Rosiglitazone fails to improve hypertriglyceridemia and glucose tolerance in CD36-deficient BN.SHR4 congenic rat strain
Ondrej Seda1,2,
Ludmila Kazdova2,
Drahomira Krenova1 and
Vladimir Kren1,3
1 Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University
2 Institute for Clinical and Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic
3 Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
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ABSTRACT
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The favorable metabolic effects of thiazolidinediones are supposedly related to the peroxisome proliferator-activated receptor-
(PPAR
)-driven changes in lipid metabolism, particularly in free fatty acid (FFA) trafficking. The fatty acid translocase CD36 is one of the proposed PPAR
targets to mediate this action. We assessed the effect of rosiglitazone (RSG, Avandia) administration in two inbred rat strains, BN/Cub and BN.SHR4 congenic strain, differing in 10 cM proximal segment of chromosome 4. Rats were fed high-sucrose diet with or without RSG for 1 wk. In BN.SHR4, which carries defective Cd36 allele of SHR origin, RSG failed to improve glucose tolerance (assessed by the oral glucose tolerance test), did not lower triglyceridemia, nor induced increases in epididymal and retroperitoneal adipose tissue weights and adipose tissue glucose utilization, effects observed in BN/Cub. On the other hand, the RSG-treated BN.SHR4 showed lower concentrations of FFA and substantial increase in glycogen synthesis and glucose oxidation in skeletal muscle. Altogether, these results support involvement of CD36 in RSG action, suggesting this pharmacogenetic interaction may be of particular importance in CD36-deficient humans.
thiazolidinediones; fatty acid translocase; insulin resistance
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INTRODUCTION
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INSULIN RESISTANCE, glucose intolerance, hypertriglyceridemia, elevated concentrations of free fatty acids (FFA) combined with central obesity and hypertension are features of the metabolic syndrome X [or insulin resistance syndrome (IRS)], a condition with rising prevalence in Western-type societies (7). There is compelling evidence that both genetic and environmental factors, including diet, physical (in)activity etc., interact within the process of IRS manifestation (23). In recent years, there has been a rapid spread of thiazolidinedione (TZD) use in therapy of type 2 diabetes and other insulin-resistant states. Although the exact mechanism of TZD insulin sensitizing and other metabolically favorable actions remains to be elucidated, it is reliably established that they act mainly as ligands of peroxisome proliferator-activated receptor-
(PPAR
), a member of the nuclear receptor superfamily (12). PPAR
, originally identified for its crucial role in differentiation and gene expression regulation in adipocytes, was subsequently found to be expressed in other tissues, and a plethora of additional functions were ascribed to it (5).
One of the possible ways for PPAR
-driven systemic actions of TZD involves the impact of PPAR
signaling pathways on control of lipid uptake, transport, storage, and disposal. TZD are, according to this theory, thought to shift the imbalanced FFA partitioning between muscle, liver, and adipose tissues toward a greater FFA uptake in adipocytes, with concomitant boost in new adipocyte differentiation, further enhancing the FFA storage capacity (3). This mechanism is also proposed to underlie the often described side effect of TZD administration, increased adiposity. Two identified PPAR
targets are likely effectors for this action, fatty acid translocase (CD36/FAT) and fatty acid transport protein (FATP). In fact, the CD36 deficiency was already associated with insulin resistance and other IRS attributes in two animal models, the spontaneously hypertensive rat (SHR) (2) and Cd36-null mice (6), documenting its metabolic importance. Since in humans the CD36 deficiency is frequent in populations with high prevalence of type 2 diabetes (although direct association still remains controversial issue) (13, 29), it would be of great interest to determine whether CD36 deficiency can affect the TZD action.
In the SHR, the most widely used model for human essential hypertension expressing also the IRS phenotype, the defective allele of Cd36/Fat was identified as a likely culprit for observed metabolic disturbances using microarray expression profiling and transgenesis (2, 17). Recently, we established a congenic strain, BN.SHR-Il6/Cd36, in which a 10-cM region of SHR chromosome 4 harboring the defective Cd36/Fat allele was introgressed onto genetic background of normotensive Brown Norway rat strain (21). According to Abumrad (1), certain nutritional conditions will need to be part of any real assessment of the role of CD36 in the etiology of insulin resistance, which is probably complex, acting through the "gene-nutrient-gene loop." So far, the studies of Cd36-deficient animals made use of diets rich in carbohydrates (9, 17, 20) and fat (9) to evaluate the extent and nature of such environmental modulatory influences.
In the light of the aforementioned, we analyzed the effect of rosiglitazone (RSG) administration in a high-sucrose diet-fed pair of congenic strains carrying either wild-type (BN/Cub) or defective (BN.SHR4) Cd36/Fat allele.
