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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 6 2989-2997
Copyright © 2004 by The Endocrine Society

Glucocorticoids Down-Regulate Glucose Uptake Capacity and Insulin-Signaling Proteins in Omental But Not Subcutaneous Human Adipocytes

M. Lundgren, J. Burén, T. Ruge, T. Myrnäs and J. W. Eriksson

Departments of Medicine (M.L., J.B., T.R., J.W.E.) and Surgery (T.M.), Umeå University Hospital, Umeå SE-901 85, Sweden

Address all correspondence and requests for reprints to: Dr. Jan W. Eriksson, Department of Medicine, Umeå University Hospital, SE-901 85 Umeå, Sweden. E-mail: jan.eriksson{at}medicin.umu.se.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Visceral adiposity is associated with insulin resistance and type 2 diabetes. This study explores the metabolic differences between sc and visceral fat depots with respect to effects in vitro of glucocorticoids and insulin on glucose uptake.

Adipocytes from human sc and omental fat depots were obtained during abdominal surgery in 18 nondiabetic subjects. Cells were isolated, and metabolic studies were performed directly after the biopsies and after a culture period of 24 h with or without dexamethasone. After washing, basal and insulin-stimulated [14C]glucose uptake as well as cellular content of insulin signaling proteins and glucose transporter 4 (GLUT4) was assessed.

Omental adipocytes had an approximately 2-fold higher rate of insulin-stimulated glucose uptake compared with sc adipocytes (P < 0.01). Dexamethasone treatment markedly inhibited (by ~50%; P < 0.05) both basal and insulin-stimulated glucose uptake in omental adipocytes but had no consistent effect in sc adipocytes. The cellular content of insulin receptor substrate 1 and phosphatidylinositol 3-kinase did not differ significantly between the depots, but the expression of protein kinase B (PKB) tended to be increased in omental compared with sc adipocytes (P = 0.09). Dexamethasone treatment decreased the expression of insulin receptor substrate 1 (by ~40%; P < 0.05) and PKB (by ~20%; P < 0.05) in omental but not in sc adipocytes. In contrast, dexamethasone pretreatment had no effect on insulin-stimulated Ser473 phosphorylation of PKB. GLUT4 expression was approximately 4-fold higher in omental than sc adipocytes (P < 0.05). Dexamethasone treatment did not alter the expression of GLUT4.

In conclusion, human omental adipocytes display approximately 2-fold higher glucose uptake rate compared with sc adipocytes, and this could be explained by a higher GLUT4 expression. A marked suppression is exerted by glucocorticoids on glucose uptake and on the expression of insulin signaling proteins in omental but not in sc adipocytes. These findings may be of relevance for the interaction between endogenous glucocorticoids and visceral fat in the development of insulin resistance.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OBESITY IS RELATED to a variety of metabolic and cardiovascular alterations such as insulin resistance, hypertension, type 2 diabetes, and atherosclerosis. Central and, in particular, visceral distribution of adiposity is considered to be most harmful in this respect (1, 2, 3, 4). The distribution of body fat is partly regulated by genetic factors (4), and it is affected by sex as well as ethnic background. For example, women on average have a much smaller proportion of visceral fat than men (4, 5), and Black women tend to have less visceral fat than white women, even at the same waist- to-hip ratio (WHR) (6).

One important role of the adipose tissue is to act as a reservoir for triglycerides, where excess energy is stored until needed, e.g. during prolonged fasting or in situations with elevated energy demands. Different hormones, in particular insulin and catecholamines, mediate the storage and use of this energy. Catecholamines bind to {alpha}- and/or ß-adrenergic receptors at the cell surface. ß-Receptors mediate a cascade reaction that, via elevated levels of cAMP, stimulates protein kinase A that in turn activates hormone sensitive lipase (HSL). HSL hydrolyzes triglycerides to glycerol and free fatty acids (FFA) that can be further metabolized by different energy-demanding tissues (7, 8, 9).

