Preadipocyte 11β-Hydroxysteroid Dehydrogenase Type 1 Is a Keto-Reductase and Contributes to Diet-Induced Visceral Obesity in Vivo

Abstract

Glucocorticoid excess promotes visceral obesity and cardiovascular disease. Similar features are found in the highly prevalent metabolic syndrome in the absence of high levels of systemic cortisol. Although elevated activity of the glucocorticoid-amplifying enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) within adipocytes might explain this paradox, the potential role of 11beta-HSD1 in preadipocytes is less clear; human omental adipose stromal vascular (ASV) cells exhibit 11beta-dehydrogenase activity (inactivation of glucocorticoids) probably due to the absence of cofactor provision by hexose-6-phosphate dehydrogenase. To clarify the depot-specific impact of 11beta-HSD1, we assessed whether preadipocytes in ASV from mesenteric (as a representative of visceral adipose tissue) and sc tissue displayed 11beta-HSD1 activity in mice. 11beta-HSD1 was highly expressed in freshly isolated ASV cells, predominantly in preadipocytes. 11beta-HSD1 mRNA and protein levels were comparable between ASV and adipocyte fractions in both depots. 11beta-HSD1 was an 11beta-reductase, thus reactivating glucocorticoids in ASV cells, consistent with hexose-6-phosphate dehydrogenase mRNA expression. Unexpectedly, glucocorticoid reactivation was higher in intact mesenteric ASV cells despite a lower expression of 11beta-HSD1 mRNA and protein (homogenate activity) levels than sc ASV cells. This suggests a novel depot-specific control over 11beta-HSD1 enzyme activity. In vivo, high-fat diet-induced obesity was accompanied by increased visceral fat preadipocyte differentiation in wild-type but not 11beta-HSD1(-/-) mice. The results suggest that 11beta-HSD1 reductase activity is augmented in mouse mesenteric preadipocytes where it promotes preadipocyte differentiation and contributes to visceral fat accumulation in obesity.

Constant expression of hexose-6-phosphate dehydrogenase during differentiation of human adipose-derived mesenchymal stem cells

“…A very recent study supports this view demonstrating that the mouse adipose stromal vascular cells (ASVCs) express H6PD, consistent with dominant reductase activity of HSD11B1 (De Sousa-Peixoto et al 2008). Conflicting results were previously reported by others in human ASVCs showing a dehydrogenase-to-reductase switch during the adipogenic differentiation (Bujalska et al 2005, Nashev et al 2007.…”

“…ASVCs are a heterogeneous population including preadipocytes, fibrocytes, monocytes, and endothelial cells. Interestingly, HSD11B1 is expressed in preadipocytes only, at levels comparable with differentiated adipocytes (De Sousa Peixoto et al 2008). The cellular heterogeneity of the preparation might thus explain the relatively high dehydrogenase activity before adipogenic differentiation.…”

“…However, SVF represents a heterogeneous cell population (Varma et al 2007, De Sousa Peixoto et al 2008; therefore, we prepared mesenchymal precursor/stem cells from human adipose tissue ADMSCs, as these cells represent undifferentiated precursor of several mesenchymal lineages including chondrocytes, osteocytes, and adipocytes (Zuk et al 2001(Zuk et al , 2002. The differentiative potentials of these mesenchymal cells were confirmed following culture in specific media for differentiation in adipogenic, osteogenic, and chondrogenic phenotypes as detailed in the 'Materials and methods' section.…”

The Hypothalamo–Pituitary–Adrenocortical Axis—An Overview of the Role of Glucocorticoids in the Pathophysiology of Endocrine Disorders and Perspectives for the Future

“…63,64 There is evidence that 11β-HSD-1 activity is impaired in the liver but enhanced in adipose tissue in obese human patients. 33,65 Furthermore, the adverse metabolic complications of obesity in mice are prevented by 11β-HSD-1 gene deletion, 66 whereas overexpression of the enzyme in adipose tissue results in metabolic abnormalities. 67 Studies on obese and lean human individuals have demonstrated increased adipose tissue 11β-HSD-1 expression in obese subjects 68 and a direct association between 11β-HSD-1 levels and metabolic abnormalities in obese women.…”

The role and regulation of 11β-hydroxysteroid dehydrogenase type 1 in the inflammatory response

“…In our own experiments, we have shown expression and activity of 11β-HSD1 in mouse bone marrow-derived and thioglycollate-elicited peritoneal Mφ (>5 pmol corticosterone/h/10 6 cells) . Moreover, although bone marrow-derived Mφ readily reactivate glucocorticoids , immunofluorescence suggests Page 5 of 23 A c c e p t e d M a n u s c r i p t 5 that even so, 11β-HSD1 levels are relatively low in both bone marrow-derived ("resting") Mφ and in resident adipose tissue Mφ from normal lean mice (De Sousa Peixoto et al, 2008). Mφ expression of 11β-HSD1 may be highly dependent upon polarisation.…”