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Endocrinology Vol. 139, No. 5 2514-2518
Copyright © 1998 by The Endocrine Society

ARTICLES

Vanadate Elevates Lipogenicity of Starved Rat Adipose Tissue: Mechanism of Action1

Natesampillai Sekar, Sun Qian and Yoram Shechter2

Department of Biological Chemistry, The Weizmann Institute of Science Rehovot-76100, Israel

Address all correspondence and requests for reprints to: Yoram Shechter, Department of Biological Chemistry, Weizmann Institute of Science, Rehovot-76100, Israel.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We have established an experimental system in rats in which the lipogenic capacity of adipose tissue was decreased in vivo by prolonged fasting, and restored in vitro by glucose together with insulin or vanadate. Incubation of fasted adipose explants for 5 h at 37 C with 2 mM glucose alone did not elevate lipogenic capacity. However, glucose with insulin (17 nM) or vanadate (100 µM), led, respectively, to 2.2- and 8- to 10-fold elevation. Actinomycin D (50 µM) completely blocked this increase, while low concentrations (ED50 = 4.0 ± 0.4 µM) of vanadate potentiated it. Neither insulin nor vanadate elevated fasted adipose explants’ lipogenic capacity in the absence of glucose, or in the presence of the nonmetabolizable glucose analog 3-O-methylglucose. Upon replacing glucose with 2-deoxyglucose (1 mM), a glucose analog that undergoes phosphorylation to 2-deoxyglucose-6-phosphate with no further metabolism, vanadate was nearly as potent as with glucose in elevating lipogenic capacity. Vanadate was superior to insulin in increasing glucose-6-phosphate level in fasted-adipose explants. Adipose glucose-6-phosphatase activity was inhibited by vanadate (IC50 = 7.0 ± 0.4 µM).

We have concluded that glucose-6-phosphate is the key metabolite of glucose involved in the transcriptionally regulated elevation of lipogenic capacity of fasted adipose explants. Vanadate has a more profound effect than insulin, as it elevates glucose-6-phosphate to higher levels and the subsequent increase in lipogenic capacity is four to five times greater than that induced by insulin. The mechanism involved is the combined action of vanadate in enchancing glucose entry and in inhibiting dephosphorylation of endogenously formed glucose-6-phosphate. The latter effect is not exerted by insulin.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
VANADATE mimics the actions of insulin in vivo and in vitro via alternative biochemical pathways (Refs. 1–7 and reviewed in Refs. 8 and 9). In insulin-resistant diabetic rodents, it induces normoglycemia, improves glucose homeostasis, and sensitizes target tissues to insulin (reviewed in Ref.10). It has been postulated that in vivo vanadium acts predominantly as an insulin enhancer, rather than as an insulinomimetic (reviewed in Refs. 10 and 11). In vivo, starvation, like diabetes, decreases the level of key enzymes participating in glucose and fat metabolism. In starved or diabetic adipose tissue, the activity of lipogenic enzymes such as fatty acid synthase and acetyl CoA carboxylase is reduced (12, 13, 14, 15, 16). Feeding starved rats with a carbohydrate diet and treatment of diabetic rats with insulin restores activities of these enzymes (13, 14, 15, 16). Because vanadate is predominantly an insulin enhancer in vivo, and minute amounts in the diet have anabolic effects in humans (11), we have hypothesized here that vanadate is capable of elevating the levels of key enzymes of fat and glucose metabolism and that it may do so at low concentrations. In this respect, it may be superior to insulin. To investigate our hypothesis, we have developed an in vivo-in vitro rat-adipose experimental system in which the lipogenic capacity of the tissue has been reduced by starvation.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Materials
D-[6-14C]glucose was purchased from New England Nuclear (Boston, MA). Collagenase type-I (134 U/mg) was obtained from Worthington Biochemicals (Freehold, NJ). Porcine insulin was obtained from Eli Lilly Co. (Indianapolis, IN).

Adipose-related in vivo/in vitro experimental system
Studies were performed on 150–180 g male Wistar rats. In a typical experiment, food (but not drinking water) was removed at 1400 h the day before the experiment. The day after, at 1000 h, rats were killed by decapitation; epididimal fat pads from three rats were removed, cut into small pieces with scissors, and distributed into several petri dishes. About 1 g of tissue was incubated in a 100-mm plastic petri dish containing 10 ml of KRB buffer pH 7.4, and 1% BSA. The medium was supplemented with glucose (2 mM or 20 mM), insulin (17 nM), or sodium metavanadate (1–100 µM), in various combinations according to the experimental conditions. The dishes were incubated for 5 h at 37 C. Adipose tissues from each dish were then collected, washed 5 times with KRB-buffer (pH 7.4)-1% BSA, and digested with collagenase for 30 min at 37 C to obtained intact adipocytes (17). The cells were resuspended in the same buffer to obtain a 4% (vol/vol) suspension, put into plastic vials, (0.5 ml/vial in tetraplicates) supplemented with D-[6-14C]glucose (final concentration 0.2 mM, 2500 cpm/nmol) and incubated for 60 min at 37 C under an atmosphere of 95% O2 and 5% CO2. Reactions were terminated by adding toluene-based scintillation fluid (1.0 ml/vial), and radioactivity incorporated into extracted lipids was determined (18). This procedure accurately reflects the lipogenic status of adipose cells.

