Introduction

Visceral obesity is associated with an increased risk for type 2 diabetes, hyperlipidemia, and hypertension (the metabolic syndrome) (1)(2). In contrast, comparable amounts of fat stored preferentially in gluteal or femoral depots (lower body obesity) showed lower risk of morbidity and mortality from metabolic abnormalities (3). Exposure to high circulating glucocorticoid (GC)¹ levels, as found in Cushing's syndrome, causes a metabolic disease that resembles features of idiopathic metabolic syndrome including pronounced visceral obesity (4). However, idiopathic obesity is not associated with high circulating GC levels (4). Rather, it seems that intracellular generation of active from inactive GCs by the enzyme 11-hydroxysteroid dehydrogenase type 1 (11HSD1) is aberrantly elevated in adipose tissue of obese individuals (4). Thus, we and others have shown that 11HSD1 mRNA and activity are elevated in abdominal subcutaneous adipose tissue from obese compared with non-obese individuals (5)(6)(7)(8)(9)(10) and in adipose depots in monogenic obesity in rodents (11)(12). In vivo microdialysis confirmed increased abdominal subcutaneous adipose regeneration of cortisol from cortisone in human obesity (13). Given the key association of intra-abdominal (visceral) adipose tissue in metabolic and cardiovascular risk, it has been hypothesized that increased 11HSD1 in the visceral, rather than subcutaneous, adipose depot causes the adverse metabolic consequences of idiopathic obesity and the metabolic syndrome (14). This hypothesis has been supported by the observation that transgenic mice overexpressing 11HSD1 in adipose tissue develop visceral obesity and the phenotype of the metabolic syndrome (12)(15). Conversely, global 11HSD1 knockout mice are protected from the metabolic consequences of dietary obesity, at least in part, through adipose tissue insulin sensitization and fat redistribution away from the visceral depot (16)(17). However, Tomlinson et al. (18) reported a negative association between omental 11HSD1 activity and BMI in primary omental human adipocytes cultured in vitro, although there was no correlation in whole adipose biopsies. A further study could not detect increased portal vein cortisol (19) or increased splanchnic cortisol production rates (20) in obesity, suggesting that if cortisol generation is indeed elevated in visceral fat, it is further metabolized or is not released at higher rates from adipocytes. Together, these data have engendered some confusion as to whether visceral and subcutaneous 11HSD1 is elevated in human obesity. Mechanistically, GCs induce adipose tissue expansion by stimulating preadipocyte differentiation (21) and lipoprotein lipase-mediated triglyceride accumulation (22)(23). A key factor in this process is tissue levels of the intracellular glucocorticoid receptor (GR). In contrast to the plethora of studies (5)(6)(7)(8)(9)(10)(14) of 11HSD1 in adipose tissue and metabolic syndrome, curiously few studies have examined associations between GR and such parameters. Genetic studies strongly support the role of the GC receptor in determining body composition and fat distribution (24)(25). Higher levels of GR found in omental compared with subcutaneous fat (26) would further be expected to have a more pronounced effect on GC action in the omental depot. However, our previous study showed no correlation between adipose tissue GR mRNA in abdominal subcutaneous adipose tissue and obesity (10), whereas Kannisto et al. (9) reported an inverse correlation between subcutaneous adipose GR mRNA and BMI. Here we hypothesized that high adipose 11HSD1, but not GR, mRNA levels predicts obesity in visceral and subcutaneous fat depots in women.

Research Methods and Procedures

Subjects

Informed, written consent was obtained from 21 women undergoing elective, laparoscopic tubal ligation surgery; the study was approved by the Mayo Clinic Institutional Review Board. Tubal ligation surgery was done routinely in the follicular phase of the menstrual cycle to eliminate the risk of pregnancy. Before surgery, body composition was assessed by measuring weight, height, body fatness (% fat) using DXA (DPX-IQ; Lunar Radiation, Madison, WI), and abdominal fat distribution using a single sliced computerized tomography scan at the L₂–L₃ level (27)(28). Visceral and subcutaneous adipose tissue areas were calculated as previously described (28). Although 8 of 21 subjects were taking oral contraceptives, there was no effect on our variables by Student's t test, and the data were pooled.

Blood Assays.

