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© 2007 American Society for Nutrition J. Nutr. 137:2616-2621, December 2007

Biochemical, Molecular, and Genetic Mechanisms

Sucrose Access Differentially Modifies 11ß-Hydroxysteroid Dehydrogenase-1 and Hexose-6-Phosphate Dehydrogenase Message in Liver and Adipose Tissue in Rats1,2

Edra London, Geeta Lala, Reisel Berger, Amy Panzenbeck, Anita A. Kohli, Michael Renner, Andrea Jackson, Tyana Raynor, Katherine Loya and Thomas W. Castonguay*

Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742

* To whom correspondence should be addressed. E-mail: twc{at}umd.edu.


   ABSTRACT
TOP
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
11ß-Hydroxysteroid dehydrogenase-1 (11ß-HSD-1) plays a key role in the regulation of intracellular glucocorticoid concentrations. Increased message and/or activity of adipose 11ß-HSD-1 are characteristics of human and animal models of obesity. Hexose-6-phosphate dehydrogenase (H6PDH) is colocalized with 11ß-HSD-1 and may be a critical factor in determining the oxo-reductase activity of 11ß-HSD-1. This study examined the effects of sucrose solution access on body weight, body composition, and message of 11ß-HSD-1 and H6PDH in mesenteric adipose and liver. Rats were assigned to 3 groups: 1) control (ad libitum intake of nonpurified diet and water only); 2) ad libitum intake of 16% sucrose solution (S16); or 3) ad libitum intake of 32% sucrose solution (S32) in addition to ad libitum intake of diet and water. The S32 group consumed more energy daily than the S16 and control groups, yet body weight did not differ among groups. Percentages of body fat did not differ between the S16 and S32 groups but were higher than in controls. Hepatic 11ß-HSD-1 message was suppressed by 46% in the S16 group and by 47% in the S32 group, whereas the H6PDH message nearly doubled in the S16 group compared to the control group. In mesenteric fat, 11ß-HSD-1 message increased 23-fold in the S16 group and 32-fold in the S32 group and the H6PDH message increased 3.5-fold in the S16 group compared to the control group. These data demonstrate that sucrose can promote increased 11ß-HSD-1 and H6PDH message in mesenteric fat while concomitantly decreasing 11ß-HSD-1 message and increasing H6PDH message in liver. These observations support the hypothesis that sucrose access causes obesity via its ability to increase adipose 11ß-HSD-1.


   Introduction
TOP
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 LITERATURE CITED
 
Approximately 60% or more of the adult U.S. population is overweight or obese and statistics indicate a continuing upward trend. While it is clear that obesity is a multifactorial disease resulting from the combined effects of genetic, physiological, environmental, social, and psychological factors, there is currently no cure. The list of regulatory factors identified as influencing food intake, energy expenditure, and body weight has increased considerably over the past few decades. It is evident that these multiple factors interact on both central and peripheral levels (in the brain, gut, liver, etc.) (1,2) and the maintenance of normal adrenal glucocorticoid levels is necessary for the normal function of these factors. More recently, there is evidence that elevated local tissue concentrations of glucocorticoids may better predict the promotion and maintenance of obesity than circulating hormone levels that are not consistently higher in obese than in lean animals (3,4). The bidirectional enzyme, 11ß-hydroxysteroid dehydrogenase-1 (11ß-HSD-1)3, interconverts the active hormone cortisol (human) or corticosterone (rat) and inert cortisone (human) or 11-dehydrocorticosterone (rat). 11ß-HSD-1 is highly expressed in adipose tissue, liver, and brain where it acts primarily as an oxo-reductase to generate active glucocorticoid. Adipose tissue taken from obese humans has 3–4 times the 11ß-HSD-1 oxo-reductase activity compared to adipose taken from lean individuals (5). This change in 11ß-HSD-1 activity in adipose tissue is likely a commonality of different forms of obesity.