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METHODS
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Rat strains.
The Brown Norway (BN/Cub) rat strain originated from wild rats captured in the United States at the beginning of the 20th century and was made inbred by Billingham and Silvers (4). Brown Norway rat was transferred from the USA to the Institute of Biology, First Faculty of Medicine in 1964 and since then has been bred by brother x sister mating for more than 70 generations. The metabolic profile of this highly inbred strain has been assessed in several studies (21, 22, 28) and BN/Cub, compared with several models of insulin resistance and dyslipidemia, was found to be markedly "normometabolic" in terms of carbohydrate and lipid metabolism.
BN.SHR-Il6/Cd36 (BN.SHR4) congenic strain was derived by introgressing RNO4 differential segment of the SHR origin onto the BN/Cub genetic background (21). It differs from the BN/Cub progenitor in approximately 10 cM segment of RNO4, containing, among others, the mutant Cd36/Fat allele of SHR origin.
All experiments were performed in agreement with the Animal Protection Law of the Czech Republic (311/1997), which corresponds fully to the European Community Council recommendations for the use of laboratory animals 86/609/ECC.
Experimental protocol.
Male rats (3 mo of age) of the BN/Cub and BN.SHR4 strains were randomly divided into two groups per strain (n = 4 for control groups and n = 6 and 8 for RSG-treated groups, respectively). The rats had free access to water and were fed standard chow followed with either 1 wk of high-sucrose diet (70% calories as sucrose) or the sucrose diet combined with RSG (Avandia, 0.4 mg/100 g total body wt).
Metabolic measurements.
The oral glucose tolerance test (OGTT) was performed after overnight fasting. Blood for glycemia determination was drawn from the tail at intervals of 0, 30, 60, and 120 min after the intragastric glucose administration to conscious rats (3 g/kg total body wt, 30% aqueous solution). Commercially available analytical kits were employed to determine plasma glucose, cholesterol, and serum triglyceride (TG) concentrations (Lachema, Brno, Czech Republic). Serum FFA were determined using an acyl-CoA oxidase-based colorimetric kit (Roche Diagnostics, Mannheim, Germany). Serum insulin concentration was determined using an RIA kit for rat insulin assay (Amersham Pharmacia Biotech UK, Little Chalfont, UK). At the end of experiment, the rats were killed, and the weights of liver, kidneys, epididymal (EFP), and retroperitoneal fat pads (RFP) were determined. A statistical summary of metabolic measurements is provided in Table 1.
Insulin-stimulated glucose oxidation and glycogen synthesis.
The insulin-stimulated glucose oxidation (glucose oxidation) and incorporation of [U-14C]glucose into muscle glycogen (glycogenesis) in soleus, the mostly oxidative muscle, and the insulin-stimulated incorporation of [U-14C]glucose into lipids of adipose tissue (lipogenesis) were determined to directly assess the influence of RSG on insulin sensitivity in these tissues. Basal and insulin-stimulated glucose incorporation into glycogen and CO2 was determined in isolated soleus muscle as described previously (26). After decapitation, the soleus muscles were attached to a stainless steel frame in situ at in vivo length and separated from other muscles and tendons and immediately incubated for 2 h in Krebs-Ringer bicarbonate buffer, at 37°C, gas phase 95% O2 + 5% CO2, pH 7.4, that contained 5.5 mM unlabeled glucose, 0.1 µCi/ml of [U-14C]glucose, and 3 mg/ml BSA (Armour, fraction V) with or without 250 µU/ml insulin. After 2-h incubation, 0.3 ml of 1 M Hyamine hydroxide was injected into central compartment of the incubation vessel and 0.5 ml of 1 M H2SO4 into the main compartment to liberate CO2. The vessels were incubated for another 30 min, the Hyamine hydroxide was then quantitatively transferred into the scintillation vial containing 10 ml of toluene-based scintillation fluid for counting of radioactivity. For measurement of glucose incorporation into glycogen, glycogen from the soleus muscles was extracted as previously described (27). Insulin-stimulated glucose incorporation into adipose tissue was determined as described previously (22).
Liver TG and cholesterol measurements.
For determination of TGs and cholesterol in liver, tissues were powdered under liquid N2 and extracted for 16 h in chloroform:methanol, after which 2% KH2PO4 was added and the solution was centrifuged. The organic phase was removed and evaporated under N2. The resulting pellet was dissolved in isopropyl alcohol, and TGs and cholesterol content were determined by enzymatic assay (Lachema).
Statistical analysis.
Data were analyzed by two-way ANOVA with strain (BN/Cub, BN.SHR4) and treatment (sucrose diet, sucrose diet + RSG) as main factors. For detailed comparisons, post hoc (Tukeys) tests were performed. Data are means ± SE.