In the postprandial state, elevated levels of insulin promote triglyceride storage in adipose tissue. Insulin inhibits lipolysis by a mechanism involving the cAMP hydrolyzing enzyme, phosphodiesterase 3B, resulting in decreased activation of protein kinase A and HSL and thus less hydrolysis of triglycerides (7, 8, 9). Simultaneously, triglyceride assembly from acylcoenzyme A and glycerol is stimulated via acylcoenzyme A carboxylase and fatty acid synthase (10), but the flux through this pathway seems to be of minor importance in human adipocytes compared with the uptake and esterification of FFA derived from plasma lipoproteins (11). Insulin also promotes glucose uptake and use in fat cells. The metabolic effects of insulin are mediated via its receptor that activates an array of insulin-signaling proteins, for example insulin receptor substrates (IRS), phosphatidylinositol 3-kinase (PI3-K), and protein kinase B (PKB). One final effect is glucose transport stimulation that occurs via translocation of the insulin-sensitive glucose transporter 4 (GLUT4) (12).

It has been hypothesized that visceral adipose tissue, due to higher lipolytic activity, larger amount of ß-adrenergic receptors on the cell surface (13), and lower sensitivity to the antilipolytic effects of insulin (14, 15), releases proportionally more FFA than sc adipose tissue (4, 16). Excess visceral fat would lead to greater FFA delivery to the liver, and this may impair insulin clearance and action and increase glucose and very low-density lipoprotein output from the liver (17, 18, 19). This concept has, however, been challenged because the quantitative contribution of visceral fat to whole-body and hepatic FFA exposure perhaps is of minor importance (20). Regardless of their site of origin, high levels of FFA in the circulation will also impair peripheral glucose disposal (21, 22, 23, 24), and, thus, they promote insulin resistance, hyperinsulinemia, and hyperglycemia.

Glucocorticoids, in man mainly cortisol, are interesting with respect to the development of insulin resistance, type 2 diabetes, and the metabolic syndrome (25). Elevated glucocorticoid levels counteract insulin’s effect to stimulate peripheral glucose use and suppress hepatic glucose output (26) and may also impair glucose-induced insulin release from ß-cells (27). Treatment with the glucocorticoid analog dexamethasone has been reported to induce defects in glucose uptake and insulin signaling in 3T3-F442A, 3T3-L1, and primary rat adipocytes (28, 29, 30). Furthermore, endogenous or exogenous hypercortisolism in humans is associated with redistribution of fat from peripheral to central depots and also with other components of the metabolic syndrome, e.g. hypertension, hyperglycemia, and dyslipidemia (31).

The aim of the present study was to investigate metabolic differences between omental and sc adipocytes with respect to regulation of cellular glucose uptake and to address possible differences in the insulin-antagonistic actions of glucocorticoids. Therefore, we assessed glucose uptake rate and the expression of insulin-signaling proteins (IRS1, PI3-K, and PKB) and GLUT4 in human adipocytes obtained from omental and sc abdominal fat biopsies, and this was done both in fresh cells and after a 24-h culture period with or without dexamethasone.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Adipocytes from human omental and sc fat depots were obtained during elective abdominal surgery, mainly cholecystectomy, at the Umeå University Hospital. In each subject, approximately 2- to 5-g biopsies of omental and sc adipose tissue, respectively, were removed at the beginning of open (n = 4) or laparoscopic (n = 14) surgery after induction of general anesthesia, and the tissue samples were kept in medium 199 at 37 C. All subjects were fasted overnight before surgery. The study group consisted of 12 women and six men. Exclusion criteria were as follows: hypertension, malignancy, or endocrine (except for treated primary hypothyroidism) or acute disease conditions. The participants thus were nondiabetic, but they had a wide range of age (15–87 yr) and body mass index (BMI) (19–49 kg/m2), and five subjects were obese (BMI ≥ 30). One to two months after surgery, fasting blood samples were obtained, and body composition (32) was assessed in 14 subjects; four subjects did not agree to return for follow-up examinations (Table 1Go). Informed consent was obtained from each individual before participation in the study. The Umeå University Ethics Committee approved the study protocol.