Fasting plasma triglycerides, glucose, and insulin levels were assayed as previously described (29). Homeostasis model of assessment insulin resistance index (HOMA-IR) was calculated by the following equation: fasting insulin (U/mL) fasting glucose (mM)/22.5 (30).

Adipose Tissue Biopsies.

Subcutaneous fat from abdominal (n = 13), thigh (n = 16), and gluteal (n = 18) regions were collected just before surgery and omental (n = 21) adipose biopsies were obtained intraoperatively. The tissue was washed to remove blood and snap frozen in liquid nitrogen and stored at -80 °C. Biopsies were homogenized in 1 to 2 mL Trizol (Gibco BRL, Paisley, United Kingdom). RNA was extracted using RNAid+ binding matrix (Anachem, Luton, UK) and eluted in diethylpyrocarbonate-treated water, containing 10 mM dithiothreitoland 400 U/mL RNasin (Promega, Southampton, UK). Total RNA was quantified using a spectrophotometer at A₂₆₀.

RNA integrity was verified by agarose gel electrophoresis. Oligo dT-primed cDNA was synthesized from 0.5 g of RNA samples using the Promega Reverse Transcription System (Promega, Madison, WI). GR and 11HSD1 mRNA levels were quantified by real-time polymerase chain reaction primer-probe sets using the ABI PRISM 7700/7900 Sequence Detection System (Applied Biosystems, Foster City, CA). The primers and probes used are as follows: 11HSD1, 5'-GGAATATTCAGTGTCCAGGGTCAA-3' (forward), 5'-TGATCTCCAGGGCACATTCCT-3' (reverse) and 5'-6-FAM-ACATTGACAACCTTCGCTGGGAGG-TAMRA-3' (probe); GR, 5'-CATTGTCAAGAGGGAAGGAAACTC-3' (forward), 5'-ATTTTCAACCACTTCATGCATAGAA-3' (reverse), and 5'-6-FAM-TTGTCAGTTGATAAAACCGCTGCCAGTTCT-TAMRA-3' (probe). Levels of GR or 11HSD1 mRNA are reported relative to human cyclophilin A RNA (Applied Biosystems, Cheshire, United Kingdom) as previously optimized (10) and are expressed in arbitrary units. Standard curves for primer-probe sets and real-time polymerase chain reaction analysis were performed as previously described (10). Fat cell size (mean diameter of mature adipocytes in micrometers) was determined using the AdCount (Biomedical Imaging Resource, Rochester, MN) approach as previously described (31).

Statistical Analysis

Repeated-measures ANOVA followed by Tukey post hoc test were performed to determine differences in transcript levels in paired adipose compartments. Pearson correlation was performed to examine the relationships between anthropometric and metabolic parameters with 11HSD1 or GR mRNA levels in different fat depots according to a priori hypotheses to minimize multiple interdependent variables. Multiple linear regression was performed to test whether relationships between fat cell sizes or triglycerides with transcript levels are independent of obesity. Data were tested for normality and were normalized by log transformation where appropriate.

Data are means standard error unless otherwise stated. Differences were considered significant at p < 0.05. All statistical analyses were performed using Sigma Stat 3.1 software (Systat Software Inc., San Jose, CA).

Results

Subject Characteristics

Volunteers were white women 35 1 years of age with a mean BMI of 32.7 1.5 kg/m² (Table 1), indicating an obese group. Their median interquartile range fasting insulin was 15.6 19.6 U/mL, and HOMA-IR as 3.3 4.6 (range, 0.42 to 47). Median fasting glucose and mean triglyceride concentrations averaged 4.9 0.44 mM and 148 19 mg/dL, respectively (Table 1).

Table 1. - Anthropometric and metabolic characteristics of study participants.

Full table

Comparison of 11HSD1 and GR mRNA Levels in Multiple Fat Depots

11HSD1 mRNA levels were greater in subcutaneous abdominal and omental adipose tissues than in other subcutaneous tissues (gluteal, thigh; Figure 1A). 11HSD1 mRNA levels were positively correlated in the three subcutaneous depots: abdominal subcutaneous vs. thigh (R = 0.83, p < 0.005) and abdominal vs. gluteal (R = 0.86, p < 0.005). There were no associations between abdominal subcutaneous and omental 11HSD1 mRNA levels. GR mRNA expression levels were highest in omental and lowest in thigh subcutaneous adipose tissue (Figure 1B) but were not correlated between any compartments. No correlation was found between 11HSD1 and GR mRNA levels in any depot (data not shown).

