Abstract
In obesity, rapidly expanding adipose tissue becomes hypoxic, precipitating inflammation, fibrosis, and insulin resistance. Compensatory angiogenesis may prevent these events. Mice lacking the intracellular glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1(-/-)) have "healthier" adipose tissue distribution and resist metabolic disease with diet-induced obesity. Here we show that adipose tissues of 11βHSD1(-/-) mice exhibit attenuated hypoxia, induction of hypoxia-inducible factor (HIF-1α) activation of the TGF-β/Smad3/α-smooth muscle actin (α-SMA) signaling pathway, and fibrogenesis despite similar fat accretion with diet-induced obesity. Moreover, augmented 11βHSD1(-/-) adipose tissue angiogenesis is associated with enhanced peroxisome proliferator-activated receptor γ (PPARγ)-inducible expression of the potent angiogenic factors VEGF-A, apelin, and angiopoietin-like protein 4. Improved adipose angiogenesis and reduced fibrosis provide a novel mechanism whereby suppression of intracellular glucocorticoid regeneration promotes safer fat expansion with weight gain.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism*
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Actins / genetics
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Actins / metabolism
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Adipokines
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Adipose Tissue / blood supply
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Adipose Tissue / enzymology*
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Adipose Tissue / pathology
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Angiopoietin-Like Protein 4
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Angiopoietins / genetics
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Angiopoietins / metabolism
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Animals
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Apelin
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Fibrosis / enzymology
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Fibrosis / genetics
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Fibrosis / physiopathology
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Hypoxia / enzymology*
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Hypoxia / pathology
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Hypoxia / physiopathology
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Insulin Resistance / genetics
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Male
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Mice
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Mice, Knockout
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Neovascularization, Physiologic*
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Obesity / enzymology*
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Obesity / pathology
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Obesity / physiopathology
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PPAR gamma / genetics
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PPAR gamma / metabolism
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Signal Transduction*
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Smad3 Protein / genetics
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Smad3 Protein / metabolism
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism
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Vascular Endothelial Growth Factor A / genetics
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Vascular Endothelial Growth Factor A / metabolism
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Weight Gain / genetics
Substances
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Actins
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Adipokines
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Angiopoietin-Like Protein 4
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Angiopoietins
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Angptl4 protein, mouse
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Apelin
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Apln protein, mouse
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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Intercellular Signaling Peptides and Proteins
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PPAR gamma
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Smad3 Protein
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Smad3 protein, mouse
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Transforming Growth Factor beta
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Vascular Endothelial Growth Factor A
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vascular endothelial growth factor A, mouse
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11-beta-Hydroxysteroid Dehydrogenase Type 1