Measurement of Glc-6-phosphate
This was measured essentially according to Lang and Michal (19). Briefly, the adipose tissue fragments were frozen in liquid nitrogen and extracted with 10% HClO4. Aliquots were adjusted to pH 3.5 with Na2CO3, and the supernatants quantitated enzymatically using Glc-6-P dehydrogenase to generate NADPH in quantities equimolar to the amount of Glc-6-P present in the adipose extracts (19).

Glc-6-Pase activity of adipose tissue was determined following washing the cells in phosphate-free buffer, and homogenizing them with 0.25 M sucrose. Fat was removed and the capacity of the homogenate to liberate Pi from Glc-6-P determined as described (see Refs. 20 and 21).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Restoration of the lipogenic capacity in adipose tissue of fasted rats by glucose and vanadate
Fasting markedly decreases the level of key enzymes participating in glucose and fat metabolism (12, 13, 14, 15, 16). Our intention therefore was to decrease the lipogenic capacity of mature adipose tissue by fasting, and subsequently investigate restoration of this parameter. The in vivo-in vitro assay, described in detail in Materials and Methods, was most suitable for this purpose. Adipose tissue fragments can be kept in vitro up to 24 h, its hormonal activity and capacity to synthesize specific proteins remaining intact (22, 23). Of the glucose analogs tested D-[6-14C]glucose best reflected fatty acid synthesis, and, therefore, the lipogenic status of the cell. Glucose carbons 5 and 6 are largely incorporated into fat as fatty acids via acetyl coenzyme A (24). Glucose (20 mM), which elevates the low level of fatty acid synthase (FAS) and acetyl CoA-carboxylase (ACC) messenger RNA in adipose pieces of suckling rats in vitro (25), was selected as a reference point. Incubation of adipose fragments of 20 h fasted rats with 20 mM glucose for 5 h at 37 C, increased lipogenicity about 1.4-fold, compared with control in the absence of glucose. Insulin (17 nM) and vanadate (100 µM) had no measurable effect on this parameter in the absence of glucose (Fig. 1AGo, columns 3 and 4). In Fig. 1BGo, we show that insulin and vanadate both elevated lipogenic capacity in the presence of 2 mM glucose. However, whereas the increase with insulin (17 nM) was only 2.2-fold (Fig. 1BGo, column 2), with vanadate (100 µM) it was 8- to 10-fold (in different experiments Fig. 1BGo, right columns). Moreover, the effect was already evident at low concentrations of vanadate. As little as 1 µM already doubled the lipogenic capacity of adipose fragments of fasted rats, and half maximal effect (ED50) was 4 ± 1 µM (Fig. 1BGo, columns 4–8). The effect of vanadate was 95% blocked by the inclusion of 50 µM actinomycin D in the medium (Fig. 1CGo). Higher concentrations of insulin (i.e. 0.17 µM) were not more effective in elevating lipogenic capacity as compared with the effect manifested by 17 nM insulin (not shown).



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  		Figure 1. Effect of glucose, insulin, and vanadate in vitro on lipogenic capacity of adipose explants from fasting rats. Epididimal adipose tissue from 20 h fasting rats was prepared for treatment in vitro, and incubated for 5 h at 37 C with the indicated concentrations of glucose, insulin, or vanadate as described in Materials and Methods. After labeling the adipocytes with D-[6-14C]glucose, lipids were extracted, and their radioactive content was counted. Results are expressed as the amount of radioactivity (in cpm) incorporated from D-[6-14C]glucose into the fat content of 3 x 105 cells/h. The figure is a representative of experiments performed three to five times with nearly identical results.

