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From the Clinical Research Centers |
Divisions of Endocrinology and Metabolism (R.V.C., L.B.W., R.L.F., P.Z.) and Biostatistics (W.T.A.), Department of Medicine, and Department of Surgery (R.M.W., R.M.J.), Indiana University School of Medicine, Indianapolis, Indiana 46202; Department of Surgery, St. Vincent’s Hospital (R.M.J., M.I., J.H.), Carmel, Indiana 46032; and Division of Endocrinology and Metabolism, Department of Medicine, University of Utah School of Medicine (R.C.C., D.A.M.), and Veterans Affairs Medical Center, Salt Lake City, Utah 84132
Address all correspondence and requests for reprints to: Robert V. Considine, Ph.D., Indiana University School of Medicine, 541 North Clinical Drive, Clinical Building 455, Indianapolis, Indiana 46202-5111. E-mail: rconsidi{at}iupui.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several lines of evidence suggest that glucose is an important determinant of leptin production. In cultured rat adipocytes leptin release is highly dependent on the extent of glucose utilization in the presence of different insulin concentrations, and inhibitors of glucose transport block leptin production (4). In vivo, 3 h of hyperglycemia with normal insulinemia increases serum leptin in rats (3). Serum leptin in humans is elevated by prolonged (9-h) euglycemic- hyperinsulinemic clamps at physiological insulin concentrations (5) or within 4–8 h with supraphysiological insulin concentrations (6, 7). Short-term fasting results in a significant reduction in serum leptin, an effect that can be attenuated by the infusion of glucose (8, 9). Taken together, these observations suggest that glucose metabolism regulates leptin production in adipocytes, an effect that could be mediated through the hexosamine biosynthetic pathway.
The first and rate-limiting step in the synthesis of UDP-N-acetylglucosamine is catalyzed by glutamine:fructose-6-phosphate amidotransferase (GFAT), which transfers the amido group from glutamine to fructose-6-phosphate, forming glucosamine-6-phosphate. Several additional nonrate-limiting enzymatic steps yield UDP-N-acetylglucosamine. Approximately 2–3% of glucose uptake into the cell enters the hexosamine biosynthetic pathway. Cellular UDP-N-acetylglucosamine content can be increased by treatment with exogenous glucosamine, which enters the biosynthetic pathway distal to the GFAT-catalyzed step, and decreased with 6-diazo-5-oxo-L-norleucine, a competitive inhibitor of GFAT that reduces the entry of fructose-6- phosphate into the pathway (10). The hexosamine biosynthetic pathway has been implicated in the development of insulin resistance in skeletal muscle and adipose tissue of rodents and in skeletal muscle in humans (10).
Recently, Wang et al. (3) suggested that hexosamine biosynthesis regulates leptin release in rats. These investigators found that infusion of glucosamine, uridine, or free fatty acids during a 3-h euglycemic hyperinsulinemic clamp significantly increased ob gene expression in the adipose tissue and leptin in the plasma of rats compared to those in saline-infused controls clamped under identical conditions. UDP-N-acetylglucosamine in the skeletal muscle was increased, and it was inferred from this observation that UDP-N-acetylglucosamine in the adipose tissue was also elevated. We recently observed that serum leptin and ob gene expression in the adipose tissue are increased (11) in a transgenic mouse model overexpressing GFAT in skeletal muscle and adipose tissue (12).
The following studies were undertaken to demonstrate that the hexosamine biosynthetic pathway regulates leptin production in human sc adipose tissue. We found that 1) hexosamine biosynthesis results in increased leptin release; 2) inhibition of hexosamine biosynthesis reduces leptin production; and 3) there is a significant positive correlation between body mass index (BMI) and adipose tissue UDP-N-acetylglucosamine and between leptin and UDP-N-acetylglucosamine in humans. These findings provide strong support for hexosamine-regulated leptin production in human adipose tissue.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Adipose tissue used for the determination of UDP-N-acetylglucosamine and ob gene expression was obtained primarily by needle liposuction. In the lean group (BMI, <27 kg/m2), 12 biopsies were obtained by needle, and 2 from surgery. In the obese group (BMI, >27 kg/m2), 11 biopsies were obtained by needle, and 6 from surgery. All samples were immediately transported to the laboratory and frozen at -70 C before use.