Diet-induced obesity in a number of rodent and non-human primate models appears to parallel human diet-induced obesity in its dependence on combined environmental and genetic factors. High-fat diets can promote increased weight gain and adiposity in rats (6,7) and certain strains are more susceptible to obesity when fed high-fat diets, demonstrating the critical interaction between genetic and environmental factors (8). Diets high in sugar have also been used to induce weight gain and obesity experimentally (9,10). Rats given access to palatable sugar solutions typically consume 60% of their daily energy intake from the solution, with the remaining 40% of total energy taken from standard nonpurified diet. Dallman et al. (11) have more recently reported that sucrose access abates the weight loss and reduced adiposity that takes place after bilateral adrenalectomy. They have speculated that by consuming sucrose at times when sham-operated rats would normally mobilize fat, adrenalectomized (ADX) rats are spared the ADX-induced deficit in gluconeogenesis, an adrenal hormone-mediated regulatory mechanism serving energy balance. Carbohydrate-induced obesity is of particular interest in the context of glucocorticoid dysregulation because of these observations in ADX rats and because of the necessity of NADPH, an oxidation by-product of various sugars, to generate active glucocorticoid.

11ß-HSD-1 resides in the endoplasmic reticulum lumen (12,13) and requires NADPH as a cofactor for its oxo-reductase activity that generates active glucocorticoid. 11ß-HSD-1 acts predominantly as an oxo-reductase in vivo and in intact cells (14,15) but acts as a dehydrogenase in cellular homogenates (16). Reductase activity in cellular homogenates can be initiated upon the addition of NADPH or a system that can generate NADPH such as glucose-6-phosphate dehydrogenase (G6PDH) (17).

Hexose-6-phosphate dehydrogenase (H6PDH) is the microsomal analogue of cytosolic G6PDH, as it catalyzes the first 2 steps, including the committed step, of the pentose phosphate pathway within the endoplasmic reticulum lumen (18,19). H6PDH has been linked to 11ß-HSD-1 through the pathogenesis of cortisone reductase deficiency (20), in which individuals that carry mutations of both 11ß HSD-1 and H6PDH are unable to generate cortisol from inactive cortisone. Spolarics et al. (21) found that increased dietary carbohydrate can promote increased pentose phosphate pathway flux via G6PDH message. The purpose of this study was to examine the effect of dietary sucrose on body weight, body composition, and other indices of obesity, including plasma glucose, insulin, and leptin as well as H6PDH and 11ß-HSD-1 message in mesenteric adipose and liver in rats.


   Materials and Methods
TOP
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 LITERATURE CITED
 
Twenty-four male adult Sprague-Dawley rats (CD strain) weighing 250 g were obtained from Charles River Laboratories. Upon arrival at the laboratory, they were individually housed in standard wire-bottom hanging stainless steel cages in a humidity-controlled room maintained at 25 ± 2°C with a 12-h-light/12-h-dark cycle. All of the rats consumed a commercial pelleted maintenance diet [Harland Teklad 7012 (19% protein, 54% carbohydrate, and 5% lipid; 14.278 kJ/g metabolizable energy)] and tap water ad libitum for a 7-d acclimating period. The rats were then assigned to 1 of the following 3 weight-matched groups (n = 8): 1) control; 2) 16% sucrose (S16); or 3) 32% sucrose (S32). Rats in the S16 group were given free access to the commercial diet, a 16% (w:v) sucrose solution, and water. Rats assigned to the S32 group were given free access to the commercial diet, a 32% sucrose solution, and water. The control group rats were given free access to the commercial diet and water only. Sucrose solutions were composed of commercially available pure cane sugar (Domino) and were prepared 24 h prior to use and kept refrigerated until 1 h prior to use. Both water and sugar solutions were provided in 200-mL plastic bottles fitted with standard no. 7 rubber stoppers and sipper tubes. Food was made available in small glass food cups that were secured to the back wall of each cage with a Plexiglas food cup holder. Spillage, though minimal, was collected and weighed daily. Total daily nonpurified diet intake was measured by subtracting the amount of nonpurified diet spillage (g) from the amount of diet consumed by each rat, as indicated by the difference in weight (g) of the food cup at the beginning and end of each 24-h period. Similarly, daily sucrose solution intake was measured by subtracting the weight of each bottle and the remaining sucrose solution from the weight of each bottle with solution when it was prepared on the previous day. These experimental conditions were in effect for 68 d. On d 69, all rats were weighed and returned to their home cages with access to only water for 24 h. On d 70, each rat was weighed and then restrained and a 500-µL tail blood sample was collected in a Sarsted capillary blood collection tube. The tubes were kept on ice until centrifuged and plasma from the food-deprived rats was saved for subsequent glucose analysis (see below). Each rat was then returned to its home cage and given free access to its appropriate sugar solution and nonpurified diet and water for an additional 2 d.

