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Department of Nutrition (W.M.M., K.L.S., J.S.S., P.J.H.), and Department of Pediatrics (F.M.G., C.H.W.), School of Medicine, University of California, Davis, California 95616; and Neurobiology of Aging Laboratories, Mount Sinai School of Medicine (C.V.M., T.M.M.), New York, New York 10021
Address all correspondence and requests for reprints to: Peter J. Havel, D.V.M., Ph.D., Department of Nutrition, University of California, Davis, California 95616. E-mail: pjhavel{at}ucdavis.edu
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Abstract |
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2-Deoxy-D-glucose (2-DG), a competitive inhibitor of glucose transport and phosphorylation, caused a concentration-dependent (2–50 mg/dl) inhibition of leptin release in the presence of 1.6 nM insulin. The inhibitory effect of 2-DG was reversed by high concentrations of glucose. Two other inhibitors of glucose transport, phloretin (0.05–0.25 mM) and cytochalasin-B (0.5–50 µM), also inhibited leptin secretion. Inhibition of leptin secretion by these agents was proportional to the inhibition of glucose uptake (r = 0.60 to 0.86; all P < 0.01). Two inhibitors of glycolysis, iodoacetate (0.005–1.0 mM) and sodium fluoride (0.1–5 mM), produced concentration-dependent inhibition of leptin secretion in the presence of 1.6 nM insulin. In addition, both 2-DG and sodium fluoride markedly decreased the leptin (ob) messenger RNA content of cultured adipocytes, but did not affect 18S ribosomal RNA content.
We conclude that glucose transport and metabolism are important factors in the regulation of leptin expression and secretion and that the effect of insulin to increase adipocyte glucose utilization is likely to contribute to insulin-stimulated leptin secretion. Thus, in vivo, decreased adipose glucose metabolism may be one mechanism by which fasting decreases circulating leptin, whereas increased adipose glucose metabolism would increase leptin after refeeding.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Short term insulin administration does not affect plasma leptin concentrations in human subjects (16, 17), but increases in circulating leptin have been reported after 4–6 h of high dose insulin administration (18, 19). These studies by necessity require the infusion of large amounts of glucose to prevent hypoglycemia. Similarly, prolonged hyperglycemia in response to extended glucose infusions increases plasma leptin after several hours in nonhuman primates (20) and human subjects (21); however, glucose administration also markedly increases endogenous insulin levels. Therefore, the role of insulin per se on the adipocyte vs. the effect of insulin to increase glucose flux into adipocytes was not addressed by these experiments.
Several lines of evidence have led us to hypothesize that glucose is an important regulator of leptin expression and secretion. First, increases in ob messenger RNA (mRNA) after glucose administration in mice are more closely related to plasma glucose concentrations than to plasma insulin concentrations (22). Second, infusion of small amounts of glucose to prevent the decline of glycemia during fasting in humans also prevents the decrease in plasma leptin (2). Third, the decrease in plasma leptin during marked caloric restriction in humans is better correlated with the decrease in plasma glucose than with changes in insulinemia (4). Fourth, we have found that low plasma leptin levels in streptozotocin diabetic rats are acutely increased by insulin administration in proportion to the degree of glucose lowering (23). Lastly, lowering plasma glucose concentrations in hyperglycemic insulin-dependent diabetic human subjects by infusing insulin at rates that produced physiological insulinemia increases circulating leptin (24).
To investigate the mechanisms by which glucose influences leptin secretion, we adapted and modified an in vitro system for culturing rat adipocytes in which the adipocytes are anchored in a defined mixture of extracellular matrix components (25) This matrix, Matrigel, appears to simulate normal basement membrane attachment of cells and may allow cell to cell interactions between adipocytes. Cells cultured in this system are, therefore, in an environment closer to their normal physiological milieu than in systems where adipocytes are free floating in the culture medium. Adipocytes cultured on Matrigel have been shown to maintain many of their differentiated characteristics and, in contrast with free-floating adipocytes, show no sign of dedifferentiation after 6 days of culture (25, 26). With this system we have investigated the regulation of leptin secretion by glucose and insulin and the effects of inhibitors of adipocyte glucose transport and metabolism on leptin secretion. The leptin (ob) mRNA content of the adipocytes after culture with insulin and inhibitors was also examined.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animals
Male Sprague-Dawley rats were obtained from Charles River
(Wilmington, MA). Animals were housed in hanging wire cages in
temperature controlled rooms (22–24 C) with a 12-h light-dark cycle
and fed Purina chow diet (Ralston-Purina, St. Louis, MO) and given
deionized water ad libitum. The study protocol was approved
by the University of California-Davis animal care and use
committee.
