Increased Angiogenesis Protects against Adipose Hypoxia and Fibrosis in Metabolic Disease-resistant 11β-Hydroxysteroid Dehydrogenase Type 1 (HSD1)-deficient Mice

被引:72
|
作者
Michailidou, Zoi [1 ]
Turban, Sophie [2 ]
Miller, Eileen [2 ]
Zou, Xiantong [2 ]
Schrader, Joerg [1 ]
Ratcliffe, Peter J. [3 ]
Hadoke, Patrick W. F. [2 ]
Walker, Brian R. [2 ]
Iredale, John P. [1 ]
Morton, Nicholas M. [2 ]
Seckl, Jonathan R. [2 ]
机构
[1] Univ Edinburgh, Queens Med Res Inst, MRC, Ctr Inflammat Res, Edinburgh EH16 4TJ, Midlothian, Scotland
[2] Univ Edinburgh, Queens Med Res Inst, Univ British Heart Fdn BHF, Ctr Cardiovasc Sci, Edinburgh EH16 4TJ, Midlothian, Scotland
[3] Univ Oxford, Nuffield Dept Clin Med, Oxford OX3 7BN, England
基金
英国惠康基金;
关键词
INDUCED VISCERAL OBESITY; INDUCIBLE FACTOR 1-ALPHA; GENE-EXPRESSION; GLUCOCORTICOID-RECEPTOR; TISSUE HYPOXIA; INFLAMMATION; INSULIN; CELLS; HIF-1-ALPHA; PATHWAY;
D O I
10.1074/jbc.M111.259325
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1(-/-)) have "healthier" adipose tissue distribution and resist metabolic disease with diet-induced obesity. Here we show that adipose tissues of 11 beta HSD1(-/-) mice exhibit attenuated hypoxia, induction of hypoxia-inducible factor (HIF-1 alpha) activation of the TGF beta/Smad3/alpha-smooth muscle actin (alpha-SMA) signaling pathway, and fibrogenesis despite similar fat accretion with diet-induced obesity. Moreover, augmented 11 beta HSD1(-/-) adipose tissue angiogenesis is associated with enhanced peroxisome proliferator-activated receptor gamma (PPAR gamma)-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.
引用
收藏
页码:4188 / 4197
页数:10
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