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

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

doi:10.1074/jbc.m111.259325

Cited by 85 publications

(83 citation statements)

References 38 publications

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“…More importantly, we found that the reduction was correlated to an increase in the expression of angiogenic factors in the tissues. 11␤-HSD1 was reported to inhibit angiogenesis through production of active GC locally (33), and 11␤-HSD1 gene inactivation was found to enhance angiogenesis in adipose tissue (24). However, 11␤-HSD1 activity during adipose tissue expansion was not examined in those early studies.…”

Section: Discussionmentioning

confidence: 98%

“…HIF-1␣ translocates to the nucleus to induce transcription of angiogenic factors, including VEGF, which stimulates endothelial cell proliferation, differentiation, and capillary formation. This angiogenic activity of VEGF promotes an increase in blood supply to the hypoxic area in tissues as being documented (12,24,34,35). In obesity, HIF-1␣ activity is upregulated by other factors such as insulin and adipogenesis in the adipose tissue in addition to hypoxia (17).…”

Section: Discussionmentioning

confidence: 99%

“…Angiogenesis that is stimulated by proangiogenic factors and inhibited by antiangiogenic factors is required for the maintenance of AT function (20,30). Restoration of angiogenesis by VEGF overexpression in transgenic mice or by thiazolidinedione treatment improved AT function (12,14,15,24,34,35). In contrast, elevation of the antiangiogenic factor pigment epithelium-derived factor reduced AT function (9, 37).…”

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confidence: 99%

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Regulation of 11β-HSD1 expression during adipose tissue expansion by hypoxia through different activities of NF-κB and HIF-1α

Lee

Gao

2013

American Journal of Physiology-Endocrinology and Metabolism

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Lee JH, Gao Z, Ye J. Regulation of 11␤-HSD1 expression during adipose tissue expansion by hypoxia through different activities of NF-B and HIF-1␣. Am J Physiol Endocrinol Metab 304: E1035-E1041, 2013. First published March 19, 2013; doi:10.1152/ajpendo.00029.2013.-11␤-Hydroxysteroid dehydrogenase type 1 (11␤-HSD1) is involved in the pathogenesis of type 2 diabetes by generating active glucocorticoids (cortisol and corticosterone) that are strong inhibitors of angiogenesis. However, the mechanism of 11␤-HSD1 gene expression and its relationship to adipose angiogenesis are largely unknown. To address this issue, we examined 11␤-HSD1 expression in visceral and subcutaneous adipose tissue (AT) of diet-induced obese (DIO) mice during weight gain and investigated the gene regulation by hypoxia in vitro. 11␤-HSD1 mRNA was reduced in the adipose tissues during weight gain in DIO mice, and the reduction was associated with an elevated expression of angiogenic factors. In vitro, 11␤-HSD1 expression was induced in mRNA and protein by hypoxia. Of the two transcription factors activated by hypoxia, the nuclear factor-B (NF-B) enhanced but the hypoxia inducible factor-1␣ (HIF-1␣) reduced 11␤-HSD1 expression. 11␤-HSD1 expression was elevated by NF-B in epididymal fat of aP2-p65 mice. The hypoxia-induced 11␤-HSD1 expression was attenuated by NF-B inactivation in p65-deficient cells but enhanced by HIF-1 inactivation in HIF-1␣-null cells. These data suggest that 11␤-HSD1 expression is upregulated by NF-B and downregulated by HIF-1␣. During AT expansion in DIO mice, the reduction of 11␤-HSD1 expression may reflect a dominant HIF-1␣ activity in the adipose tissue. This study suggests that NF-B may mediate the inflammatory cytokine signal to upregulate 11␤-HSD1 expression.11␤-hydroxysteroid dehydrogenase type 1; nuclear factor-B; hypoxiainducible factor-1␣; hypoxia; hyperinsulinemia; angiogenesis; inflammation; obesity; type 2 diabetes 11␤-HYDROXYSTEROID DEHYDROGENASE TYPE 1 (11␤-HSD1) that converts inactive glucocorticoids (GCs; cortisone and 11-dehydrocorticosterone) into active GCs (cortisol and corticosterone) plays a role in the pathogenesis of insulin resistance. Global inactivation of 11␤-HSD1 by gene knockout prevents insulin resistance and reduces hepatic gluconeogenesis in obese mice (21). 11␤-HSD1 overexpression in adipose tissue (AT) generates visceral obesity and systemic insulin resistance in transgenic mice (23). Liver-specific overexpression of 11␤-HSD1 leads to insulin resistance in the absence of obesity in mice (31). Conversely, global inactivation of the 11␤-HSD1 gene protects mice from diet-induced obesity (21,25,26). 11␤-HSD1 has been a drug target in the study of insulin resistance, and its inhibition using a pharmacological approach improves insulin sensitivity in diabetic mice (2). 11␤-HSD1 is expressed in many cell types, including adipocytes, and the expression is increased during adipocyte differentiation (7). 11␤-HSD1 elevation in adipocytes is proposed to be a common molecular etiology for visceral obe...