 
Effects on adipose tissue from fed rats
Figure 2Go summarizes the findings from equivalent experiments using adipose fragments from fed rats. The basic differences are as follows: 1) basal-lipogenic capacity was about 3-fold higher; 2) vanadate (but not insulin) elevated lipogenic capacity (about 1.6-fold) also in the absence of glucose in the medium (Fig. 2Go, left columns); 3) in the presence of 2 mM glucose, vanadate (100 µM), but not insulin, increased lipogenic capacity 3.7-fold, the ED50 being about 25 ± 3 µM. As the basal level was a priori higher, the potentiating effect of vanadate was more modest, and had higher ED50 value (Fig. 2Go).



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  		Figure 2. Effect of glucose, insulin, and vanadate on elevating the lipogenic capacity of adipose explants derived from nonfasted rats. Adipose explants from nonfasted rats were treated in an identical manner to the fasted explants, as described in the legend to Fig. 1Go and Materials and Methods. Determination of their lipogenic capacity is also described in the legend to Fig. 1Go.

 
Vanadate also elevates the lipogenic capacity, if 2-deoxyglucose is substituted for glucose
Vanadate elevated lipogenic capacity in the presence, but not in the absence, of glucose (Fig. 1Go). To determine whether the elevation was signaled through glucose itself, or through a glucose metabolite, glucose was substituted with either 3-O-methylglucose (3-OMG) or with 2-deoxy glucose (2DG), both of which undergo insulin (or vanadate) evoked influx into the cell via the same glucose transporters (26). The former, however, is a nonmetabolizable analog of glucose, whereas the latter undergoes in situ phosphorylation to form 2-deoxy glucose-6-phosphate with no further metabolism. 2-Deoxyglucose-6-phosphate resembles Glc-6-P in elevating lipogenic enzyme gene expression in adipose tissue of suckling rats (Ref.25) As shown in Fig. 3Go, neither insulin nor vanadate elevated the lipogenic capacity of fasted rat adipose explants, when glucose was replaced by 3-OMG (Fig. 3Go, middle columns). In contrast, when incubated with 2-DG (1 mM), insulin elevated the lipogenic capacity 2 ± 0.2 and vanadate 8.0 ± 0.7-fold (Fig. 3Go, right columns), strongly suggesting that Glc-6-P is the metabolite involved in elevating lipogenic index of fasted adipose explants.



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  		Figure 3. Effect of analogs of glucose on elevating the lipogenic capacity of adipose explants of fasted rats. Adipose fragments, of 20 h fasted rats were incubated in the presence or the absence of insulin (17 nM) or vanadate (100 µM) with 2 mM glucose (left columns); with 2 mM 3-O-methylglucose (middle columns); or with 1 mM 2-deoxyglucose (right columns). Their lipogenic capacity was measured with D[6-14C]glucose, as described in the legend for Fig. 1Go.

 
Vanadate is superior to insulin in increasing Glc-6-P level in adipose tissue of fasted rats
The greater action of vanadate, compared with insulin, in elevating the lipogenic index (Fig. 1Go), and the conclusion that Glc-6-P was the active metabolite (Fig. 3Go), indicated that vanadate was more efficient than insulin in facilitating in situ formation of Glc-6-P. This point was analyzed directly. Following 5 h incubation, Glc-6-P levels were 9.6 ± 0.7 nmol/0.5 g adipose tissue, whether or not 2 mM glucose was present, showing that glucose alone at this concentration does not elevate Glc-6-P level (Fig. 4Go, left columns). Adding insulin or vanadate to the incubation medium led to a significant increase in Glc-6-P levels. These were 12 ± 1.5, 14 ± 1.2 and 17 ± 1.3 nmol per 0.5g adipose tissue for 17 nM insulin, 10 µM and 100 µM vanadate, respectively (Fig. 4Go). Thus, in the presence of glucose, vanadate (100 µM) was about 3.5 times stronger than insulin in forming Glc-6-P in situ in adipose explants of fasted rats.



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  		Figure 4. Glucose-6-phosphate level in fasted adipose explants, following incubation with glucose, insulin and vanadate. Adipose explants from fasted rats were incubated in the absence or presence of 2 mM glucose with the indicated concentrations of insulin or vanadate. The adipose fragments were then washed, homogenized, and glucose-6-phosphate level was quantitated enzymatically using glucose-6-phosphate dehydrogenase and NADPH (Materials and Methods). Results are expressed as nmol Glc-6-P/500 mg adipose tissue; triplicates of each treatment.

 
Vanadate inhibits adipose glucose-6-phosphatase
Both insulin and vanadate facilitate glucose entry into adipose or muscle tissues (27). However, the markedly higher potency of vanadate suggested an additional contribution by vanadate, but not insulin, to the elevation of Glc-6-P in cells. We therefore examined whether adipose tissue contains vanadate inhibitable Glc-6-Pase activity. Table 1Go shows that the adipose homogenate had Glc-6-Pase activity. This was inhibited by vanadate in a concentration dependent manner. Half maximal inhibition was 7.0 ± 0.7 µM (Table 1Go). Insulin whether added to the assay, or to the adipose tissue before homogenization, had no effect on Glc-6-Pase activity (Table 1Go).