For the in vitro experiments, adipocytes were isolated from adipose tissue biopsies obtained during bariatric surgery or by needle liposuction. Samples were from 31 obese subjects (29 women and 2 men; BMI, 49.9 ± 10.0 kg/m2; age, 41 ± 11 yr; 26 Caucasion and 5 African American) and 6 lean subjects (2 women and 4 men; BMI, 23.2 ± 1.6 kg/m2; age, 34 ± 11 yr; 3 Caucasion and 3 African American). Of the 31 adipose tissue samples from obese subjects used for the in vitro experiments, 2 were obtained from subjects with type 2 diabetes. Results from these 2 samples were not different from those for the nondiabetic subjects and were thus included in the analyses. Adipocytes were isolated by collagenase (Worthington Biochemical Corp., Freehold, NJ) digestion (13) and cultured (2 mL packed cell volume) in 10 mL DMEM without glucose or glutamine in 125 mL polycarbonate flasks at 37 C and 95% O2/5% CO2. BSA, glucose, and glutamine were added to the medium for each experiment as described in Results. Medium was replaced with fresh medium every 24 h. Culture medium (D5030), glucosamine (G4875), inosine (I4125), and 6-diazo-5-oxo-L-norleucine (D2141) were purchased from Sigma (St. Louis, MO). Sodium azide (BP922–500) was obtained from Fisher Scientific (Fair Lawn, NJ), and BSA (160069) was purchased from ICN Biomedicals, Inc. (Aurora, OH). Culture flasks were obtained from Corning, Inc. (Corning, NY).
Leptin was measured in the serum of subjects and in the medium of cultured adipocytes with a commercially available RIA kit (Linco Research, Inc., St. Charles, MO). Serum samples were obtained in the morning (0700–0900 h) after an overnight fast. The limit of detection of this assay is 0.5 ng/mL. The within- and between-assay coefficients of variation are 4.6% and 5.0%, respectively, at 7.2 ng/mL. Leptin was not determined for four subjects in which adipose tissue hexosamines were measured due to the lack of a serum sample. Culture medium contained no detectable leptin.
UDP-N-acetylglucosamine was quantitated as previously described (11). Briefly, adipose tissue was lysed with 4 vol 300 mmol/L perchloric acid (300 mmol/L), the mixture was vortexed, and precipitates were pelleted by centrifugation for 15 min at 10,000 x g. The supernatant was extracted with 2 vol tri-n-octylamine:1,1,2-trichloro-trifluoroethane (1:4) and then filtered (0.45 µm pore size). High performance liquid chromatography was performed on a 4.6 x 250-cm Partisil SAX anion exchange column (Whatman, Clifton, NJ). UDP-N-acetylglucosamine was eluted with a concave gradient of potassium phosphate (0.005 mol/L, pH 8, to 1 mol/L, pH 4.5) over 48 min at a flow rate of 1 mL/min. The peak corresponding to the elution position of UDP-N-acetylglucosamine was quantitated by UV absorption (A254) and compared to external standards. UDP-N-acetylglucosamine was normalized to the protein content of the extract before addition to the column.
The ob messenger ribonucleic acid (mRNA) was determined by RT-PCR as previously described (14). All comparisons between samples were made on the linear portion of the amplification curve (between cycles 20–35), and no product was obtained in the absence of reverse transcriptase. The data are expressed as the ratio of ob complementary DNA (cDNA) to actin cDNA. There was no difference in the amount of actin cDNA among the samples studied. ob gene expression was not determined in six samples due to poor RNA quality.
