Expression of 11β-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue Is Not Increased in Human Obesity

Abstract

Central obesity is associated with increased morbidity and mortality. Preadipocyte proliferation and differentiation contribute to increases in adipose tissue mass, yet the mechanisms that underlie these processes remain unclear. Patients with glucocorticoid excess develop a reversible form of central obesity, but circulating cortisol levels in idiopathic obesity are invariably normal. We have hypothesized that the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), by converting inactive cortisone to active cortisol in adipose tissue, might be an important autocrine regulator of fat mass. Paired omental and sc fat biopsies were obtained from 32 women (median age, 43 yr; range, 28-65; median body mass index, 27.5 kg/m(2); range, 19.7-39.2) undergoing elective abdominal surgery. 11beta-HSD1 activity and mRNA levels were assessed in whole tissue and in isolated preadipocytes and adipocytes using specific enzyme assays and real-time PCR. Preadipocyte proliferation was measured using tritiated thymidine incorporation. Whole adipose tissue 11beta-HSD1 mRNA levels did not differ between omental and sc samples (P = 0.73). In addition, mRNA levels did not correlate with body mass index (omental: r = 0.1; P = 0.6; sc: r = 0.15; P = 0.4). In keeping with earlier studies, 11beta-HSD1 mRNA levels were higher in omental compared with sc preadipocytes. However, in cultured omental preadipocytes, 11beta-HSD1 activity inversely correlated with body mass index (r = -0.47; P = 0.03). In omental preadipocytes, both cortisol and cortisone decreased proliferation (P < 0.05). Inhibition of 11beta-HSD1 with glycyrrhetinic acid partially reversed the cortisone-induced decrease in preadipocyte proliferation (P < 0.05). Enhanced preadipocyte proliferation within omental adipose tissue as a consequence of decreased 11beta-HSD1 mRNA levels and activity may contribute to increases in visceral adipose tissue mass in obese patients.

Obesity and corticosteroids: 11β-Hydroxysteroid type 1 as a cause and therapeutic target in metabolic disease

“…This suggested that an as yet unidentified post-transcriptional level effect might exaggerate the cortisol reactivation potential of 11 -HSD1 in visceral fat preadipocytes, potentially augmenting the accumulation of visceral adiposity in obesity. This may also occur in human adipose stromal cells which express H6PDH uniformly highly throughout differentiation whilst 11 -HSD1 expression increases (Senesi et al, 2008), although previous studies suggested increasing H6PDH expression may control a switch in enzyme directionality throughout differentiation (Bujalska et al, 2002). Further clarification of this will be needed in human cells.…”

“…In humans, 11 -HSD1 mRNA and activity is increased in subcutaneous abdominal adipose tissue of obese subjects both in vivo and in vitro (Rask et al, 2001, Lindsay et al, 2003, Kannisto et al, 2004, Goedecke et al, 2006, Michailidou et al, 2007, Paulsen et al, 2007 -not a comprehensive list) with few exceptions (Tomlinson et al, 2002).…”

“…M a n u s c r i p t 9 It is of note that mice and rats with obesity of polygenic origin have low or unchanged (Kloting et al, 2006) adipose, but elevated liver 11 -HSD1. Therefore, the finding of high adipose 11 -HSD1 in obesity may not be universal and tissue 11 -HSD1 levels must be carefully considered in each model system as well as in humans (Tomlinson et al, 2002).…”

Is ?Cushing?s disease of the omentum? an affliction of mouse and men?

“…In men and women with idiopathic obesity it has emerged that there are tissue-specific alterations in 11β HSD-1 activity. Thus, regeneration of cortisol in the liver was decreased [16,17,18], while 11β HSD-1 activity and mRNA were increased in subcutaneous adipose tissue in most [17,18,19,20,21,22], but not all [23], studies. It would be gratifying to extrapolate that 11β HSD-1 is also increased in omental adipose tissue in obesity, and many authors have written as though this had already been documented.…”

“…Most groups have not attempted to biopsy omental adipose and have restricted their observations to subcutaneous fat. Stewart's group studied omental adipose tissue obtained during surgery and reported that 11β HSD-1 mRNA in freshly isolated tissue did not predict obesity, while enzyme activity and mRNA in cells cultured from omental fat are inversely associated with indices of central obesity [23]. However, in the same subjects, 11β HSD-1 mRNA in subcutaneous abdominal fat was not correlated with obesity either, suggesting that the removal of biopsies during major surgery obscures the relationships that several other groups have found in biopsies obtained electively with local anaesthesia.…”