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RESULTS
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Effect of RSG on metabolic profile of BN/Cub and BN.SHR4.
ANOVA revealed a significant strain*treatment interaction (P < 0.001) for triglyceridemia. BN/Cub rats treated with RSG showed, as expected, significantly lower nonfasted (postprandial) serum TG levels compared with the control BN/Cub group (P = 0.001). However, no significant difference was found between the treated and untreated groups of BN. SHR4. The RSG-treated BN.SHR4 thus had higher TG than the treated BN/Cub (Table 2). No significant differences were observed in levels of fasting TGs and cholesterol between strains or treatment groups. Surprisingly, both groups treated with RSG exhibited significantly lower FFA concentrations compared with their respective controls (P = 0.011 and P = 0.008 for BN/Cub and BN.SHR4, respectively).
Fasting glycemia was not affected by the RSG treatment in BN/Cub strain; however, it was significantly higher in BN.SHR4 treated with RSG compared with the untreated control group (P = 0.01). Incremental area under the curve (AUC) was lowered by RSG in BN/Cub (P = 0.003), but not in BN.SHR4 (P = 0.07, Fig. 1). The AUC of BN.SHR4 on RSG was thus significantly higher than that of BN/Cub treated group (P = 0.006). We have not observed statistically significant differences in insulin levels between strains or treatment groups.

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Fig. 1. Oral glucose tolerance test in BN (top) and BN.SHR4 (bottom) fed high-sucrose diet with or without rosiglitazone (RSG). Solid and open columns/circles represent measurements in groups fed high-sucrose diet without and with RSG, respectively. The area under the curve (AUC) values are calculated as incremental areas over baseline. Statistical comparison refers to differences between the two diets. *P < 0.05. **P < 0.01.
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Effect of RSG administration on fat depots.
RSG induced significant increase in adiposity index (calculated as EFP wt/100 g total body wt) in BN/Cub (P = 0.009), although no change was observed between the BN.SHR4 experimental groups (Table 2). The relative weight of RFP weight was significantly lower in BN.SHR4 than in BN/Cub treated with RSG (P = 0.003).
Liver TG concentrations were significantly higher in control (P < 0.001) and RSG-treated (P = 0.05) BN.SHR4 compared with the respective BN/Cub groups; RSG-induced decrease was observed only in BN.SHR4 (P = 0.02). No significant effects of strain or treatment factors were observed in liver cholesterol content. Prior to the experimental protocol, the total body weights of the experimental groups were similar. We observed no effect of RSG administration on total body weight, but the relative liver weight was higher in treated vs. untreated BN.SHR4 (P = 0.05).
Effect of RSG on insulin action in tissues.
When fed high-sucrose diet, BN.SHR4 exhibited significantly higher utilization of glucose in adipose tissue compared with the BN/Cub both in absence and presence of insulin (P = 0.032 and P = 0.001, respectively). However, the RSG administration induced significant increase in insulin-stimulated lipogenesis in BN/Cub (P = 0.046), whereas no effect was observed in BN.SHR4 (Fig. 2A). The insulin-stimulated glycogenesis and glucose oxidation were both more substantially increased by RSG in BN.SHR4 than in BN/Cub (53 vs. 140% and 8 vs. 51%, respectively). Therefore, insulin-stimulated glycogenesis and glucose oxidation were higher in RSG-treated BN.SHR4 compared with RSG-treated BN/Cub (Fig. 2, B and C).

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Fig. 2. Incorporation of [U-14C]glucose into adipose tissue (A), glycogen synthesis (B), and glucose oxidation (C) in soleus muscle in BN and BN.SHR4 fed high-sucrose diet with or without RSG. Solid and open columns represent measurements in groups fed high-sucrose diet without RSG and with RSG, respectively. Statistical comparison refers to differences between the two diets. Units are nmol glucose per mg protein per 2 h for lipogenesis, and nmol glucose per g per 2 h for glycogenesis and glucose oxidation. Presence or absence of insulin in the medium is indicated. *P < 0.05. **P < 0.01.
