Increased plasma adiponectin in response to pioglitazone does not result from increased gene expression
Abstract
Plasma levels of adiponectin are lower in obese and insulin-resistant subjects compared with lean and insulin-sensitive ones. Thiazolidinediones increase plasma adiponectin levels in diabetic subjects, although the mechanism of this increased plasma adiponectin has not been well studied. In the present study, we compared the plasma levels and adipose tissue expression of adiponectin in subjects with normal (NGT) and impaired glucose tolerance (IGT) and also studied the effects of metformin and pioglitazone on plasma and adipose tissue mRNA level of adiponectin in IGT subjects. IGT subjects had lower plasma adiponectin levels compared with NGT subjects, and similarly IGT subjects had lower adiponectin mRNA levels. In contrast, the increased plasma levels of adiponectin in response to pioglitazone were not associated with increased adiponectin expression in adipose tissue. Metformin did not cause any change in plasma or expression levels of adiponectin. Other adipokines were examined, and both pioglitazone and metformin decreased plasma levels of resistin in IGT subjects, and pioglitazone (but not metformin) decreased plasma levels of leptin. These data suggest that pioglitazone increases plasma adiponectin levels by posttranscriptional regulation in contrast to transcriptional regulation of adiponectin in relation to insulin sensitivity in NGT vs. IGT subjects.
adiponectin is a 29-kDa adipocyte-specific secretory protein abundant in plasma that has been linked to the insulin resistance of obesity and lipodystrophy (27, 33). Adiponectin is lower in obese and insulin-resistant subjects compared with lean and insulin-sensitive ones (14), and decreased adiponectin is a predictor for the development of type 2 diabetes (16). Among the drugs used to treat patients with type 2 diabetes, the thiazolidinediones [TZD; pioglitazone (PIO), and rosiglitazone] are noteworthy because they improve peripheral and hepatic insulin sensitivity, and they increase plasma adiponectin levels (4, 19, 24, 36, 37). TZDs are agonists of peroxisome proliferator-activated receptor-γ (PPARγ), which is found predominantly in adipose tissue, the major organ of adiponectin expression. Although the mechanism of TZD-mediated improvement in insulin sensitivity is likely complex, one proposed mechanism of action for the TZDs could be a PPARγ-mediated increase in adipose tissue adiponectin expression, followed by peripheral effects of adiponectin on muscle and liver fat oxidation and improved insulin action (13, 30).
Numerous studies have examined the effects of adiponectin on a number of target tissues. Two adiponectin receptors have been described, and the R1 receptor, which demonstrates preference for the globular head form of adiponectin, is abundant in skeletal muscle (13).
Although the above studies suggest that the increase in plasma adiponectin after TZD treatment results in improved muscle lipid oxidation, this question has not been examined in humans. In addition, the mechanism of increased plasma adiponectin by TZDs has not been well studied. Several studies have treated diabetic patients with TZDs and examined adiponectin expression, and the large increase in plasma adiponectin protein level was generally not accompanied by similar increases in mRNA levels (29, 31). Furthermore, previous human studies have generally examined patients with diabetes and have not studied subjects with metabolic syndrome or prediabetic conditions such as impaired glucose tolerance (IGT).
To better understand the regulation of adiponectin, we compared plasma levels and mRNA expression of adiponectin in subjects with normal glucose tolerance and compared them to subjects with IGT. In addition, we treated IGT subjects with the insulin sensitizers PIO and metformin (MET) and examined the plasma level and expression of adiponectin.
MATERIALS AND METHODS
Human subjects.
