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

Zoi Michailidou; Sophie Turban; Eileen Miller; Xiantong Zou; Joerg Schrader; Peter J. Ratcliffe; Patrick W. F. Hadoke; Brian R. Walker; John P. Iredale; Nicholas M. Morton; Jonathan R. Seckl

doi:10.1074/jbc.M111.259325

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

From the ^‡Medical Research Council (MRC) Centre for Inflammation Research and
^§University/British Heart Foundation (BHF) Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland and
the ^¶Nuffield Department of Clinical Medicine, University of Oxford, Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford OX3 7BN, United Kingdom

↵1 To whom correspondence should be addressed. Tel.: 44-131-2426670; E-mail: v1zmicha{at}staffmail.ed.ac.uk.

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.

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.

Footnotes

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