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DISCUSSION
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RSG treatment has been shown to reduce hypertriglyceridemia and to improve the insulin-mediated glucose utilization in human type 2 diabetes patients and several animal models of type 2 diabetes and IRS (14, 16). Although the exact mechanism of TZD insulin-sensitizing action is not clear, evidence is mounting that the activation of PPAR
and its downstream targets involved in lipid and carbohydrate metabolism and trafficking may represent a major contribution to the final effect of TZD administration. Among the RSG-regulated genes of considerable importance is CD36/FAT, preferentially expressed in tissues with high fatty-acid processive capacity (10, 24, 25). It has been suggested that by enhanced expression of CD36/FAT (and FATP) in adipose tissue, the flux of FFA to muscle, heart, and liver is diminished and better insulin sensitivity is achieved at the cost of rise in adiposity. In SHR, the defective allele of Cd36/Fat was identified by linkage and microarray studies, and transgenic rescue proved its detrimental effect on SHR metabolism (17). Only recently Hajri et al. (8) assessed the extent of functional defect in CD36/FAT, concluding that SHR indeed exhibits loss of CD36 function in fatty acid uptake in the adipose, heart, and oxidative muscle tissues. The SHR was shown to bear additional genetic variations contributing to the IRS phenotype (19), and some of them, like a mutation in sterol regulatory element binding protein-1c (SREBP-1c) (18), are directly involved in the regulation of fatty acid metabolism. Therefore, we used a congenic strain, carrying only 10-cM region of SHR origin with the defective Cd36/Fat allele. The observed differences between BN/Cub and BN.SHR4 are thus attributable to gene(s) present in the differential segment, with Cd36/Fat being the most likely candidate.
The BN.SHR4 fed high-sucrose diet showed excessive hepatic TG accumulation, similar to that observed in Cd36-null mice fed high-fructose diet (9). This possibly reflects impaired peripheral utilization of FFA and their enhanced flux to liver. Subsequently, the RSG administration lowered the hepatic TG content in BN.SHR4, but not the postprandial TG levels. Oakes et al. (15) reported that, in ZDF rats, the TG-lowering action of RSG was due to the lowered hepatic TG production and accelerated removal of TG from very low-density lipoprotein (VLDL) particles, constituting two separate kinetic effects. In the same study, the lowered hepatic TG output was, according to authors, possibly mediated by RSG-induced reductions in intrahepatic TG stores, important source of lipids for VLDL assembly. In our study, FFA levels were significantly reduced by RSG in both strains, but only BN/Cub displayed increase in adiposity. This is consistent with the proposed function of CD36 as a fatty-acid transporter, suggesting that the Cd36-mediated FFA flow into adipocytes was blunted in BN.SHR4. Moreover, the insulin-stimulated adipose tissue glucose utilization was not changed and the baseline lipogenesis was even lowered by RSG in BN.SHR4, contrasting again with BN/Cub. The observed increase of fasting glycemia of RSG-treated BN.SHR4 may be thus due to the increased hepatic glucose production under conditions of enhanced influx of FFA. Notably, the absolute extent of glucose utilization in adipose tissue was, as well as the insulin-stimulated glycogenesis and glucose oxidation in soleus muscle, higher in BN.SHR4 than in BN/Cub, documenting the switch toward a greater glucose utilization in the presence of FFA trafficking defect. These observations were consistent with studies in Cd36-null mice (9) and with reported RSG-induced GLUT-1 protein increase in adipose tissue of Zucker rats (11). Taken together, we can hypothesize that the defect in Cd36-mediated transport of FFA favored their Cd36-independent utilization, i.e., the induced production of glucose and TG-rich VLDL in liver, leading to the observed elevated levels of serum TG and glucose. However, direct methods of measurement would be needed for ascertainment of such effect.
A recent study by Qi et al. (20) shows distinct metabolic actions of pioglitazone on SHR (Cd36-deficient), SHR.BN4 congenic rat and SHR transgenic (both carrying wild-type Cd36) rat strains. Interestingly, several observed effects (adiposity, glucose oxidation) are not shared with our study. This shows the involvement of gene-gene interactions in TZD action, i.e., the importance of genetic background, and may possibly indicate intra-class differences among TZD drugs (pioglitazone vs. RSG).
This study points out the substantial role of intact Cd36 in RSG action and further supports the importance of FFA concentration and fluxes in insulin resistance. Although it is not possible to make direct extension to human CD36 deficiency, the described pharmacogenetic interaction with TZD therapy should be taken into account when treating type 2 diabetes in CD36-deficient patients.
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ACKNOWLEDGMENTS
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We thank Marie Uxova, Zdena Kopecka, and Michaela Janku for technical assistance.
This work was supported by Grant Agency of Charles University Grant 7/2000/C, Grant Agency of the Czech Republic Grants 303/01/1010 and 204/98/K015, and Internal Grant Agency of the Ministry of Health of Czech Republic Grant 6367-3.
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FOOTNOTES
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Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).
Address for reprint requests and other correspondence, and present address of O. Seda: Laboratory of Molecular Medicine (7-017), Research Centre, Centre Hospitalier de lUniversité de Montreal, 3850 St-Urbain, Montreal, Quebec H2W 1T8, Canada (E-mail: oseda{at}aol.com).
10.1152/physiol-genomics.00113.2002.
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