The rats were killed on d 72 by first administering light anesthesia (CO2 gas) followed by rapid decapitation and exsanguination. Blood was collected in EDTA-treated tubes and kept on ice until centrifuged. The plasma collected was then frozen for subsequent leptin, insulin, and glucose analyses. Small (~1 g) mesenteric adipose and liver (lobus lateralis sinister) tissue samples were dissected quickly and flash-frozen. Each carcass was then prepared for body composition analyses and frozen (–20°C). All of the above care and treatment protocols received prior approval by the University of Maryland Institutional Animal Care and Use Committee.

    Body composition. Rat carcasses were thawed and total body composition of each was measured using an EchoMRI-900 quantitative NMR analyzer (Echo Medical Systems). Output included measurement of fat mass, lean tissue mass, and free body fluids. It has been demonstrated that this technique has excellent linearity and reproducibility with CV of ~1.7% in rats (22).

    Measurement of plasma insulin and leptin. Radioimmunoassay kits purchased from Linco Research (Millipore) were used to measure plasma leptin (kit RL-83K) and insulin (kit RI-13K) of the samples obtained when the rats were killed. Samples were counted on a Packard Cobra gamma counter for 1 min each.

    Measurement of plasma glucose. Glucose concentrations of plasma samples were determined using a Yellow Springs Instruments glucose analyzer.

    Rate of weight loss and metabolic rate. We calculated the percentage of body weight lost by dividing the amount of weight (g) lost during 24 h by body weight at the outset of the food-deprivation period. The mean rate of weight lost by each group was used to estimate differences in basal metabolic rates among the groups (23). It should be noted that differences in locomotor activity were not assessed nor was the type of body mass lost during food deprivation.

    Extraction of RNA from tissue. Frozen liver and adipose samples were thawed and 30 mg and 100 mg, respectively, of each sample was homogenized in buffer and total RNA was extracted according to the RNeasy Mini and RNeasy Lipid Tissue Mini protocols (Qiagen). Total RNA was purified to remove contaminating DNA with DNA-free (Ambion). Concentration and quality of RNA were then measured using a NanoDrop spectrophotometer.

    Measurement of 11ß-HSD-1 and H6PDH message in liver and adipose tissue. cDNA template was created from 500 ng of purified RNA extract using SuperScript III Reverse Transcriptase (Invitrogen). RNA message levels for 11ß-HSD-1 as well as the housekeeper gene ß-actin, were determined by performing separate quantitative RT-PCR (qRT-PCR) programs (IQ5 cycler, Bio-Rad) using appropriate forward and reverse primers for rat H6PDH (24), 11ß-HSD-1 (25), and ß-actin and Syber Green Supermix (Bio-Rad). The following primer sequences were used: H6PDH (forward) 5'-GGGCTATGTTCGGATCTTGTTTA-3', H6PDH (reverse) 5'-GTTCCGGCACCCAGTGTCT-3'; 11ß-HSD-1 (forward) 5'-TGCTCTGGATGGGTTCTTTT-3', 11ß-HSD-1 (reverse) 5'-GAAGCCGAGGACACAGAGAG-3'; ß-actin (forward) 5'-TCGGCAATGAGCGGTTCC-3', and ß-actin (reverse) 5'-CAGCACTGTGTTGCATAGAG-3'. All reactions were carried out in triplicate according to manufacturer's protocol. Differences in message in experimental groups were assessed by comparing the cycle threshold (CT) among treatment groups. The {Delta}{Delta}CT for treatment and the control groups were calculated and then used to determine the fold change (2 –{Delta}{Delta}CT) in message (26).

    Statistical methods. All data were evaluated using SAS software V9.1.2. ANOVA adjusted for repeated measures (where appropriate) was used to evaluate daily body weight and intake data. The significance of differences between group means was evaluated using Duncan's new multiple range test. Regression analyses were used to determine the correlation between body fat mass and plasma glucose, insulin, and leptin. Levene's test for homogeneity of variance was performed to confirm that the variance among fold changes for enzyme message met the assumption of homogeneity to perform ANOVA. Percentage data were first converted to arcsine square root values prior to the application of ANOVA. Differences were considered significant at P < 0.05. The values in the text are means ± SEM.