Cell isolation/preparation
Adipocytes were prepared from epididymal fat pads of male
Sprague-Dawley rats (300–600 g) anesthetized with halothane.
Epididymal fat depots were resected under aseptic conditions, and
adipocytes were isolated by collagenase digestion according to the
Rodbell procedure (27) with minor modifications as described below. The
fat pads were minced into pieces in Krebs-Ringer HEPES buffer (pH 7.4;
containing 5 mM D-glucose, 2% BSA, 135
mM NaCl, 2.2 mM
CaCl2.2H2O, 1.25 mM
MgSO4·7H2O, 0.45 mM
KH2PO4, 2.17 mM
Na2HPO4, and 10 mM HEPES). Adipose
tissue fragments were digested in the same buffer in the presence of
type II collagenase (2.5 mg/2 ml buffer·g tissue) at 37 C with gentle
shaking at 60 cycles/min for 45 min. The resulting cell suspension was
diluted in 24 ml cold HEPES-phosphate buffer. Isolated adipocytes were
separated from undigested tissue by filtration through a 400-µm nylon
mesh and washed three times. For washing, cells were centrifuged at 500
rpm for 5 min. Each time the infranatant was discarded, and the
adipocytes were resuspended in Krebs-Ringer HEPES buffer, with the
final wash being in 0, 5, or 10 mM glucose culture medium
supplemented with 1% or 5% FBS. The isolated adipocytes were then
incubated for 30 min at 37 C before being plated in Matrigel-coated
culture plates.
Adipocyte culture
Matrigel was thawed on ice to a liquid and uniformly applied to
the surface of the culture dish (300 µl Matrigel/35-mm well). After
the incubation, 150 µl of the adipocyte suspension (2:1 ratio of
packed cells to medium) were plated on the liquid matrix. The warmth of
the cells and buffer caused the Matrigel to gel around the adipocytes,
effectively anchoring them to the culture dish. After a 30-min
incubation at 37 C, 2 ml warm culture medium supplemented with FBS were
added. The cells were maintained in an incubator at 37 C in 6%
CO2 for 96 h.
The initial medium concentration of glucose for the cultures conducted
in the insulin dose-response experiment was 10.0–10.5 mM
(180–190 mg/dl) to ensure that the cells would not deplete the glucose
supply during the 96-h incubation when higher concentrations of insulin
were used. Only 1% FBS was used in the insulin dose-response study to
minimize the small amount of insulin present in the serum, which at 1%
was less than 0.1 µU/ml. In the fructose study, medium made with
glucose-free DMEM and 1% fetal serum was used to minimize the amount
of glucose available to the adipocytes (<0.1 mmol/liter). However, it
was not possible to eliminate all glucose from culture preparation
because the Matrigel matrix itself contains 
4.2 mmol/liter glucose.
For the fructose experiment, the Matrigel was diluted 1:2 with
glucose-free medium to approximately 1.5 mmol/liter glucose.
In the other experiments with inhibitors of glucose transport, 2-DG (28), phloretin (29), and cytochalasin B (30), or with inhibitors of glycolysis, iodoacetate (31), and NaFl (32), the initial medium glucose concentration was (5.0–5.5 mM; 90–100 mg/dl) with 5% fetal serum. These agents were used at concentrations at or below those typically employed to inhibit glucose transport or glycolysis in adipocytes (28, 29, 30, 31, 32). Cytochalasin B was initially dissolved in ethanol and diluted to 0.5% ethanol in the well with the highest dose. Therefore, the medium in all wells in the cytochalasin B experiment was equalized to 0.5% ethanol. Aliquots of adipocytes from each animal were divided into wells with the responses to insulin, the various inhibitors, or fructose being compared with those of an appropriate control well containing adipocytes from the same animal. In a preliminary insulin dose-response study, we found that medium leptin concentrations in the presence of insulin were not increased over those in control medium (no insulin) until after 24 h of incubation. Therefore, for the remainder of the studies, 300-µl samples (15% of the medium volume) were collected at 24, 48, 72, and 96 h and replaced with 300 µl fresh medium containing the appropriate concentrations of glucose, insulin, and/or inhibitors. Cultures were observed daily with a phase contrast microscope. After 96 h, a subset of the culture plates was frozen until analyzed for leptin (ob) mRNA content by Northern blot.
Assays
Leptin concentrations in the medium were determined with a
sensitive and specific RIA for mouse leptin as previously described (7)
(Linco Research, St. Charles, MO). Leptin concentrations in medium from
cultured rat adipocytes measured with this assay are very similar to
those obtained with a newly developed assay specific for rat leptin.
