Increased Angiogenesis Protects against Adipose Hypoxia and Fibrosis in Metabolic Disease-resistant 11 beta-Hydroxysteroid Dehydrogenase Type 1 (HSD1)-deficient Mice
| Autor: | Zoi Michailidou, Brian R. Walker, Nicholas M. Morton, John P. Iredale, Sophie Turban, Patrick W. F. Hadoke, Jonathan R. Seckl, Xiantong Zou, Peter J. Ratcliffe, Joerg Schrader, Eileen Miller |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A Angiogenesis Adipose tissue Weight Gain Biochemistry Mice 0302 clinical medicine Transforming Growth Factor beta 11β-hydroxysteroid dehydrogenase type 1 Fibrosis 11-beta-Hydroxysteroid Dehydrogenase Type 1 Hypoxia Mice Knockout Extracellular Matrix Proteins 0303 health sciences biology Molecular Bases of Disease 3. Good health Apelin Adipose Tissue Fibroblast Intercellular Signaling Peptides and Proteins Collagen Signal Transduction medicine.medical_specialty Adipose tissue macrophages Neovascularization Physiologic Adipokine 030209 endocrinology & metabolism Angiopoietin-like 4 Protein 03 medical and health sciences Adipokines Internal medicine medicine Angiopoietin-Like Protein 4 Animals Obesity Smad3 Protein Glucocorticoids Molecular Biology 030304 developmental biology Cell Biology Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Actins PPAR gamma Endocrinology biology.protein Insulin Resistance Angiopoietins |
| Zdroj: | Journal of Biological Chemistry; Vol 287 The Journal of Biological Chemistry Michailidou, Z, Turban, S, Miller, E, Zou, X, Schrader, J, Ratcliffe, P J, Hadoke, P W F, Walker, B R, Iredale, J P, Morton, N M & Seckl, J R 2012, ' Increased Angiogenesis Protects against Adipose Hypoxia and Fibrosis in Metabolic Disease-resistant 11β-Hydroxysteroid Dehydrogenase Type 1 (HSD1)-deficient Mice ', Journal of Biological Chemistry, vol. 287, no. 6, pp. 4188-4197 . https://doi.org/10.1074/jbc.M111.259325 |
| ISSN: | 1083-351X |
| DOI: | 10.1074/jbc.M111.259325 |
| Popis: | Background: Adipose hypertrophy limits fat cell oxygenation, promotes scarring, and associates with increased local glucocorticoid regeneration (higher 11βHSD1 enzyme). Results: 11βHSD1 knock-out mice have reduced scarring and better vascularization and oxygenation in their adipose tissue. Conclusion: Elevated adipose 11βHSD1 contributes to obesity pathogenesis by suppressing adipose angiogenesis. Significance: Enhancement of adipose oxygenation and vascularization is a novel therapeutic modality for 11βHSD1 inhibitors. 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. |
| Databáze: | OpenAIRE |
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