We recruited generally healthy subjects without diabetes by local advertisement. All subjects provided written, informed consent under protocols approved by the local Institutional Review Board, and studies were conducted at the University of Arkansas for Medical Sciences General Clinical Research Center. After an initial 75-g oral glucose tolerance test, subjects were classified as either normal glucose tolerant (NGT; FBS <6.1 mM, 2-h glucose <7.8 mM) or IGT (2 h glucose 7.8–11.1 mM). A total of 41 subjects were recruited, of which 15 were NGT and 26 were IGT. All subjects were weight stable, 35–65 yr old, with body mass index (BMI) 25–38 kg/m2; 37 were women. Subjects with a history of coronary artery disease, or who were being treated with fibrates or angiotensin-converting enzyme inhibitors, were excluded. Statin therapy was not excluded by protocol, but only two subjects were taking a statin. Excluding these subjects did not alter any of the results. Total body fat percentage was determined by dual-energy X-ray absorptiometry, and insulin sensitivity was measured using an insulin-modified frequently sampled intravenous glucose tolerance test in fasting status. On another day, all subjects underwent an incisional subcutaneous adipose tissue biopsy from the lower abdominal wall and a muscle biopsy from the vastus lateralis under local anesthesia (1% lidocaine) while they were fasting. The subjects with IGT were then randomized to receive either MET or PIO for a 2-wk dose escalation followed by 8 wk at a maximum dose (1,000 mg MET two times daily or 45 mg PIO daily). After 10 wk of treatment, all baseline studies, including the oral and intravenous glucose tolerance tests, and biopsies were repeated. In premenopausal women, the measurement of insulin sensitivity was preformed in the follicular phase to reduce the effect of hormonal variability on insulin sensitivity.
Insulin sensitivity measurement.
Insulin sensitivity was measured by an insulin-modified intravenous glucose tolerance test using 11.4 g/m2 glucose and 0.04 U/kg insulin, as described elsewhere (6). Insulin was measured using an immunochemiluminescence assay (MLT Assay, Wales, UK) in the General Clinical Research Center Core Laboratory. The assay has sensitivity of 0.25 mU/l for insulin, with 1% cross-reactivity with proinsulin and 4%-8% coefficient of variation. Plasma glucose was measured in duplicate by a glucose oxidase assay. Insulin sensitivity was calculated from the insulin and glucose data using the MinMod program (5).
Adipokine measurement.
Plasma adiponectin was measured using ELISA (Linco Research, St. Charles, MO) following the manufacturer's instructions. We also measured the local secretion of adiponectin in the medium. Immediately after the biopsy, adipose tissue pieces of ∼500 mg were minced and placed in serum-free DMEM (pH 7.4, 10 mM HEPES) at 37°C. Adiponectin secretion in medium was measured after 2 h using the ELISA method (Linco Research). Total RNA from adipose tissue was isolated using an RNAeasy Lipid Tissue Mini kit (Qiagen, Valencia CA), following the manufacturer's instruction. The quantity and quality of the isolated RNA was determined by ultraviolet spectrophotometry and formaldehyde-agarose gel electrophoresis, respectively. Total RNA (1 μg) was reverse transcribed using random hexamer primers with TaqMan reverse transcription reagents (Applied Biosystems, Foster City, CA). Reverse-transcribed RNA was amplified with 1× SYBR Green PCR Master Mix (Applied Biosystems) plus 0.3 μM gene-specific upstream and downstream primers during 55 cycles on a Rotor-Gene 3000 Real-Time Thermal Cycler (Sydney, Australia). Each cycle consisted of denaturation at 94°C for 20 s, annealing at 60°C for 20 s, and extension at 72°C for 20 s. Amplified 18S expression was used as standard control to normalize the differences in individual samples. All data were expressed in relation to 18S RNA, where the standard curves was generated using pooled RNA from the samples assayed. The primer sequences were as follows: 18S forward 5′-TTCGAACGTCTGCCCTATCAA-3′, 18S reverse 5′-ATGGTAGGCACG CGACTA-3′; adiponectin forward 5′-ATGCCCAAAGAGGAGAGAGGAA-3′, adiponectin reverse 5′-TGGTCAGAAACAGGCACACAAC-3′.
Plasma leptin and resistin levels were measured using ELISA (Linco Research and American Research Products, Belmont, MA, respectively) following the manufacturer's instructions.
Statistical analysis.
All data are expressed as means ± SE unless otherwise noted. Baseline and posttreatment variables within groups were compared using the paired t-test, and the variables between groups were compared by the unpaired t-test. Data that were not normally distributed were log transformed to normality before analysis. An α level of 0.05 was considered significant. To compare the plasma levels and the adipocyte mRNA expression of adiponectin in NGT and IGT subjects, we included only Caucasian female subjects in both groups to avoid any interference by race or sex.
RESULTS
Adiponectin expression in NGT vs. IGT subjects.