All data in the text and tables are the mean ± SD. Comparisons of lean and obese subjects were made using a two-sample t test for UDP-N-acetylglucosamine and the Wilcoxon rank-sum test for BMI, serum leptin, and ob gene message (the SDs within the two groups were not equal). Spearman’s correlation coefficient was used to describe the relationship between BMI and UDP-N-acetylglucosamine and between leptin and UDP-N-acetylglucosamine. Analysis of covariance (ANCOVA) was used to predict UDP-N-acetylglucosamine, using gender and BMI as predictors, and to predict leptin, using UDP-N-acetylglucosamine and BMI as predictors. The logarithm of the response variable was used in these models. The partial coefficient of determination (15) was used to quantify the predictive ability of the independent variables. It can be interpreted as the proportion of the residual variance explained by that predictor after adjusting for the other predictors. The effects of glucosamine and 6-diazo-5-oxo-L-norleucine (DON) on leptin production and ob gene expression at 24 and 48 h were tested using a one-sample t test on the percent change between treatment and control groups. The percent change was used because the raw changes were not normally distributed. No adjustments for multiple comparisons were made. n denotes one comparison (control and treatment) for adipocytes from one individual.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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UDP-N-acetylglucosamine was quantitated in sc adipose
tissue from 14 lean (11 women and 3 men; BMI, <27
kg/m2; age, 33 ± 11 yr) and 17 obese (10
women and 7 men; BMI, >27 kg/m2; age, 31 ±
5 yr) subjects. As shown in Fig. 1
, there
was a significant correlation between the
UDP-N-acetylglucosamine content of the sc adipose tissue and
BMI. Gender did not have a significant effect on adipose tissue
UDP-N-acetylglucosamine content after adjustment for BMI. A
significant correlation also existed between serum leptin and
UDP-N-acetylglucosamine (Spearman correlation = 0.465;
P = 0.0145; Fig. 2). On
the average, UDP-N-acetylglucosamine in obese subjects was
significantly elevated 3.2-fold over that in lean subjects (Table 1). Serum leptin in obese subjects was
elevated 2.7-fold, and ob gene expression in the adipose
tissue obtained from obese subjects was significantly increased 2-fold
over that in the lean.
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Glucosamine stimulates leptin production
To demonstrate that UDP-N-acetylglucosamine synthesis
results in increased leptin production, adipocytes isolated from
morbidly obese subjects (BMI, 55.4 ± 13.0
kg/m2; n = 9) were cultured with glucosamine
in the absence of glucose and glutamine (glucosamine competes poorly
with glucose for uptake into the cell). In the absence of extracellular
glucose, leptin released into the medium was significantly greater at
48 h than at 24 h (Fig. 3),
demonstrating the viability of the cells under these culture
conditions. The addition of 1 mmol/L glucosamine to the medium
increased leptin release 33.3 ± 55.4% over the control value
within the first 24 h of treatment (P = 0.109).
Glucosamine-stimulated leptin release increased to 74.5 ± 82.8%
over the control level by 48 h of culture (P =
0.0271). Culture of adipocytes from lean subjects (BMI, 23.2 ±
1.6 kg/m2; n = 6) with glucosamine also
resulted in a significant increase in leptin release by 48 h of
treatment (3.7 ± 2.2 vs. 4.5 ± 2.6 ng/mL leptin
released by control and treated cells, respectively,=;
P = 0.0365). As a percent increase over control, there
was no difference in glucosamine-stimulated leptin production between
adipocytes from lean and obese subjects.
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In the second experiment sc adipocytes (BMI, 44.0 ± 1.0 kg/m2; n = 3) were cultured for 48 h in DMEM (no glucose or glutamine) and 6 mmol/L sodium azide, a potent mitochondrial toxin that depletes ATP stores. Exposure to sodium azide resulted in an almost complete inhibition of leptin production within the first 24 h of treatment (4.51 ± 0.74 vs. 0.45 ± 0.09 ng/mL leptin released; P = 0.0002; n = 3), which was maintained to 48 h (8.81 ± 0.78 vs. 0.76 ± 0.09 ng/mL leptin released; P = 0.0002; n = 3). Based on the observations in these two experiments it is unlikely that glucosamine increases leptin production from human sc adipocytes through a reduction in intracellular ATP.
DON attenuates leptin production
DON is a competitive inhibitor of GFAT that reduces the flux of
glucose through the hexosamine biosynthetic pathway. Subcutaneous
adipocytes from morbidly obese subjects were cultured in DMEM
containing 1 g/L glucose, 0.584 g/L glutamine, and 1% BSA. As shown in
Fig. 4, 20 µmol/L DON significantly
attenuated leptin release from sc adipocytes 21.8 ± 32.4%
(P = 0.0395; n = 12) by 48 h.
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, the amount of ob mRNA in
adipocytes was reduced 19.9 ± 18.9% by 48 h of DON
treatment, suggesting that hexosamines regulate leptin production
through effects on the transcription or stability of ob
mRNA.