With the rat-specific assay, measured leptin concentrations in culture
medium were 86 ± 3% of the mouse values and were highly
correlated between the two assays (r = 0.97; P <
0.0001; unpublished data). Therefore, measurements of rat leptin made
with the mouse assay provide a reliable measurement of leptin
concentrations. The intra- and interassay coefficients of variation for
this assay are 4.0% and 11.2%, respectively (7). The antibody used in
the assay does not cross-react with insulin, proinsulin, glucagon,
pancreatic polypeptide or somatostatin. Glucose and lactate were
measured with a YSI glucose analyzer (model 2300, Yellow Springs
Instruments, Yellow Springs, OH).
Northern blot procedure
The following procedures were performed on culture plates
incubated with 5 mM glucose and 5% fetal serum alone
(control), 1.6 nM insulin, and 1.6 nM insulin
with 10 mg/dl 2-DG or 1 mM NaFl for 48 and 96 h.
Northern blot analysis was performed as previously described (33). In
brief, 1 ml RNAzol B (Tel-Test, Friendswood, TX) was added directly to
the wells containing the adipocytes and matrix. The solution was
repetitively taken in and expelled from the pipette to maximize
dissolution of the adipose tissue. UV absorbance and integrity gels
were used to estimate RNA. To allow loading of equal mass of RNA in
each well, after analysis of leptin mRNA using a single-stranded
complementary DNA probe followed by quantification of bands on a
phosphoimager as well as from film, the blots were reanalyzed using a
probe complementary to mouse 18S ribosomal RNA. Leptin mRNA was then
normalized with respect to the 18S ribosomal signal, according to the
absolute signal. The 18S RNA results were virtually identical in all
cases. In particular, experimental conditions did not influence the 18S
ribosomal signal.
Calculations and data analysis
The uptake of glucose was assessed by measuring the
concentration of glucose in the medium in each well before and after
96 h of incubation and calculating the decrease over 96 h. To
examine the relationship between adipocyte carbon flux and leptin
secretion in response to increased insulin-mediated glucose uptake, the
amount of carbon released as lactate per amount of carbon taken up as
glucose over 96 h was calculated as 
[lactate]/[glucose],
where is the change, and expressed as a percentage. The area under
the curve for leptin concentrations in the medium between 0–96 h was
calculated by the trapezoidal method. The means of two groups were
compared by paired t test. The means of more than two groups
were compared by ANOVA. To examine the relationships between the medium
concentrations of insulin or inhibitors employed, the amount of glucose
taken up by the adipocytes, and leptin secretion, simple and multiple
linear regression analyses were performed with a statistics software
package (StatView for Macintosh, Abacus Concepts, Inc., Berkeley, CA).
Data are expressed as the mean ± SEM.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). With no
added insulin, the medium glucose concentration decreased from
10.1 ± 0.1 to 8.2 ± 0.3 mmol/liter (, -1.9 ± 0.3
mmol/liter; P < 0.0001). The addition of 0.16, 1.6,
and 16.0 nM insulin increased glucose uptake (glucose,
-2.7 ± 0.4, -3.3 ± 0.3, and -3.9 ± 0.4 mmol/liter,
respectively; all P < 0.01 vs. no insulin).
Insulin also produced a concentration-dependent increase in lactate
production (r = 0.70; P < 0.0001), which was well
correlated with the decrease in glucose in the medium over 96 h
(r = 0. 61; P < 0.0002), suggesting that a
significant portion of the glucose entering the adipocytes was
metabolized only as far as lactate and released from the cells into the
medium (34, 35).
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). The production of lactate was not
related to the leptin response (r = 0.10; P =
0.59). The area under the leptin concentration curve (AUC) from 0–96 h
was independently related to the decrease in glucose in the medium
during the incubation (Fig. 1C), but not to the insulin concentration
(Table 1). Similarly, with a multiple
regression model, the AUC for leptin was related to the decrease in
glucose, but not to the insulin concentration. In addition, the
percentage of carbon released as lactate per amount of carbon taken up
as glucose was calculated. Overall, in the insulin experiment between
10–68% of the amount of carbon taken up as glucose was released as
lactate (mean, 34 ± 2%). There was no direct relationship
between this parameter and the insulin concentration; however, it was
inversely proportional to the amount of leptin secreted, as expressed
by the 0–96 h leptin AUC (r = 0.64; P < 0.0001).