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  		TABLE 1. Subject characteristics and fasting blood chemistry (n = 18)1

 
Chemicals

DMEM and Hanks’ medium 199 were obtained from Invitrogen BV, Life Technologies (Groningen, The Netherlands). Penicillin/streptomycin and fetal calf serum were purchased from Gibco BRL, Life Technologies, Inc., (Paisley, Strathclyde, UK). Adenosine deaminase (ADA) and collagenase A were from Roche Diagnostic Scand AB (Bromma, Sweden). D-[U-14C]glucose (specific activity, 200–300 mCi/mmol) was purchased from Amersham Pharmacia Biotech (Buckinghamshire, UK). BSA (fraction V), dexamethasone, and N6-(R-phenyl-isopropyl)adenosine (PIA), were from Sigma-Aldrich Sweden AB (Stockholm, Sweden). Human insulin (Actrapid, 100 U/ml) was from Novo Nordisk A/S (Copenhagen, Denmark). The anti-phospho-Akt1 (Ser473) antibody was from New England Biolabs (Beverly, MA), and the anti-IRS1 antibody was from Upstate Biotechnology (Lake Placid, NY). Anti-p85{alpha}/ß (PI3-K), -Akt1/2 (PKB), and -GLUT4 polyclonal as well as secondary antibodies were from Santa Cruz Biotechnology Inc. (Santa Cruz, CA).

Isolation and primary culture of human sc and omental adipocytes

Isolated fat cells were obtained by mincing and thereafter shaking the tissue samples obtained at surgery in polypropylene containers at 37 C for 1 h in medium 199, containing 5.6 mmol/liter glucose, 40 mg/ml BSA, and 0.6 mg/ml collagenase. The cells were then filtered through a nylon mesh and washed four times with fresh medium. In some experiments, the isolated fat cells were then cultured for 24 h at 37 C. They were placed in flasks containing DMEM with 6 mMD-glucose, 10% fetal calf serum, penicillin (100 U/ml), and streptomycin (100 µg/ml) with or without 0.3 µmol/liter dexamethasone, and they were incubated under a gas phase of 95% O2 and 5% CO2. Before further assessments, the cells were washed four times in fresh medium.

Adipocyte cell size was significantly greater (P < 0.05) in sc than visceral fat, but it was not altered by dexamethasone treatment (diameter of sc cells after 24 h culture, 105.1 ± 3.3 and 105.3 ± 4.3 µm; and diameter of omental cells after 24 h culture, 95.8 ± 5.4 and 92.9 ± 6.2 µm for control and dexamethasone-treated cells, respectively). There were no alterations in cellular integrity on microscopic examination, either after dexamethasone treatment or between the two fat depots. Furthermore, after the culture period, cells from both fat depots clearly respond to insulin with respect to glucose transport, although this response is slightly attenuated compared with fresh cells (Fig. 1Go and Fig. 2Go, A and B). Taken together, these observations indicate that with the employed culture conditions, the fat cells, regardless of origin and treatment during culture, are equally viable.



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  		FIG. 1. [14C]Glucose uptake in fresh omental and sc adipocytes examined directly after the isolation process, i.e. 1–1.5 h after the biopsies. Isolated cells were washed, and insulin (0–1000 µU/ml) was added for 15 min. Then, [14C]glucose uptake during 60 min was measured. Results are given as means ± SEM of 10 separate experiments (i.e. fat cells from both depots in 10 subjects). Differences between cell types were assessed with two-way ANOVA. **, Overall P < 0.01 for sc vs. omental cells.

 


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  		FIG. 2. A–C, Effects of long-term (24-h) treatment with dexamethasone (Dex) on glucose uptake in primary cultured omental (A) and sc (B) human adipocytes and dose-response curves in both cell types (C). Isolated cells were cultured for 24 h in DMEM medium with or without Dex (0.3 µmol/liter in A and B and at the indicated concentrations in C). After washing, insulin (0–1000 µU/ml as indicated) was added for 15 min, and then [14C]glucose uptake during 60 min was measured. Results are given as means ± SEM (A and B, n = 10; C, n = 2 and 3 for omental and sc cells, respectively). Differences between treatments were assessed with two-way ANOVA. *, Overall, P < 0.05 vs. untreated cells.