Figure 1.

11HSD1 and GR mRNA levels in multiple adipose tissue compartments in women. (A) 11HSD1 mRNA levels were higher in abdominal and omental compared with thigh and gluteal adipose tissues. (B) GR mRNA levels were higher in omental and lower in thigh compared with the other adipose tissue compartments. Data are presented as mean standard error.

Full figure and legend (65K)

Association of Obesity with Elevated 11HSD1 but Reduced GR mRNA in Omental Fat

A strong positive association between BMI and omental adipose 11HSD1 mRNA levels was observed (R = 0.570; Figure 2A; Table 2; p < 0.01). Moreover, visceral fat tissue [visceral adipose tissue (VAT)] area by computed tomography was correlated with increased 11HSD1 mRNA levels in the omentum (Figure 2B; Table 2). Omental 11HSD1 mRNA levels were consistently and positively associated with general adiposity (as defined by percent of body fat; R = 0.462, p < 0.05) and with subcutaneous/peripheral adiposity (Table 2). In contrast, obesity was associated with decreased GR mRNA levels in the omental depot (R = -0.627, p < 0.001; Figure 2D; Table 2). Visceral adiposity (Figure 2E) was negatively correlated with omental GR mRNA levels (VAT; R = -0.507, p < 0.05).

Figure 2.

Correlation of 11HSD1 and GR transcript levels with anthropometric parameters and fat cell size in the omental adipose compartment. Correlation of (A) BMI with 11HSD1, (B) VAT with 11-HSD1, (C) fat cell size with 11HSD1, (D) BMI with GR mRNA levels, (E) VAT with GR mRNA levels, and (F) fat cell size with GR mRNA levels. Regression lines and R and p values are indicated in each graph. NS, non-significant correlation.

Full figure and legend (148K)

Table 2. - Pearson correlation (R) of 11HSD1 and GR mRNA levels in multiple adipose tissue depots with body composition, metabolic parameters, and fat cell sizes.

Full table

Association of Omental Fat Cell Hypertrophy with Increased 11HSD1 but Reduced GR

Fat cells were smaller in the omental depot than in subcutaneous adipose tissue (SAT) (omental, 84 4 m; vs. abdominal subcutaneous, thigh, gluteal, 104 3, 109 3, and 106 2 m, respectively; p < 0.0001). Omental fat cell size was positively correlated (R = 0.72, p < 0.001) with 11HSD1 mRNA levels (Figure 2C; Table 2). In contrast, GR transcript levels were negatively correlated with omental fat cell size (Figure 2F; Table 2). To test for independent effects, multiple regression analyses were performed to understand the effects of obesity (BMI) and fat cell size on 11HSD1 or GR mRNA. Omental fat cell size was strongly and independently correlated with 11HSD1 (standardized coefficient, 1.2; p < 0.05), whereas GR was not associated with fat cell size independently of obesity.

Association of Obesity with Increased 11HSD1 mRNA Levels in Subcutaneous Depots but Reduced GR mRNA in the Abdominal Subcutaneous Fat

Because reporting on glucocorticoid action has been largely in the abdominal subcutaneous depot, we extended our subcutaneous depots to gluteal and thigh to test whether the expected relationships held in these distinct compartments. Positive associations with BMI and 11HSD1 mRNA levels were detected in all subcutaneous adipose compartments examined (e.g., abdominal subcutaneous adipose: R = 0.584, p < 0.05; Table 2). Thigh adipose 11HSD1 mRNA correlated positively with SAT, and this relationship showed a consistent trend in the other depots (Table 2). In contrast, abdominal subcutaneous GR mRNA levels were inversely correlated with BMI (R = -0.589, p < 0.05; Table 2). No significant associations were observed between SAT and abdominal subcutaneous GR mRNA levels (Figure 3B) or GR mRNA levels in any other subcutaneous depots (Table 2).

Figure 3.

Correlation of 11HSD1 and GR transcript levels with peripheral adiposity and fat cell size in abdominal subcutaneous compartment. Correlation of (A) SAT with 11HSD1 mRNA levels, (B) SAT with GR mRNA levels, (C) fat cell size (FCS) with 11HSD1 mRNA levels, and (D) FCS with GR mRNA levels. Regression lines and R and p values are indicated in each graph. NS, non-significant correlation.