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Regulation of 11β-HSD1 expression during adipose tissue expansion by hypoxia through different activities of NF-κB and HIF-1α

Lee

Gao

2013

American Journal of Physiology-Endocrinology and Metabolism

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“…Recently, ␣-SMA was also reported to be expressed in fibrotic regions in adipose tissue (4,17). Furthermore, Spencer and colleagues (25,26) reported that M2 macrophages are associated with adipose tissue fibrosis by secreting TGF-␤.…”

Section: Discussionmentioning

confidence: 99%

Involvement of mast cells in adipose tissue fibrosis

Hirai

Ohyane

Kim

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Recently, fibrosis is observed in obese adipose tissue; however, the pathogenesis remains to be clarified. Obese adipose tissue is characterized by chronic inflammation with massive accumulation of immune cells including mast cells. The objective of the present study was to clarify the relationship between fibrosis and mast cells in obese adipose tissue, as well as to determine the origin of infiltrating mast cells. We observed the enhancement of mast cell accumulation and fibrosis in adipose tissue of severely obese diabetic db/db mice. Furthermore, adipose tissue-conditioned medium (ATCM) from severely obese diabetic db/db mice significantly enhanced collagen 5 mRNA expression in NIH-3T3 fibroblasts, and this enhancement was suppressed by the addition of an anti-mast cell protease 6 (MCP-6) antibody. An in vitro study showed that only collagen V among various types of collagen inhibited preadipocyte differentiation. Moreover, we found that ATCM from the nonobese but not obese stages of db/db mice significantly enhanced the migration of bone marrow-derived mast cells (BMMCs). These findings suggest that immature mast cells that infiltrate into adipose tissue at the nonobese stage gradually mature with the progression of obesity and diabetes and that MCP-6 secreted from mature mast cells induces collagen V expression in obese adipose tissue, which may contribute to the process of adipose tissue fibrosis. Induction of collagen V by MCP-6 might accelerate insulin resistance via the suppression of preadipocyte differentiation.

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“…Consequently, adipose tissue synthesizes hypoxia-inducible factor-1␣ (HIF-1␣), potentially precipitating inflammation and fibrosis (258). 11␤-HSD1 deficiency attenuates adipose tissue hypoxia, with reduced induction of HIF-1␣ and less fibrogenesis, associated with reduced activation of the transforming growth factor (TGF)-␤/Smad3/␣-smooth muscle actin signaling pathway (467). Underlying this is greater angiogenesis in 11␤-HSD1-deficient adipose tissue, plausibly driven by PPAR␥-stimulated expression of the proangiogenic factors VEGF-A, apelin, and angiopoietin-like protein 4.…”

Section: ␤-Hsd1 Adipose Tissue Hypoxia and Fibrosismentioning

confidence: 99%

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

Chapman

Holmes

Seckl

2013

Physiological Reviews

734

601

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Glucocorticoid action on target tissues is determined by the density of “nuclear” receptors and intracellular metabolism by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyze interconversion of active cortisol and corticosterone with inert cortisone and 11-dehydrocorticosterone. 11β-HSD type 1, a predominant reductase in most intact cells, catalyzes the regeneration of active glucocorticoids, thus amplifying cellular action. 11β-HSD1 is widely expressed in liver, adipose tissue, muscle, pancreatic islets, adult brain, inflammatory cells, and gonads. 11β-HSD1 is selectively elevated in adipose tissue in obesity where it contributes to metabolic complications. Similarly, 11β-HSD1 is elevated in the ageing brain where it exacerbates glucocorticoid-associated cognitive decline. Deficiency or selective inhibition of 11β-HSD1 improves multiple metabolic syndrome parameters in rodent models and human clinical trials and similarly improves cognitive function with ageing. The efficacy of inhibitors in human therapy remains unclear. 11β-HSD2 is a high-affinity dehydrogenase that inactivates glucocorticoids. In the distal nephron, 11β-HSD2 ensures that only aldosterone is an agonist at mineralocorticoid receptors (MR). 11β-HSD2 inhibition or genetic deficiency causes apparent mineralocorticoid excess and hypertension due to inappropriate glucocorticoid activation of renal MR. The placenta and fetus also highly express 11β-HSD2 which, by inactivating glucocorticoids, prevents premature maturation of fetal tissues and consequent developmental “programming.” The role of 11β-HSD2 as a marker of programming is being explored. The 11β-HSDs thus illuminate the emerging biology of intracrine control, afford important insights into human pathogenesis, and offer new tissue-restricted therapeutic avenues.

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

Cited by 85 publications

References 38 publications

Regulation of 11β-HSD1 expression during adipose tissue expansion by hypoxia through different activities of NF-κB and HIF-1α

Regulation of 11β-HSD1 expression during adipose tissue expansion by hypoxia through different activities of NF-κB and HIF-1α

Involvement of mast cells in adipose tissue fibrosis

11β-Hydroxysteroid Dehydrogenases: Intracellular Gate-Keepers of Tissue Glucocorticoid Action

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