 
Glucose uptake assay

Due to the limited amount of fat obtained with biopsies, in some subjects, fat was either used for glucose uptake measurement (n = 3) or Western analysis of cellular proteins (n = 6). In nine subjects, fat amount was sufficient for assays of both types. The glucose uptake assay was performed essentially as previously reported (33) in both freshly isolated cells and in cells cultured for 24 h. After collagenase treatment, washing, and, in some experiments, 24-h culture as described above, cells were incubated without glucose at 37 C in vials containing medium 199, BSA (4%), ADA (1 U/ml), PIA (1 µmol/liter), and insulin (0–1000 µU/ml). After 15 min, D-[U-14C]glucose was added (10 µl of a stock solution at 10.5 µCi/ml to a total of 0.5 ml cell suspension, i.e. 0.21 µCi/ml, 0.7–1.0 µmol/liter) and the incubation continued for another 60 min. The assay was terminated by transferring the cell suspension to prechilled tubes and separating the cells from the glucose-containing medium by centrifugation through silicone oil. Thereafter, cell-associated radioactivity was determined by scintillation counting. Under these experimental conditions, glucose uptake is mainly determined by the rate of transmembrane glucose transport (34). Glucose uptake is calculated according to the following formula:


Western analysis of proteins in cellular lysates

As mentioned above, these assays were performed in adipocytes from a total of 15 subjects. Cells were cultured for 24 h, washed four times with fresh medium, and incubated 10 min at 37 C in vials containing glucose, medium 199, BSA (4%), ADA (1 U/ml), and PIA (1 µmol/liter) with or without a maximal insulin concentration (1000 µU/ml). The cells were then centrifuged through silicone oil, as previously described, collected, and thereafter lysed with 0.1–0.2 ml lysis buffer [25 mmol/liter Tris-HCl, pH 7.4; 0.5 mmol/liter EGTA; 25 mmol/liter NaCl; 1% Nonidet P-40; 1 mmol/liter Na3VO4; 10 mmol/liter NaF; 0.2 mmol/liter leupeptin; 1 mmol/liter benzamidine; and 0.1 mmol/liter 4-(2-aminoethyl)-benzenesulfonylfluoride hydrochlorine] and rocked for 2 h at 4 C. Insoluble substances were sedimented by centrifugation at 12,000 x g at 4 C, and supernatants were collected and frozen in aliquots at –70 C. Protein content was measured with the bicinchoninic acid protein assay kit (Pierce Chemical Co., Rockford, IL) and BSA as standard.

Separation of proteins was performed by SDS-PAGE using appropriate gel concentration and time. The total amount of protein added per lane was either 10 or 20 µg and was the same within each set of experiments. Proteins were then transferred to an Immobilon-P membrane (Millipore, Bedford, MA), which was blocked with 5% dry milk dissolved in PBS (pH 7.4) at 4 C overnight. Detection of the various signaling proteins and GLUT4 was performed using polyclonal antibodies designed for each protein. An enhanced chemiluminescence Western blotting kit was used to visualize immunoreactive bands.

Blood chemistry

Serum insulin concentrations were measured by microparticle enzyme immunoassay (Immulite 2000, DPC, Los Angeles, CA). FFA were analyzed with a commercial enzymatic kit (nonesterified fatty acid C, Wako Chemical USA Inc., Richmond, VA). All other measurements were done according to the routine methods at the Department of Clinical Chemistry, Umeå University Hospital. Insulin resistance was estimated by using the homeostasis model assessment insulin resistance index (HOMA-IR) derived from fasting serum insulin and glucose concentrations [insulin (pmol/liter) x glucose (mmol/liter)]/22.5) (35).

Statistical analysis

Statistical analyses were performed using the SPSS package (SPSS Inc., Chicago, IL). Results are given as means ± SEM. Comparisons between cells from the two fat depots and between dexamethasone-treated and untreated cells were performed within subjects, i.e. cells from the same individuals were used in each set of analyses. Statistical significance of differences in glucose uptake was determined using two-way ANOVA or paired t test, as appropriate. The amount of protein expressed in cells was analyzed with Wilcoxon signed ranks test. Simple linear or multiple step-wise regressions were used for analyses of associations between variables. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Glucose uptake in omental and sc adipocytes

As shown in Fig. 1Go, the rate of insulin-stimulated glucose uptake was higher (~100%) in fresh omental adipocytes compared with sc adipocytes (P < 0.01). Basal, nonstimulated glucose uptake also tended to be higher in omental cells, but this was not significant (P = 0.25). However, the maximum relative response to insulin (1000 µU/ml), i.e. approximately 3- to 4-fold (362 ± 51% of basal, P < 0.01, in omental cells; and 334 ± 60% of basal, P < 0.01, in sc cells), and the sensitivity to insulin (e.g. EC50) did not differ significantly (Fig. 1Go and data not shown). These differences and similarities between omental and sc adipocytes were also found after a 24-h culture period (Fig. 2Go, A and B), although basal glucose uptake was slightly higher (P = 0.17 and P = 0.05 for omental and sc adipocytes, respectively), and the relative insulin response tended to be somewhat lower (not significant) than in freshly isolated cells (omental cells, 221 ± 30% of basal, P < 0.01; and sc cells, 171 ± 10%, P < 0.01).

