor 1
Induces Fibrosis and Insulin Resistance in White Adipose Tissue 
,
Nils Halberg,1,8
Tayeba Khan,2
Maria E. Trujillo,2,3
Ingrid Wernstedt-Asterholm,1
Alan D. Attie,4
Shariq Sherwani,5
Zhao V. Wang,1
Shira Landskroner-Eiger,2
Sean Dineen,6
Ulysses J. Magalang,5
Rolf A. Brekken,6 and
Philipp E. Scherer1,7*
Touchstone Diabetes Center, Department of Internal Medicine,1 Hamon Center for Therapeutic Oncology and Division of Surgical Oncology,6 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390,7 Department of Cell Biology, Diabetes Research Center, Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York 10461,2 Lead Optimization Pharmacology, Merck Research Laboratories, Rahway, New Jersey 07065,3 Department of Biochemistry, University of Wisconsin—Madison, Madison, Wisconsin 53706-1544,4 Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, The Ohio State University, Columbus, Ohio 43210,5 Department of Biomedical Sciences, Faculty of Health Science, University of Copenhagen, Copenhagen 2100, Denmark8
Received 10 February 2009/ Returned for modification 19 March 2009/ Accepted 5 June 2009
Adipose tissue can undergo rapid expansion during times of excess caloric intake. Like a rapidly expanding tumor mass, obese adipose tissue becomes hypoxic due to the inability of the vasculature to keep pace with tissue growth. Consequently, during the early stages of obesity, hypoxic conditions cause an increase in the level of hypoxia-inducible factor 1
(HIF1) expression. Using a transgenic model of overexpression of a constitutively active form of HIF1, we determined that HIF1 fails to induce the expected proangiogenic response. In contrast, we observed that HIF1 initiates adipose tissue fibrosis, with an associated increase in local inflammation. "Trichrome- and picrosirius red-positive streaks," enriched in fibrillar collagens, are a hallmark of adipose tissue suffering from the early stages of hypoxia-induced fibrosis. Lysyl oxidase (LOX) is a transcriptional target of HIF1 and acts by cross-linking collagen I and III to form the fibrillar collagen fibers. Inhibition of LOX activity by β-aminoproprionitrile treatment results in a significant improvement in several metabolic parameters and further reduces local adipose tissue inflammation. Collectively, our observations are consistent with a model in which adipose tissue hypoxia serves as an early upstream initiator for adipose tissue dysfunction by inducing a local state of fibrosis.
* Corresponding author. Mailing address: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8549. Phone: (214) 648-8715. Fax: (214) 648-8720. E-mail: Philipp.Scherer{at}utsouthwestern.edu
Published ahead of print on 22 June 2009.
Supplemental material for this article may be found at http://mcb.asm.org/.
Molecular and Cellular Biology, August 2009, p. 4467-4483, Vol. 29, No. 16
0270-7306/09/$08.00+0 doi:10.1128/MCB.00192-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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