   Results
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 LITERATURE CITED
 
    Body weight and body fat. Body weights did not differ among the 3 groups at any point during the 10-wk experimental period (Table 1). However, within each group, body weight increased as a function of time (P < 0.0001). The percentages of body fat for the S16 (17.7 ± 2.3%) and S32 groups (15.6 ± 0.9%) did not differ, but both were greater than that of the control group (12.4 ± 0.9%) (P = 0.03). Lean body mass and free body fluid mass did not differ among the 3 groups (data not shown).


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  		TABLE 1 Body weight and food, sucrose, and energy intakes by control, S16 and S32 rats12

 
    Food and energy intake. As expected, the control group ate more nonpurified diet each day than did the S16 and S32 groups, which did not differ from one another (Fig. 1A). However, the S32 group consumed significantly more total energy per day than did the S16 and control groups, which did not differ (Fig. 1B). Cumulative total energy intake during the 10-wk study was higher for the S32 group than for both the S16 and control groups (P < 0.0001) and the S16 group consumed more total energy than the control group (P < 0.0001) (Table 1).


Figure 1
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  		FIGURE 1  Food (A) and energy (B) intakes of male rats in the control, S16, and S32 groups during the 10-wk study. Values are means ± SEM, n = 8. 1 kcal = 4.187 kJ.

 
Daily sucrose solution intake by the S16 group (86.1 ± 1.1 g) was significantly higher than that of the S32 group (66.3 ± 1.4 g) (Fig. 2A). Daily solute intake for the S16 group was 13.8 ± 0.2 g and 21.2 ± 0.5 g for the S32 group (Fig. 2B). Cumulative sucrose intake was also higher for the S32 group compared to that of the S16 group during the 10-wk experimental period (P < 0.0001) (Table 1). The percentage of total daily energy intake derived from sucrose was greater for the S32 group than for the S16 group (P = 0.006).


Figure 2
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  		FIGURE 2  Sucrose solution (A) and sucrose intakes (g) (B) of male rats in the S16 and S32 groups during the 10- wk study. Values are means ± SEM, n = 8.

 
    Circulating insulin, leptin, and glucose and correlation with fat mass. The plasma insulin concentration was higher in the S16 and S32 groups compared to the control group (Table 2). The percentage of body fat as measured by MRI was positively correlated with circulating levels of plasma insulin (R2 = 0.84; P < 0.0001). Percentage of body fat was higher in the S16 and S32 groups compared to the control group. The plasma glucose concentration in food-deprived rats in the S32 group was significantly lower than that of the control and S16 groups but did not differ between the S16 and control groups (Table 2). Further, the plasma concentration of leptin and the plasma glucose concentration in fed rats did not differ among the 3 groups and circulating leptin and percent body fat did not correlate in the 24 rats (R2 = 0.14; P = 0.257).


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  		TABLE 2 Rate of weight loss during 24-h food deprivation, and plasma leptin, insulin, and glucose concentrations in control, S16, and S32 rats1

 
    Rate of weight loss after 24-h food deprivation. During the 24-h deprivation period, both S16 and S32 groups lost less body weight as a percentage of initial body weight than did rats in the control group (P < 0.001).

    11ß-HSD-1 and H6PDH messenger RNA in liver and mesenteric adipose tissue. qRT-PCR analysis of messenger RNA (mRNA) extracted from liver revealed 46 and 47% suppressions of 11ß-HSD-1 message among the rats in the S16 and S32 groups, respectively, compared to the level of message in the control group (Table 3; P = 0.027). Conversely, 11ß-HSD-1 message in mesenteric fat was 23- and 32-fold greater, respectively, in the S16 and S32 groups compared to the control group (P = 0.006). The hepatic concentration of H6PDH mRNA in the S16 group was greater than in the control group at wk 10 (Table 3; P = 0.009). However, the S32 group did not differ from either of the other 2 groups. In mesenteric adipose tissue, the S16 group had higher mRNA levels than both the control and S32 groups (P = 0.003), which did not differ from one another.