Effects of dexamethasone on glucose uptake

When omental fat cells were treated with 0.3 µmol/liter dexamethasone for 24 h, both basal and insulin-stimulated glucose uptake were inhibited by approximately 50% (P < 0.05) as compared with untreated cells, whereas the relative insulin effect was not significantly altered (299 ± 31% of basal; P < 0.01) (Fig. 2AGo). In sc adipocytes, however, dexamethasone only displayed a small tendency to inhibit basal glucose uptake (10.8 ± 2.3 and 8.1 ± 2.9 fl/cell·sec for cells treated without and with dexamethasone respectively; P = 0.47), whereas insulin-stimulated glucose uptake was left intact (232 ± 27% of basal; P < 0.01) (Fig. 2BGo).

It has been shown that dexamethasone has different dose-response characteristics in sc and visceral adipose tissue with respect to regulation of lipoprotein lipase (36). To exclude the possibility that the lack of effect of dexamethasone on glucose uptake in sc fat cells was a result of using only a high, supraphysiological concentration, dose-response studies were performed in additional subjects (n = 3) including lower concentrations of dexamethasone (3 and 30 nmol/liter, respectively, and also the usually employed concentration, 0.3 µmol/liter). During a 24-h cell culture, dexamethasone at the lower concentrations did not exert any impairment of basal or insulin-stimulated glucose uptake in sc cells, and, in omental cells, there was a dose-response relationship with maximal inhibition at 0.3 µmol/liter (Fig. 2CGo and data not shown). Additional control experiments including an even lower (0.3 nmol/liter) and a higher (1 µmol/liter) concentration of dexamethasone showed no effects in sc cells, and the maximal effect in omental cells occurred at 0.3 µmol/liter (data not shown). We chose 0.3 µmol/liter as the standard dexamethasone concentration because other work has shown that it exerts a maximal inhibitory effect on glucose transport (37).

The time course for the dexamethasone effect was also studied in three additional subjects. Subcutaneous cells were cultured for a total of 36 h, with dexamethasone (0.3 µmol/liter) present during the last 6, 12, 24, or 36 h of the incubation period or without dexamethasone. Incubating the cells with dexamethasone for 6, 12, or 36 h exhibited no consistent effect on basal or insulin-stimulated glucose uptake, i.e. similar to a 24-h treatment (not shown). In omental adipocytes, incubated with dexamethasone for the last 6, 12, or 24 h of a 24-h culture period, a maximal inhibitory effect was seen at 12 h of dexamethasone treatment, and this persisted unchanged at 24 h (not shown).

Cellular content of insulin signaling proteins and GLUT4

IRS1 expression tended to be higher in omental compared with sc adipocytes, but this difference was not statistically significant (P = 0.35; Fig. 3AGo). PI3-K expression was similar in sc and omental adipocytes (data not shown), but the amount of PKB tended to be approximately 3-fold larger in omental cells (P = 0.09; Fig. 3BGo). There was, however, no difference between the depots with respect to amount of Ser473-PKB-phosphorylation after insulin stimulation (Fig. 3CGo). GLUT4 (P < 0.05) expression was higher in the omental adipocytes (Fig. 3DGo).



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  		FIG. 3. Content of IRS1 (A), PKB (B), pSer473-PKB (C), GLUT4 (D), and ß-actin and GAPDH (E) in cellular lysates. Isolated cells were cultured for 24 h at 6 mM glucose with or without dexamethasone (0.3 µM). After washing, total cellular lysates were prepared, proteins were separated by SDS-PAGE, and Western blotting was performed as described in Subjects and Methods. One representative blot from each set of experiments is shown. Data from video densitometry analyses are shown (except for ß-actin and GAPDH) and, in each subject, they are calculated as percentage of the amount of protein in sc adipocytes without dexamethasone. Data are means ± SEM (A, n = 6, and the subjects who were deficient in IRS1 in either or both omental and sc fat were not included; B, n = 10; C, n = 7–8; D, n = 7; E, n = 3). *, P < 0.05 vs. untreated cells or sc cells, respectively.