Full figure and legend (168K)

Abdominal Subcutaneous Hypertrophy is Associated with Reduced GR mRNA Levels

Although multiple regression analysis with small numbers of abdominal subcutaneous biopsies should be interpreted cautiously, our data nevertheless indicate the following. Surprisingly, in subcutaneous abdominal adipose tissue, 11HSD1 mRNA levels were not associated with fat cell size (Figure 3C). In contrast, abdominal subcutaneous GR transcript levels were negatively correlated with fat cell size (Figure 3D). Multiple regression analysis confirmed that GR mRNA levels were independently and negatively correlated with abdominal subcutaneous fat cell size (standardized coefficient, -0.014; p < 0.05). Although GR levels were negatively correlated with fat cell size in the thigh, this relationship did not hold when tested by multiple regression analysis.

Associations of Depot-specific Glucocorticoid Action with Metabolic Parameters

Pearson correlation was used to examine interrelationships between transcript levels and metabolic parameters (Table 2). Higher omental and thigh 11HSD1 levels were associated with increased triglycerides levels (omental: R = 0.46, p < 0.05; thigh: R = 0.57, p < 0.01). This effect was not independent of obesity as confirmed by multiple linear regression analysis. There were no significant associations between fasting glucose, insulin, or HOMA-IR and 11HSD1 transcript levels. In contrast, there was a negative correlation between GR mRNA levels and plasma triglycerides levels selectively in the omental compartment (R = -0.50, p < 0.05). Moreover, there was a trend for inverse associations between omental GR and fasting plasma insulin levels (R = -0.48, p = 0.052).

Discussion

This study examined relationships between two major determinants of tissue glucocorticoid action in multiple adipose tissue depots in lean and obese women. The key findings were 1) 11HSD1 mRNA is most highly expressed in subcutaneous abdominal and omental tissues, whereas GR mRNA is highest in omental adipose tissue; 2) within individuals, there are positive associations between 11HSD1 mRNA levels in subcutaneous adipose depots but not omental fat, whereas GR mRNA levels do not correlate between depots; 3) between individuals, 11HSD1 mRNA levels in all adipose depots, including omentum, are positively associated with BMI and local fat mass, whereas for GR mRNA the main relationships were negative associations in the omentum; 4) increased fat cell size strongly associates with increased 11HSD1 but reduced GR in the omentum.

Here we extend our (4)(6)(8)(10) and others (5)(7)(9) previous observations on abdominal subcutaneous adipose to show a positive relationship between BMI and 11HSD1 mRNA levels in all four adipose compartments examined. This implies an up-regulation of glucocorticoid production in multiple adipose tissue compartments, including the visceral fat depot. Increased visceral fat is a better predictor of metabolic abnormalities compared with upper-body subcutaneous fat (1)(2) and is independently correlated with increased morbidity and mortality (32). In contrast, lower-body obesity may even show a protective effect with respect to metabolic abnormalities (33). In our cohort, omental 11HSD1 mRNA levels were also most strongly associated with increased general adiposity (% body fat). Kannisto et al. (9) previously reported a positive association between percent body fat and 11HSD1 mRNA levels in subcutaneous in obese male and female monozygotic twins. In our study, subcutaneous adipose expression of 11HSD1 mRNA did not correlate with percent body fat. Differences between these studies may be caused by the distinct populations studied and/or our limited power to detect this interaction because 11HSD1 did correlate with other markers of generalized obesity such as BMI. Although in this study we did not measure 11HSD1 activity levels because of limited sizes of biopsies, we expect, from previous studies (7)(10), that activity and mRNA levels are correlated in abdominal subcutaneous adipose tissue biopsies.

