Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue.
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 1alpha (HIF1alpha) expression. Using a transgenic model of overexpression of a constitutively active form of HIF1alpha, we determined that HIF1alpha fails to induce the expected proangiogenic response. In contrast, we observed that HIF1alpha 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 HIF1alpha 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.
Halberg
Nils
N
Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Khan
Tayeba
T
Trujillo
Maria E
ME
Wernstedt-Asterholm
Ingrid
I
Attie
Alan D
AD
Sherwani
Shariq
S
Wang
Zhao V
ZV
Landskroner-Eiger
Shira
S
Dineen
Sean
S
Magalang
Ulysses J
UJ
Brekken
Rolf A
RA
Scherer
Philipp E
PE
D052436:Adipose Tissue, White / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008084:Lipoxygenase / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D005810:Multigene Family; D018919:Neovascularization, Physiologic; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D014158:Transcription, Genetic
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008084:Lipoxygenase