 
After dexamethasone treatment for 24 h, omental adipocytes expressed approximately 40% less IRS1 (P < 0.05) compared with untreated cells (Fig. 3AGo). In omental adipocytes, dexamethasone also reduced PKB expression by approximately 20% (P < 0.05, Fig. 3BGo), but, in contrast, it had no effect on the amount of Ser473-phosphorylated PKB after insulin stimulation (Fig. 3CGo). In sc fat cells, dexamethasone pretreatment exerted no significant effects on cellular content of IRS1 and PKB proteins or on Ser473-phosphorylated PKB after insulin stimulation (Fig. 3Go, A–C). The amount of GLUT4 in omental as well as sc adipocytes was unaffected by dexamethasone treatment (data not shown).

Four of the 11 subjects that were evaluated with respect to cellular IRS1 content displayed no or very low IRS1 expression, either in the sc cells (n = 1), in the omental cells (n = 1), or in fat cells from both depots (n = 2). In sc cells with deficient IRS1 expression, the maximal insulin effect on glucose uptake appeared to be impaired (P = 0.08) as also reported in other studies (38, 39), whereas no clear alteration in glucose uptake was found in IRS1-deficient omental cells (data not shown). Subjects with IRS1-deficient adipocytes were not significantly different from those with normal IRS1 expression regarding age, BMI, or sex (data not shown).

There were no differences either between the depots or after dexamethasone treatment regarding glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (a marker of differentiation) and ß-actin expression (reflecting general protein synthesis) after the culture period (Fig. 3EGo). This suggests that there was no difference in the degree of cell differentiation or in general protein synthesis between fat depots or after dexamethasone treatment.

Correlation analyses

Correlation analyses were run between the maximal insulin effect (1000 µU/ml) on glucose uptake (MGU, expressed as percentage of basal glucose uptake) and anthropometric characteristics [sex, weight, systolic blood pressure (SBP) and diastolic blood pressure (DBP), BMI, WHR, percentage of body fat, and age], blood chemistry (glycosylated hemoglobin, HOMA-IR index and insulin, glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides in serum and FFA in plasma), as well as adipocyte cell size. MGU in sc adipocytes was inversely correlated with DBP (r = –0.84; P = 0.009), serum insulin (r = –0.63; P = 0.127), serum triglycerides (r = –0.72; P = 0.044), and omental (r = –0.49; P = 0.131) and sc (r = –0.49; P = 0.128) adipocyte size. MGU in omental adipocytes was inversely correlated with SBP (r = –0.71; P = 0.047), DBP (r = –0.83; P = 0.011), percentage of body fat (r = –0.74; P = 0.035), age (r = –0.74; P = 0.006), serum cholesterol (r = –0.65; P = 0.078), plasma FFA (r = –0.63; P = 0.098), serum triglycerides (r = –0.77; P = 0.025), and omental (r = –0.81; P = 0.001) and sc adipocyte cell size (r = –0.61; P = 0.034). Stepwise multiple regression analysis including these variables was used to identify independent associations between variables. Omental adipocyte size was the only variable that significantly correlated with MGU in sc adipocytes (ß = –0.91; P = 0.004), whereas omental adipocyte size (ß = –0.69; P = 0.002) and SBP (ß = –0.51; P = 0.008) were independently and significantly correlated with MGU in omental adipocytes. Omental adipocyte size alone created a regression equation in which MGU in omental cells was predicted with R2 = 0.70 (P < 0.01), and omental adipocyte size together with SBP as independent variables created a regression equation in which omental MGU was predicted with R2 = 0.94 (P < 0.001).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study, we compared glucose uptake rate and content of critical insulin signaling proteins in human omental and sc adipocytes, and we examined effects of the glucocorticoid analog dexamethasone. Omental adipocytes had an approximately 2-fold higher rate of basal as well as insulin-stimulated glucose uptake compared with sc adipocytes. This is in accordance with previous studies in vitro and in vivo (40, 41). The relative responsiveness as well as the sensitivity to insulin per se did not, however, differ significantly between the two fat depots. Omental adipocytes had a greater content of PKB and GLUT4 (~200% and ~450% of sc cells, respectively) and possibly more IRS1 than sc adipocytes, and this is consistent with previous work (15, 40). Surprisingly, the amount of Ser473-phosphorylated PKB after insulin stimulation was roughly equal in the different fat depots, and this might suggest a more efficient phosphorylation and activation of PKB in sc adipocytes. The elevated levels of GLUT4 seen in omental adipocytes might possibly account for the higher rate of glucose uptake in this depot. It could be speculated that in situations with high calorie intake, a higher rate of glucose uptake and, subsequently, lipogenesis might be one mechanism by which triglyceride storage preferentially ends up in the visceral depot. However, previous results suggest that the de novo fatty acid synthesis, from glucose via acetylcoenzyme A, is minimal in human adipose tissue and only slightly stimulated by high calorie or glucose intake (11). On the other hand, enhanced glucose utilization in visceral fat would be accompanied by less lipid oxidation and hence would indirectly promote triglyceride storage (42).