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  		Table 1. Glucose-6-phosphatase activity in rat-adipose tissue: inhibitory effect of vanadate

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Vanadium therapy in insulin-resistant rodents was shown to rectify the poor sensitivity of peripheral tissues to insulin (28–30, and reviewed in Ref. 10). Neither the number and affinity of insulin receptors, nor the content of GLUT4 glucose transporters were modified by vanadium (28, 29, 30). We therefore hypothesized that the basis of the therapeutic effect of vanadate might be an increase in synthesis and activity of key enzymes of glucose and fat metabolism. These are markedly suppressed in diabetes (31). To study the validity of this hypothesis, we established an adipose-related in vivo-in vitro experimental system, in which the lipogenic capacity was decreased by fasting and its restoration was studied in vitro. Elevation of adipose-lipogenic capacity was a most suitable parameter as it reflects the net, and desirable, result of activity of several enzymes, which individually might be altered in different directions in diabetes or starvation. We found that vanadate (ED50 = 4.0 ± 0.4 µM), and to lesser extent insulin, elevated lipogenic capacity of fasted adipose explants 8- to 10-fold. The increase occurred within 5 h incubation and required the presence of glucose in the medium. It was almost entirely suppressed by 50 µM actinomycin D (Fig. 1Go). Altogether the findings strongly suggest that the increase in lipogenic capacity is transcriptionally regulated and is facilitated through glucose or a glucose metabolite(s). We subsequently found that vanadate is incapable of inducing lipogenic capacity when glucose is replaced with the nonmetabolizable 3-OMG, but the metabolizable 2-DG was nearly as potent as glucose (Fig. 3Go). Following this observation, we measured Glc-6-P levels directly and found that vanadate(10 µM and 100 µM) was 2- and 3.5-fold more potent than insulin in forming Glc-6-P in situ in the presence of glucose (Fig. 4Go). In conjunction with previous studies, it is tempting to speculate that Glc-6-P is the metabolite signaling the expression of lipogenic enzymes whether their level is low due to immaturity (as in suckling rats, Ref.25), as a result of starvation (this study) or due to the effects of diabetes mellitus (our manuscript, in preparation).

Curious as to why vanadate was more potent than insulin, we delved further and found that adipose tissue contains Glc-6-Pase activity that is inhibited by micromolar concentrations of vanadate (IC50 = 7.0 ± 0.7 µM, Table 1Go). In the rat liver, Glc-6-Pase activity was also inhibited by vanadate, IC50 = 4.0 µM (32). It should be mentioned that Glc-6-Pase has rarely been studied in nongluconeogenic tissues such as fat. Recently, however, we found that lipolytic hormones activate glycogenolysis in rat adipocytes (32A ). As Glc-6-Pase is the terminal enzyme of glycogenolysis (33), we looked for, and found, Glc-6-P dephosphorylating activity in this tissue too. Glc-6-Pase forms an enzyme phosphate intermediate during catalysis through an active site histidyl moiety. Vanadate, being a phosphate analog, inhibits this enzymatic activity (34, 35). Thus, vanadate, in addition to activating glucose entry (2, 8), appears to increase Glc-6-P by inhibiting dephosphorylation of this endogenously formed metabolite. As far as we know, the effect of insulin on elevating Glc-6-P level is exclusively attributed to its facilitating glucose entry. Insulin does not activate hexokinase, nor does it inhibit Glc-6-Pase.

In summary, vanadate is capable of restoring low lipogenic capacity to normal levels in adipose explants, through a mechanism favoring the formation of Glc-6-P in situ. We are now in the process of analyzing whether this is the mechanism by which vanadate remedies the poor sensitivity of peripheral tissues to insulin in type-II insulin-resistant diabetic rodents (our manuscript, in preparation).


   Acknowledgments
 
We thank Elana Friedman for typing this manuscript and Dr. Sandra Moshonov for editing it.


   Footnotes
 
1 This study was supported in part by grants from the Minerva Foundation (Germany), the Rowland Shaefer Contribution to Diabetes Research, the Levine Fund, Teva Pharmaceutical Fund, and the Israel Academy of Sciences and Humanities. Back

2 Incumbent of the C. H. Hollenberg Chair in Metabolic and Diabetes Research, established by the Friends and Associates of Dr. C. H. Hollenberg of Toronto, Canada. Back

Received November 7, 1997.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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