Subjects with IGT and NGT were all Caucasian women, and there were no significant differences in age, BMI, or body fat, as shown in Table 1. However, IGT subjects had higher fasting and 2-h glucose and a higher low-density lipoprotein cholesterol level. Despite there being no significant differences in body fat content or BMI between the two groups, subjects with IGT were more insulin resistant compared with subjects with NGT [insulin sensitivity index (SI) of 1.95 ± 0.26 × 10−5 min−1/pM for IGT and 4.06 ± 0.50 × 10−5 min−1/pM for NGT, P < 0.001]. Plasma adiponectin levels were lower in the IGT group (8.92 ± 0.71 ng/ml, 12.57 ± 1.47 μg/ml, P = 0.04 IGT vs. NGT) despite similar degrees of adiposity. Likewise, adiponectin mRNA levels from subcutaneous adipose tissue were lower in IGT compared with NGT subjects, 0.52 ± 0.14 vs. 1.14 ± 0.23, P = 0.04 for IGT vs. NGT (Fig. 1). Thus the decrease in plasma adiponectin found in IGT subjects was reflected in lower adiponectin mRNA levels, suggesting transcriptional regulation in insulin resistance.
Fig. 1.Plasma levels and the expression of adiponectin message in adipose tissue were lower in impaired glucose tolerance (IGT) compared with normal glucose tolerance (NGT) subjects. *P < 0.05.
| NGT | IGT | P | |
|---|---|---|---|
| Age, yr | 43.0±2.0 | 38.9±2.0 | 0.16 |
| BMI, kg/m2 | 33.1±0.9 | 35.0±0.7 | 0.11 |
| Body fat, % | 43.0±0.9 | 43.7±0.6 | 0.54 |
| Cholesterol, mmol/l | 5.32±0.28 | 4.82±0.30 | 0.23 |
| HDL, mmol/l | 1.51±0.07 | 1.29±0.09 | 0.07 |
| LDL, mmol/l | 3.24±0.27 | 2.45±0.20 | 0.02 |
| Triglyceride, mmol/l | 1.43±0.15 | 2.10±0.31 | 0.07 |
| FBS, mmol/l | 4.51±0.11 | 5.10±0.16 | 0.01 |
| 2-h Glucose, mmol/l | 5.84±0.31 | 9.92±0.38 | <0.001 |
| SI, 10−5 min−1/pM | 4.06±0.50 | 1.95±0.26 | <0.001 |
Treatment of IGT subjects with insulin sensitizers.
Because both adiponectin plasma and mRNA levels were lower in IGT subjects, independent of BMI, we asked whether levels would be restored by interventions that improve insulin sensitivity in IGT subjects. We randomized 26 subjects with IGT to treatment for 10 wk with either PIO or MET. The characteristics of these IGT subjects are shown in Table 2. There were no significant differences of the baseline characteristics of subjects between two groups. SI increased significantly in subjects treated with PIO but not MET (from 1.93 ± 0.17 to 2.93 ± 0.34 × 10−5 min−1/pM, P < 0.001 vs. baseline in PIO group and from 2.33 ± 0.37 to 2.63 ± 0.26 × 10−5 min−1/pM, P = 0.3 vs. baseline in the MET group, Table 2). After treatment, 2-h glucose decreased significantly in the PIO, but not MET, group, although Hb A1C was normal and did not change in either group (Table 2). The PIO subjects gained 2.5 kg, although there was no change in percent body fat. Plasma lipids were unchanged in both groups. Along with improvement in insulin sensitivity, plasma adiponectin and adiponectin secretion from adipose tissue increased significantly after treatment with PIO (8.5 ± 0.7 to 20.5 ± 2.2 μg/ml, P < 0.01 and 0.72 ± 0.12 to 1.3 ± 0.16 μg/g, P = 0.01 respectively, Fig. 2). Surprisingly, the increase in plasma adiponectin levels was not reflected in a change in adiponectin mRNA expression in adipose tissue (Fig. 2). The results were the same if only female subjects were studied. Consistent with the lack of MET effect on SI, MET had no effect on adiponectin plasma levels, adipose adiponectin secretion, or adipose adiponectin mRNA expression (Fig. 2).