Interestingly, omental adipocyte cell size was independently and inversely related to insulin responsiveness in both sc and omental adipocytes. No such independent effect was seen with sc fat cell size. In other studies, however, sc adipocyte size was strongly associated with insulin resistance in the same cells as well as in the whole body (M-value) in type 2 diabetic subjects (43), and it was also reported to predict the risk for developing type 2 diabetes in nondiabetic individuals (44). Nevertheless, omental adipocytes may influence sc fat and, hence, potentially also other tissues with respect to insulin action, and, possibly, omental fat cell size could serve as a marker of a general insulin resistance and the metabolic syndrome. The signals involved obviously remain to be established, but adipocyte-derived molecules like FFA, IL-6, TNF-{alpha}, resistin, adiponectin, and leptin are potential candidates.

Dexamethasone treatment inhibited the basal as well as the insulin-stimulated rate of glucose uptake in omental human adipocytes by approximately 50%. This is consistent with our studies on rat adipocytes from epididymal fat pads (30), which also represent an intraabdominal fat depot and possibly are more similar to omental than sc adipose tissue with respect to metabolic regulation. In contrast, dexamethasone had no significant effect on glucose uptake in human sc adipocytes. Earlier reports also suggest that the sc and visceral fat depots are regulated differently by glucocorticoids, and, for example, dexamethasone increases lipoprotein lipase activity and leptin production in sc adipocytes to a lesser degree than in omental adipocytes (36, 45, 46).

Dexamethasone treatment for 24 h significantly decreased the expression of the insulin signaling proteins IRS1 and PKB in omental adipocytes. The expression of GLUT4 and, surprisingly, the amount of phosphorylated PKB after acute insulin stimulation were left intact after dexamethasone treatment. PKB activation is considered to be a critical step involved in the translocation of GLUT4 from the cytosol to the plasma membrane after insulin stimulation. A marked inhibition of GLUT4 translocation upon insulin stimulation has been seen after inhibition of the PKB action (47, 48). Furthermore, in a previous study by our group (30) on epididymal fat cells, dexamethasone was shown to reduce insulin-stimulated glucose uptake as well as IRS1 and PKB content. There is, however, some uncertainty about the critical role of PKB in glucose transport (49) and, obviously, other insulin signaling pathways, e.g. the Cbl pathway (50), might also be of importance. The translocation of GLUT4 to the cellular membrane was not assessed in this study, but dexamethasone has previously been shown to interfere with GLUT4 translocation (51). This could be associated with PKB and IRS1 depletion that also might be critical for the effects presently demonstrated in human omental cells. In rat adipocytes, our previous results indicated that the glucocorticoid-induced down-regulation of basal and maximally insulin-stimulated glucose transport is partly regulated by different mechanisms (30). Due to limited amounts of tissue, we did not specifically look into this issue in the present study. Certainly, a suppression of the overall glucose uptake capacity, rather than of the insulin effect per se, could possibly explain the reduced insulin-stimulated glucose uptake after glucocorticoid treatment. Alterations in the amount or function of GLUT1, which is considered to account for most of the basal glucose uptake (52), could potentially also be involved.

