title: Increased angiogenesis protects against adipose hypoxia and fibrosis in metabolic disease-resistant 11β-hydroxysteroid dehydrogenase type 1 (HSD1)-deficient mice.
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.
authors.affiliation: Medical Research Council Centre for Inflammation Research, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland. v1zmicha@staffmail.ed.ac.uk
authors.forename: Zoi
authors.initials: Z
authors.lastname: Michailidou
authors.forename: Sophie
authors.initials: S
authors.lastname: Turban
authors.forename: Eileen
authors.initials: E
authors.lastname: Miller
authors.forename: Xiantong
authors.initials: X
authors.lastname: Zou
authors.forename: Joerg
authors.initials: J
authors.lastname: Schrader
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
authors.forename: Patrick W F
authors.initials: PW
authors.lastname: Hadoke
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
authors.forename: John P
authors.initials: JP
authors.lastname: Iredale
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Morton
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Seckl
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000199:Actins / Q000235:genetics / Q000378:metabolism; D054392:Adipokines; D000273:Adipose Tissue / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000073861:Apelin; D005355:Fibrosis / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D000860:Hypoxia / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D009765:Obesity / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D015430:Weight Gain / Q000235:genetics
chemical_list: D000199:Actins; D054392:Adipokines; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; C407088:Angptl4 protein, mouse; D000073861:Apelin; C402826:Apln protein, mouse; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D047495:PPAR gamma; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1