Fig. 2.Pioglitazone increased plasma adiponectin 2.5-fold and adiponectin secretion 2-fold but did not have any effect on adiponectin expression. Metformin did not change the adiponectin plasma level, secretion, or expression. *P < 0.001 and †P < 0.01.
| Pioglitazone | Metformin | |
|---|---|---|
| M/F | 1/12 | 3/10 |
| Age, yr | 47.2±2.2 | 49.9±1.6 |
| BMI, kg/m2 | 33.5±1.2 | 33.4±0.9 |
| Body fat, % | 41.8±1.5 | 39.6±2.0 |
| Cholesterol, mmol/l | 5.32±0.41 | 4.55±0.28 |
| HDL, mmol/l | 1.22±0.05 | 1.30±0.11 |
| LDL, mmol/l | 2.76±0.29 | 2.41±0.22 |
| Triglyceride, mmol/l | 2.43±0.44 | 1.82±0.28 |
| FBS, mmol/l | 5.0±0.7 | 5.0±0.6 |
| 2-h glucose, mmol/l | 9.58±0.32 | 9.47±0.42 |
| Post-2 h glucose, mmol/l | 6.7±0.42* | 9.0±0.68 |
| Hb A1C, % | 5.25±0.08 | 5.38±0.18 |
| Post-Hb A1C, % | 5.42±0.12 | 5.34±0.09 |
| Baseline-SI, ×10−5 min−1/pM | 1.93±0.17 | 2.33±0.37 |
| Post-SI, ×10−5 min−1/pM | 2.93±0.34* | 2.63±0.26 |
As shown in Table 3, plasma leptin levels were decreased after PIO but not MET treatment (38.4 ± 3.6 to 32.4 ± 3.2 ng/ml, P = 0.02 in PIO, 33.9 ± 4.8 to 33.3 ± 5.0 ng/ml, P = 0.87 in MET group, Table 3). In addition, the plasma concentration of resistin decreased after both PIO (from 5.4 ± 0.5 to 4.1 ± 0.5 ng/ml, P = 0.06) and MET (from 6.5 ± 0.9 to 5.5 ± 0.7 ng/ml, P = 0.05; Table 3) treatment.
| Pioglitazone | Metformin | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Baseline | Post | P | Baseline | Post | P | |||||
| Plasma adiponectin, μg/ml | 8.45±0.67 | 20.47±2.17 | 0.0003 | 7.90±1.37 | 9.45±2.08 | 0.41 | ||||
| Plasma leptin, ng/ml | 38.36±3.58 | 32.44±3.18 | 0.02 | 33.90±4.77 | 33.34±4.98 | 0.87 | ||||
| Plasma resistin, ng/ml | 5.37±0.50 | 4.05±0.51 | 0.06 | 6.48±0.86 | 5.5±0.65 | 0.05 | ||||
DISCUSSION
Adiponectin is an important adipokine with anti-diabetic, anti-inflammatory, and anti-atherosclerotic properties (32). Adiponectin is secreted only from adipose tissue, and adiponectin levels are paradoxically lower in obese than in lean humans (2, 14). Low levels of adiponectin are associated with insulin resistance and atherosclerosis (12–14), and plasma levels of adiponectin were found to be lower in age- and BMI-matched diabetic patients compared with nondiabetic subjects (11).
Impaired muscle lipid oxidative capacity has been noted to be an early feature of insulin resistance (23). Numerous studies have demonstrated that TZDs improve both peripheral and hepatic insulin sensitivity (4, 7, 9, 10, 18), and other studies demonstrated increased AMPK activity and lipid oxidation by the addition of adiponectin to muscle cells in vitro (30, 35). These and other studies led to a hypothesis suggesting that adiponectin improves insulin resistance through the improvement in tissue lipid oxidation, leading to a decrease in lipotoxicity (13).
Several previous studies have examined the effects of TZDs on adiponectin. TZDs, but not MET, increased adiponectin plasma levels in diabetic subjects (24). Other studies in animals or in vitro (3T3-L1 cells) showed that adiponectin mRNA levels were increased (12, 17). Indeed, one previous study showed markedly enhanced adiponectin gene promoter activity with TZDs (12). Two recent human studies demonstrated increases in adiponectin mRNA levels, but not in proportion to the increase in plasma adiponectin levels. In a study of overtly diabetic subjects, 16 wk of rosiglitazone therapy showed only a 30% increase in adipocyte adiponectin expression but a doubling of the plasma adiponectin level (29). A second study also showed a twofold increase in plasma adiponectin levels after 3 wk of PIO therapy, but only a 70% increase in adiponectin mRNA during a hyperinsulinemic clamp study (31). In contrast to our studies, both of these studies were performed in diabetic subjects in whom a reduction in glucotoxicity might have played a role. Additionally, adiponectin expression in the second study was likely influenced by the high insulin level during the hyperinsulinemic, euglycemic clamp. The IGT subjects in this study had a normal Hb A1C, which did not change during treatment with the insulin sensitizers, although the decrease in 2-h glucose after PIO treatment may have represented a small relief of glucotoxicity.