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Discussion |
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Leptin is not stored to any appreciable extent in adipose tissue, and its synthesis and release therefore appear to be determined by the amount of ob gene message present in the cells. ob gene expression and leptin release are greater in adipocytes from obese subjects than in those from lean individuals (14, 17), a finding attributed in part to the larger size of the adipocytes from the obese subjects. In support of this, ob gene expression is greater in larger adipocytes than in the smaller adipocytes isolated from the same piece of adipose tissue (18), and leptin secretion in vitro correlates strongly with fat cell volume (19). In the current study, UDP-N-acetylglucosamine and ob gene expression were significantly greater in adipose tissue of obese subjects, a finding suggesting that elevated hexosamines could contribute to the increase in ob gene expression. However, due to variability in both ob gene expression and UDP-N-acetylglucosamine content of the adipose tissue, a significant linear correlation between UDP-N-acetylglucosamine and ob gene expression was not found in our study population (Spearman’s correlation = 0.2720; P = 0.1884). This variability may be due to differences in the number and size of adipocytes in the biopsies from different individuals (20). For example, adipose tissue comprised of many small adipocytes would have lower ob gene expression but greater UDP-N-acetylglucosamine content than an equivalent amount of tissue comprised of fewer, but larger, adipocytes. To minimize the variability in the measurement of ob gene expression and hexosamines and to more fully investigate the relationship between these two measures, experiments using isolated adipocytes from lean and obese subjects will be needed.
The finding that adipose tissue UDP-N-acetylglucosamine is not a significant predictor of serum leptin after adjusting for BMI in the ANCOVA is disappointing, but perhaps not unexpected. Serum leptin is the sum of leptin release from adipose tissue located throughout the body, of which BMI provides a measure. The UDP-N-acetylglucosamine quantitated in an adipose tissue biopsy from a single fat depot, although highly correlated with BMI, is not a measure of the entire mass of adipose tissue in the body. Therefore, BMI is a better predictor of leptin than UDP-N-acetylglucosamine because it is a better measure of total body adiposity. Despite this, the significant correlation between UDP-N-acetylglucosamine and BMI suggests that hexosamines increase as the number and/or size of the adipocytes in the adipose tissue increase, thus providing a signal for leptin production.
As observed previously, gender is a significant predictor of serum leptin after accounting for BMI (14). However, gender does not have a significant effect on adipose tissue UDP-N-acetylglucosamine content. This finding might suggest that the effect of gender on serum leptin levels is not directly mediated through hexosamine biosynthesis. However, additional studies will be needed to fully address this point.
To directly test the role of UDP-N-acetylglucosamine in
leptin production, we incubated adipocytes in 1 mmol/L glucosamine to
increase the intracellular content of
UDP-N-acetylglucosamine. Glucosamine significantly increased
leptin production 21.4 ± 17.6% and 74.5 ± 82.8% over the
control value by 48 h in adipocytes from lean and obese subjects,
respectively. These increases in leptin production, induced by
manipulation of hexosamine biosynthesis in vitro, are
consistent with the magnitude of change seen in serum leptin under
normal physiological conditions in vivo. Over the course of
the day serum leptin gradually increases only approximately 30% over
the morning fasting value in both lean and obese subjects (21).
Although larger changes in serum leptin can be achieved by fasting for
24–36 h [
65% reduction (8, 9)] or with pharmacological doses of
dexamethasone [2-fold increase within 16 h (22, 23)], these
conditions reflect the extremes for leptin production in humans.
Therefore, the magnitude of the hexosamine-induced change in leptin
production that we observed in vitro appears to be
reasonable and physiologically relevant.