GR transcript levels were highest in omental (visceral) fat, as previously reported in humans (26) and mice (12). The major new finding is that in omental and abdominal subcutaneous adipose, GR is inversely associated with adiposity and fat cell size. A previous study also reported lower GR mRNA levels in subcutaneous adipose tissue in severely obese women (34). Moreover, omental GR mRNA levels were negatively associated with plasma triglyceride and, albeit as a trend, insulin levels. This finding is perhaps counterintuitive because GR polymorphisms causing increased glucocorticoid sensitivity lead to increased visceral fat accumulation (25). Our data suggest that reduction of GR levels to the degree we observe in obesity does not sufficiently compensate for the hypertrophy caused by increased ligand regeneration (i.e., 11HSD1). This notion is supported by data from transgenic animal models. Thus, fat-specific 11HSD1 overexpressing mice (12) have increased visceral adiposity, and 11HSD1 null mice have reduced visceral adiposity (16), despite unaltered GR levels. In contrast in humans, to our knowledge, this is the first study describing a consistent opposing change in 11HSD1 and GR mRNA in multiple adipose compartments with obesity. However, because the two transcripts were not correlated in any depot, consistent with previous observations in subcutaneous adipose tissue (9), it seems unlikely that GR and 11HSD1 directly regulate each other. Naturally, there are clearly limitations with association studies, which do not test causality, and further direct study is needed to elucidate possible mechanisms involved.

The volunteers who participated in our study had normal glucose and triglyceride levels but impaired insulin sensitivity. Increased plasma triglycerides were associated with increased 11HSD1 in both thigh and omental regions but with reduced GR mRNA levels selectively in the omental compartment. Neither 11HSD1 nor GR mRNA levels were associated with fasting glucose, which is consistent with our previous report (7). However, there seemed to be a trend for a negative association of omental and thigh GR mRNA with fasting insulin levels that would be interesting to confirm in larger cohorts.

Visceral fat adipocytes are more resistant to insulin's anti-lipolytic effects compared with subcutaneous adipocytes (35). Transgenic mice overexpressing 11HSD1 in fat develop central obesity attributed to adipocyte hypertrophy, particularly in the mesenteric depot (12). To our knowledge, this is the first study that addressed the relationship of 11HSD1 or GR mRNA levels with regional fat cell size. Consistent with previous studies (36)(37)(38), we found larger adipocytes in the abdominal subcutaneous compared with omental depot, indicating higher fat storage in this depot in women. We showed a strong positive correlation between 11HSD1 and adipocyte size in the omental depot, independent of obesity. Despite the negative association of GR mRNA with omental fat cell size, this was not independent of obesity. Although 11HSD1 was equally high in the abdominal subcutaneous and omental depot, we did not find an association between 11HSD1 mRNA levels and abdominal fat cell size, despite the strong positive correlation with BMI. This may seem counterintuitive. The reasons for this might be our limited power to detect a possible correlation because we had fewer abdominal subcutaneous compared with omental depot biopsies. Alternatively, 11HSD1 is not a strong predictor of subcutaneous hypertrophy in our cohort. This is supported by the lack of correlation between 11HSD1 and fat cell size in the thigh and gluteal depots. In contrast to findings in the omental depot, GR mRNA was negatively associated with fat cell size in the abdominal subcutaneous depot, independent of obesity. It would seem that obesity is associated with a down-regulation of GR that is expected to limit the hypertrophic effects of GCs in adipose tissue (21)(22)(23). However, our data suggest that this GR down-regulation cannot entirely counteract increased ligand levels, particularly in the omental depot. It will be important to determine whether and how altered GR levels can indeed reach a functionally limiting state with respect to adipose hypertrophy in obesity.

In conclusion, 11HSD1 mRNA is a strong predictor of omental fat hypertrophy, whereas GR mRNA is negatively associated with obesity.

Notes

¹ Nonstandard abbreviations: GC, glucocorticoid; 11HSD1, 11-hydroxysteroid dehydrogenase type 1; GR, glucocorticoid receptor ; HOMA-IR, homeostasis model of assessment insulin resistance index; VAT, visceral adipose tissue; SAT, subcutaneous adipose tissue.

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Acknowledgments

This work was supported by the Wellcome Trust (PhD studentship awarded to ZM; Programme Grant to J.R.S., B.R.W., and K.E.C.; Intermediate Fellowship to N.M.M.), DK45343 (P.I.M. Jensen), DK50456, and RR-0585 from the U.S. Public Health Service and by the Mayo Foundation. We are grateful to the staff of the Genetics Core Laboratory, Wellcome Trust CRF, Western General Hospital, Edinburgh, for assistance in the real-time polymerase chain reaction assays and to members of the Endocrinology Unit for helpful discussions.