Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 29, Issue 16, Pages 4467-4483Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00192-09
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Funding
- NIH [R01-DK55758, R01-CA112023]
- TORS Consortium [1PL1DK 081182]
- Faculty of Health Science of the University of Copenhagen
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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 alpha (HIF1 alpha) expression. Using a transgenic model of overexpression of a constitutively active form of HIF1 alpha, we determined that HIF1 alpha fails to induce the expected proangiogenic response. In contrast, we observed that HIF1 alpha 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 alpha and acts by cross-linking collagen I and III to form the fibrillar collagen fibers. Inhibition of LOX activity by beta-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.
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