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

https://doi.org/10.1074/jbc.M111.259325Get rights and content
Under a Creative Commons license
open access

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.

Adipose Tissue
Collagen
Extracellular Matrix Proteins
Fibroblast
Hypoxia
Angiogenesis
Fibrosis
Glucocorticoids

Cited by (0)

*

This work was supported by a Henry Wellcome Postdoctoral Fellowship (to Z. M.), a Wellcome Trust Programme Grant (to J. R. S.), and a grant from the European Community 7th Framework Programme (FP7/2007-2013) under Grant Agreement 201608, entitled Targeting Obesity-driven Inflammation (TOBI). B. R. W., J. R. S., and N. M. M. are inventors on relevant patents owned by the University of Edinburgh. B. R. W. and J. R. S. have consulted on 11βHSD1 inhibitors for a number of pharmaceutical companies.

This article contains supplemental Figs. S1–S4.

2

Supported by a Wellcome Trust Career Development Fellowship (079660/z/06/z).