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  		TABLE 3 Relative enzyme message for 11ß-HSD-1 and H6PDH in liver and mesenteric adipose in the S16 and S32 groups compared to control rats1

 

   Discussion
TOP
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
LITERATURE CITED
 
The aim of this study was to investigate whether a high-sucrose diet would alter the level of message of H6PDH and 11ß-HSD-1 in mesenteric adipose and liver in rats. Previous studies have reported obesity resistance to high-fat diets in 11ß-HSD-1 null mice (27,28), but the specific effects of diet on the message, expression, or activity of 11ß-HSD-1 or H6PDH have not previously been reported. High-sucrose diets increase cytosolic pentose pathway flux via G6PDH (21), so it seems likely that increased microsomal pentose pathway flux could be achieved with a high-sucrose diet via increased H6PDH activity. Additionally, Bujalska et al. (29) demonstrated that it is H6PDH and not G6PDH activity that impacts the activity of 11ß-HSD-1 and Lavery et al. (30) confirmed the necessity of H6PDH for 11ß-HSD-1 oxo-reductase activity in their experiments with H6PDH knock-out mice. Here, we show that sucrose access leads to increased H6PDH message in both adipose and liver of Sprague-Dawley rats. The importance of this observation is that it now provides a mechanism by which sucrose access leads to conditions favoring the oxo-reductase activity of 11ß-HSD-1 in adipose. Dietary sucrose led to increased H6PDH message and, presumably, the increased NADPH that resulted promoted increased 11ß-HSD-1 oxo-reductase activity, resulting in increased intracellular glucocorticoids (Fig. 3).


Figure 3
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  		FIGURE 3  Proposed mechanism for glucocorticoid dysregulation that results from a high-sucrose diet. The sequence of metabolic and glucocorticoid mediate events in liver and mesenteric adipose are shown, beginning with the uptake of dietary sugars into the adipose; circled numbers indicate the proposed chronology of events and arrows identify the flow of the hypothesized pathway. Abbreviations: CORT, corticosterone; 11-DHC, 11-dehydrocorticosterone; GK, glucokinase (or hexokinase); GPL, phosphogluconolactone; G6P, glucose-6-phosphate; ME, malic enzyme; PEPCK, phosphoenolpyruvate carboxykinase.

 
There are several questions that remain to be addressed regarding these observations. While we do not know when the increased H6PDH message first occurs or whether these changes are reflected in increased protein levels, the increased H6PDH message was observed after 10 wk of access to 16% sucrose solution, during which time rats consumed an average of 63% of their daily energy intake from sucrose. Although significant changes were also observed in mean 11ß-HSD-1 message in liver and adipose between the S32 and control groups, H6PDH message levels in liver and adipose of the S32 group did not differ from the S16 or control group (P = 0.226). We suspect that this may have been a result of the increased inter-rat variability that was observed in the S32 group for sucrose and total energy intake throughout the 10-wk experimental period (Figs. 1 and 2). This same day-to-day variability was not observed in the S16 group, possibly leading to more sustained, robust metabolic changes.

    Changes in 11ß-HSD-1. Livingstone et al. (31) found that 11ß-HSD-1 activity increased in adipose whereas 11ß-HSD-1 message and activity decreased in liver of obese Zucker rats compared to their lean counterparts. This finding of increased 11ß-HSD-1 activity in adipose and decreased activity in liver has since been extended to obese humans (5). We replicate the finding of decreased 11ß-HSD-1 mRNA in rat liver and extend what is known about the generality that 11ß-HSD-1 activity is increased with obesity by showing increased 11ß-HSD-1 message in mesenteric adipose of the obese rat. Further, we demonstrated that these changes can be initiated by dietary manipulations. These data provide evidence that alterations in the message of both 11ß-HSD-1 and H6PDH occur as a result of physiological changes that arise in sucrose-induced obesity. In this study, obesity was defined in the rats as significantly increased percentage of total body fat. Mean body weight between the control and sucrose-fed rats did not differ. This finding suggests that altered glucose homeostasis and tissue-specific glucocorticoid regulation may occur as a function of increased visceral fat depots and altered enzyme action within adipose.