Glucosamine treatment has been extensively used to model the desensitization of insulin-stimulated glucose uptake induced by hyperglycemia or hyperlipidemia (10). It has been generally accepted that the ability of glucosamine to induce insulin resistance is mediated through the production of UDP-N-acetylglucosamine, although the exact mechanism through which hexosamines inhibit glucose transport has not been completely elucidated. However, Hresko et al. (16) recently reported that glucosamine, at concentrations routinely used to attenuate insulin-stimulated glucose transport, significantly reduces ATP in 3T3-L1 adipocytes. These researchers provide evidence to suggest that the glucosamine-mediated reduction in intracellular ATP is responsible for inhibition of glucose uptake, and that this effect of glucosamine is independent of UDP-N-acetylglucosamine synthesis. To rule out the possibility that glucosamine stimulated leptin production from adipocytes through the depletion of ATP in our studies, adipocytes were cultured with the mitochondrial toxin sodium azide. Exposure to sodium azide resulted in almost complete inhibition of leptin production. In other words, ATP depletion leads to reduced leptin production, and it is therefore unlikely that 1 mmol/L glucosamine increases leptin production from adipocytes through a toxic effect to reduce ATP. Hresko et al. (16) have also shown that the addition of 20 mmol/L inosine to the culture medium as an alternative energy source almost completely prevents the reduction in ATP in 3T3-L1 cells induced by 1 mmol/L glucosamine. In our studies 1 mmol/L glucosamine significantly increased leptin production in the presence of inosine as an alternative energy source. Our data are therefore consistent with the idea that a glucosamine-mediated increment in UDP-N-acetylglucosamine results in increased leptin production.
DON is a competitive inhibitor of GFAT, the rate-limiting enzyme in UDP-N-acetylglucosamine synthesis. At a concentration of 20 µmol/L, DON significantly inhibited leptin production. These data are consistent with the hypothesis that a reduction in cellular UDP-N-acetylglucosamine results in a reduction in leptin synthesis. As discussed above, the elevated UDP-N-acetylglucosamine content of adipocytes from obese subjects may influence the kinetics of the DON-induced reduction in UDP-N-acetylglucosamine and may explain our observation that 48 h of treatment are required to observe a significant DON-induced reduction in leptin release. Much more likely, however, these observations suggest that UDP-N-acetylglucosamine is not the only regulator of leptin production, as inhibition of GFAT, which should be maximal at 20 µmol/L, does not completely inhibit leptin production.
Taken together, our in vitro observations with glucosamine and DON suggest that hexosamine biosynthesis regulates leptin production. However, it is important to note that these are pharmacological manipulations and that glucosamine and DON could have effects on metabolism other than regulation of hexosamine biosynthesis. As discussed above, glucosamine may reduce the intracellular ATP content of the adipocyte. DON, as an inhibitor of glutamine transamidases (24), could have altered the activity of enzymes other than GFAT, which could influence leptin production. Evidence in support of the specificity of our in vitro observations is provided by a transgenic mouse model that overexpresses GFAT in skeletal muscle and adipose tissue (12). UDP-N-acetylglucosamine and ob gene expression in the epididymal fat pad of GFAT-overexpressing mice are significantly increased compared to those in wild-type control mice of similar body weight. This increase in ob gene expression results in greater serum leptin in the transgenic mice (11). These observations demonstrate that increased flux through the hexosamine biosynthetic pathway does indeed increase leptin release from the adipose tissue and is consistent with our in vitro findings.
UDP-N-acetylglucosamine has been implicated in the regulation of transcription (25). O-Linked glycosylation is the covalent linkage of N-acetylglucosamine, derived from UDP-N-acetylglucosamine, to serine or threonine residues of proteins. In many cases O-GlcNac transferase may modify amino acids that can also be phosphorylated. Evidence suggests that O-linked glycosylation/deglycosylation may provide a regulatory function analogous to protein phosphorylation/dephosphorylation or, alternatively, that O-linked glycosylation may regulate the extent of phosphorylation by blocking sites of modification (26). The transcription factors Jun, Fos, HNF1, c-Myc, Sp1, p53, and others have all been identified to contain O-linked N-acetylglucosamine, and this modification may influence the activities of these factors (26). O-Linked glycosylation of transcription factors specific for the ob gene promoter may be the mechanism through which hexosamines regulate leptin production.
In summary, the current study demonstrates for the first time in human adipose tissue that 1) there is a significant positive correlation among BMI, serum leptin, and adipose tissue UDP-N-acetylglucosamine; 2) UDP-N-actylglucosamine synthesis increases leptin release; and 3) inhibition of hexosamine biosynthesis reduces leptin production. These findings provide evidence that UDP-N-acetylglucosamine acts as an intracellular signal that regulates leptin synthesis and release in human adipocytes.
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Acknowledgments |
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Footnotes |
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Received March 2, 2000.
Revised May 31, 2000.
Accepted June 26, 2000.
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