In sc adipocytes, dexamethasone treatment had no effect on the cellular content of insulin signaling proteins and GLUT4. Nor was there any change in insulin-stimulated phosphorylation of PKB. Taken together, these findings may suggest that the glucocorticoid-induced impairment of glucose transport is linked to alterations in IRS1 and PKB expression and that this occurs in omental but not in sc adipocytes.

Elevated levels of glucocorticoids, either derived endogenously or as a result of treatment, are associated with a redistribution of fat from peripheral to more central fat depots in humans (31). This is probably not mediated through glucose uptake and subsequent lipogenesis in omental adipose tissue because dexamethasone attenuated the glucose uptake in this depot. It has, however, been shown that dexamethasone elevates lipoprotein lipase expression as well as activity, preferentially in visceral adipose tissue in humans (36). Thus, a higher rate of FFA delivery from triglyceride-rich lipoproteins might contribute to the visceral fat accumulation seen in states of glucocorticoid excess.

Selective overexpression of GLUT4 in adipose tissue in transgenic mice has been shown to elevate the glucose uptake rate in adipocytes but also to enhance whole-body glucose turnover in these mice, and this is probably mainly mediated via an increase in skeletal muscle glucose uptake (53). Along with this, although the relative contribution of adipose tissue glucose uptake in humans is smaller than in mice, the perturbations in glucose uptake rate in omental adipocytes seen after treatment with dexamethasone could possibly be accompanied by secondary effects that would lead to altered glucose turnover, and potentially other metabolic consequences of insulin resistance, in other tissues. Furthermore, effects of glucocorticoids on the amount of different adipokines (e.g. TNF-{alpha}, IL-6, leptin, and adiponectin) released from the cells could possibly be involved (54, 55, 56). Possibly, alterations in such factors after glucocorticoid exposure could occur selectively in omental fat, similar to the suppression of glucose transport.

In this study, we wished to address possible differences in the interaction between glucocorticoids and insulin action in sc and omental fat depots in a sample of the general population. In this respect, the wide ranges of age and BMI in our cohort could be considered appropriate. However, it must be acknowledged that the number of subjects was limited. Nevertheless, as comparisons between sc and omental cells as well as between the dexamethasone-treated and untreated cells were performed within the same individuals, possible confounding factors such as sex, BMI, and age will be mainly adjusted for.

We conclude that human omental adipocytes display a higher basal and insulin-stimulated glucose uptake rate compared with sc adipocytes. Omental but not sc fat cells are susceptible to effects of glucocorticoids to suppress basal as well as insulin-stimulated glucose uptake, and this may partly be related to a concomitant down-regulation of IRS1 and PKB protein expression. These findings may be of relevance for the interaction between endogenous glucocorticoids and visceral fat in the development of insulin resistance and the metabolic syndrome.


   Acknowledgments
 
We are grateful to Ewa Strömqvist-Engbo and Frida Renström for skillful experimental work and assistance, to the helpful surgeons and staff at "Surgery 3" and Metabolenheten at Umeå University Hospital, and to Professor Gunilla Olivecrona for help in starting the project.


   Footnotes
 
This work was supported by the Swedish Research Council (Medicine, Project 14287); the Swedish Diabetes Association; the Faculty of Medicine at Umeå University; and the Novo Nordisk, the Elsa and Folke Sahlberg, the Sigurd and Elsa Golje, and the Torsten and Ragnar Söderberg Foundations.

Abbreviations: ADA, Adenosine deaminase; BMI, body mass index; DBP, diastolic blood pressure; FFA, free fatty acid(s); GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GLUT4, glucose transporter 4; HOMA-IR, homeostasis model assessment insulin resistance index; HSL, hormone sensitive lipase; IRS1, insulin receptor substrate 1; MGU, maximal insulin effect (at 1000 µU/ml) on adipocyte glucose uptake; PIA, N6-(R-phenyl-isopropyl)adenosine; PI3-K, phosphatidylinositol 3-kinase; PKB, protein kinase B; SBP, systolic blood pressure; WHR, waist-to-hip ratio.

Received July 8, 2003.

Accepted February 23, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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