At the conclusion of our 10-wk study, the rats were food deprived for 24 h prior to blood collection and glucose analysis. Interestingly, during the 24-h food deprivation, the sucrose-fed rats lost a significantly lower percentage of their initial body weights than did the control rats. This and the differences we observed in 11ß HSD-1 and H6PDH message between groups suggest underlying metabolic and physiologic changes occur as a result of high-sucrose diets. Dallman et al. (11) found that sucrose access blocked most of the metabolic, behavioral, and neuroendocrine effects of ADX in rats, including circumventing the loss of gluconeogenesis caused by corticosterone deficit and providing negative feedback input to the hypothalamus to reduce corticotropin-releasing factor secretion. From the results of our study, we propose that sucrose access likely causes increased gluconeogenesis in the liver via elevated corticosterone levels resulting from increased substrate availability for H6PDH and subsequent increased 11ß HSD-1 activity, which affect local glucocorticoid levels and thereby enable increased weight gain and fat deposition.

    Novel hypothesis regarding diet composition, NADPH availability, and message of 11ß-HSD-1. Visceral obesity may likely be promoted by elevated oxo-reductase activity of 11ß-HSD-1 in adipose tissue and the resulting abnormally elevated local (intracellular) levels of active glucocorticoid. We hypothesize that excess dietary sugar contributes to enhanced microsomal pentose phosphate pathway flux in adipose tissue, which in turn increases local 11ß-HSD-1 oxo-reductase activity. Hypercortisolemia increases transcription of phosphoenolpyruvate carboxykinase, decreases insulin sensitivity, and increases hepatic gluconeogenesis flux (32). It is possible that in the initial stages of glucocorticoid dysregulation, increased availability of 6-carbon sugars in adipose tissue (Fig. 3) leads to increased production of NADPH via the pentose phosphate pathway. This increased production of NADPH could subsequently increase 11ß-HSD-1 reductase activity and in turn increase adipose corticosterone levels, which eventually reach the liver via the hepatic portal vein. We hypothesize that corticosterone levels then begin to increase in the liver, which causes the upregulation of phosphoenolpyruvate carboxykinase, thereby increasing gluconeogenesis and concomitantly decreasing 11ß-HSD-1 reductase activity. Both H6PDH and 11ß-HSD-1 may likely be upregulated in adipose tissue as an adaptive response, favoring further increases in intracellular corticosterone that then migrate back to the liver in the bloodstream. The excess of 6-carbon sugars provided by a high-sucrose diet might also increase production of the reducing equivalent NADH in the liver via enhanced glycolysis and subsequent citric acid cycle activity, thereby providing more cofactor to fuel the inappropriately increased gluconeogenic pathway. This might provide an explanation for the onset and maintenance of the improper response of increased gluconeogenesis to hyperglycemia observed in diabetes and obesity and may also explain the decreased 11ß-HSD-1 oxo-reductase activity observed in the obese liver.


   ACKNOWLEDGMENTS
 
We thank Dr. Randall Sakai and Ms. Susan Melhorn of the University of Cincinnati School of Medicine for assistance with body composition analyses and Dr. Jianghong Meng of the University of Maryland for assistance with the qRT-PCR analyses.


   FOOTNOTES
 
1 Supported in part by grants from the Maryland Agricultural Experiment Station and the Maryland Industrial Partnership program. Back

2 Author disclosures: E. London, G. Lala, R. Berger, A. Panzenbeck, A. A. Kohli, M. Renner, A. Jackson, T. Raynor, K. Loya, and T. W. Castonguay, no conflicts of interest. Back

3 Abbreviations used: ADX, adrenalectomized; 11ß-HSD-1, 11 ß-hydroxysteroid dehydrogenase type 1; CT, cycle threshold; G6PDH, glucose-6-phosphate dehydrogenase; H6PDH, hexose-6-phosphate dehydrogenase; mRNA, messenger RNA; qRT-PCR, quantitative RT-PCR; S16, 16% sucrose solution-fed treatment group; S32, 32% sucrose solution-fed treatment group. Back

Manuscript received 11 June 2007. Initial review completed 8 July 2007. Revision accepted 20 September 2007.


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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
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A. Balachandran, H. Guan, M. Sellan, S. van Uum, and K. Yang
Insulin and Dexamethasone Dynamically Regulate Adipocyte 11{beta}-Hydroxysteroid Dehydrogenase Type 1
Endocrinology, August 1, 2008; 149(8): 4069 - 4079.
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