In the present study, we found that improving insulin sensitivity in the IGT subjects with PIO increased primarily the plasma levels of adiponectin without a significant effect on adiponectin gene expression in subcutaneous adipose tissue. In the IGT subjects treated with PIO, plasma adiponectin levels increased much more than did SI (Fig. 3). The lack of a proportionate increase in SI compared with plasma adiponectin levels in subjects treated with PIO suggests that the improvement in insulin sensitivity by TZDs cannot be solely explained by increased plasma adiponectin levels. In contrast, IGT subjects differed from weight- and sex-matched NGT subjects with respect to plasma adiponectin levels and adipocyte mRNA levels independent of obesity. Both the plasma levels and the subcutaneous adipose tissue mRNA expression were lower in IGT compared with NGT subjects. These findings suggest that TZDs induce translational or posttranslational changes that increase protein levels without increasing mRNA levels. However, the changes in adiponectin plasma levels that accompany metabolic syndrome appear to be reflected by changes in adiponectin mRNA.
Fig. 3.Comparison of plasma adiponectin levels and insulin sensitivity index (SI, ×10−5 min−1/pM) in NGT, IGT and pioglitazone (PIO)-treated subjects. *P < 0.05 NGT vs. IGT (*), NGT vs. IGT + PIO (†), and IGT vs. IGT + PIO (§).
This study measured adiponectin expression only in subcutaneous adipose tissue. One study reported higher adiponectin secretion from visceral adipocytes, along with a greater responsiveness to insulin and rosiglitazone (20), although another study found higher adiponectin secretion and mRNA from subcutaneous fat (15). Although plasma adiponectin correlates with many features of metabolic syndrome, one study found that there was a relatively high correlation between adiponectin and visceral adipose tissue volume (8). Therefore, it is possible that the mechanism of gene expression is different in visceral fat. However, visceral adipose tissue is only a small fraction of total adipose tissue, even in obese subjects (1, 25). Therefore, the effect of PIO to increase adiponectin through posttranscriptional mechanisms in subcutaneous adipose tissue is probably an important means of regulating plasma adiponectin.
Once adiponectin is synthesized, it undergoes posttranslational modifications including hydroxylation and glycosylation (26, 34). Functional analysis of full-length glycosylated mammalian adiponectin has revealed that it was significantly more potent as an insulin sensitizer than the recombinant nonglycosylated bacterial product. In addition, the plasma forms of adiponectin include trimers, hexamers, and high molecular weight forms that likely require considerable cellular assembly and could be subject to regulation (21). Recently, Pajvani et al. (22) showed that treatment of diabetic or prediabetic subjects with troglitazone improved insulin sensitivity and also increased the proportion of the high-molecular-weight forms of adiponectin. Therefore, the posttranscriptional regulation of adiponectin that we demonstrate in this paper may also extend to the cellular formation of complex forms that are then secreted in plasma.
The decrease in resistin by TZDs has been shown previously (3, 28); however, the effect of MET on plasma resistin had not been investigated previously. The mechanism of resistin reduction by MET is unclear. However, because there was no change in SI, this effect of MET may have been mediated though its effects on hepatic insulin sensitivity.
In summary, we showed that insulin resistance in subjects with IGT compared with NGT was associated with decreased plasma adiponectin levels along with lower expression of adiponectin in subcutaneous fat. In contrast, the improvement in insulin sensitivity by PIO was linked to increased plasma adiponectin levels without a significant change in mRNA level. We postulate that PIO regulates adiponectin mainly through posttranscriptional modification in contrast to transcriptional regulation of adiponectin in relation to insulin sensitivity in NGT vs. IGT subjects.
GRANTS
This work was supported by a Veterans Affairs Merit Review Grant, a VISN Career Development Award from the Veterans Administration, and grants from the American Diabetes Association and National Institutes of Health Grants M01 RR-14288 and DK-39176.
FOOTNOTES
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
We thank the nursing and laboratory staff of the General Clinical Research Center at the University of Arkansas for Medical Sciences. We acknowledge the technical support of Tong Lu and Ryan A. Hueter and the secretarial assistance of Sarah Dunn.
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