By multiple regression analysis, the relationship between glucose
conversion to lactate and leptin secretion was not significantly
related to lactate production (P = 0.06), but leptin
secretion was equally related to both the change in glucose and the
amount of glucose carbon released as lactate (both P <
0.001).
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, 0.1 ± 0.3 mmol/liter) in the presence of 1.6
nM insulin (glucose, -4.0 ± 0.6 mmol/liter) and
inhibited the leptin response (AUC 0–96 h) by 69 ± 4%
(P < 0.0001) compared with insulin alone (Fig. 2A). At a lower concentration of 2-DG (10
mg/dl), glucose uptake was still markedly inhibited (, -0.1 ±
0.4 mmol/liter) and leptin secretion was inhibited by 47 ± 5%
(P < 0.0001). The lowest concentration of 2-DG (2
mg/dl) produced less of an inhibition of glucose uptake (,
-1.5 ± 0.9 mmol/liter; P < 0.01 vs.
insulin alone). At this concentration, the leptin response was not
significantly inhibited until the 96 h point (P <
0.02 vs. insulin alone; Fig. 2A).
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). By multiple regression, the leptin
concentration in the medium at 96 h was significantly correlated
with the change in glucose, but not to the 2-DG concentration (Table 1). The addition of glucose (55.5 mM) at 48 h reversed
the inhibition of leptin secretion produced by 2-DG at 10 mg/dl by
96 h (P < 0.01 vs. 2-DG; NS
vs. insulin alone; Fig. 2).
Effects of phloretin (0.05–0.25 mM)
The effect of inhibiting glucose uptake with phloretin on leptin
secretion was examined. Phloretin at a concentration of 0.25
mM completely inhibited leptin secretion (Fig. 3). The 0–96 h AUC for leptin was
inhibited by 91 ± 2% of insulin alone (P <
0.0001). This higher concentration of phloretin (0.25 mM)
also completely blocked glucose uptake in the presence of 1.6
nM insulin (glucose, 0.7 ± 0.1 mmol/liter).
Overall, the leptin response was inversely related to the concentration
of phloretin and was highly correlated with the decrease in glucose in
the medium (Table 1). However, by multiple regression, the leptin
response was correlated with the decrease in glucose, but not with the
concentration of phloretin (Table 1). The addition of 55.5
mM glucose at 48 h did not reverse the inhibition of
leptin secretion by phloretin (Fig. 3).
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). The leptin response
was significantly correlated with glucose uptake by simple regression
(Table 1), but was not significantly correlated with glucose uptake (as
observed with the other inhibitors; Table 1) by multiple regression,
perhaps due to the smaller number of replicates (n = 19) in this
experiment.
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glucose,
-0.1 ± 1.1, 0.5 ± 0.2, and 0.3 ± 0.2 mmol/liter,
respectively) and leptin secretion. The 0–96 h AUC for leptin was
inhibited by -95 ± 2%, -91 ± 2%, and -87 ± 3%,
respectively, compared with insulin alone; (all P <
0.0001). The lowest concentration of iodoacetate (0.005 mM)
produced less of an inhibition of glucose uptake (glucose,
-1.8 ± 0.8 mmol/liter) and less of an inhibition of leptin
secretion (-51.0 ± 16%) than insulin alone (P
< 0.02; Fig. 5). By simple regression,
the release of leptin was related to the concentration of iodoacetate
and was highly correlated with the change in glucose in the medium
(Table 1). However, by multiple regression, the leptin secreted at
96 h was related to the change in glucose, but not to the
concentration of iodoacetate (Table 1).
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glucose, 0.2 ± 0.1 and
0.0 ± 0.3 mmol/liter, respectively). The 0.5 mM
concentration of NaFl produced less of an inhibition of glucose uptake
(, -2.1 ± 0.6 mmol/liter), and the lowest concentration (0.1
mM) of NaFl did not inhibit glucose uptake (glucose,
-3.9 ± 0.5 mmol/liter) compared with the effect of insulin
alone. The two highest concentrations of NaFl (5.0 and 1.0
mM) markedly inhibited leptin secretion (-81 ± 6%
vs. insulin alone; P < 0.0001). The next
concentration of NaFl (0.5 mM) produced an intermediate
inhibition of leptin secretion (-47 ± 15% of insulin alone;
P < 0.05). The 0.1-mM concentration of
NaFl did not inhibit leptin secretion (-4 ± 15% vs.
insulin alone; P = NS; Fig. 6).
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). By multiple regression, the amount of
leptin secreted at 96 h was strongly correlated with the change in
glucose in the medium (P < 0.0001), but not to the
NaFl concentration (Table 1).
Effects of insulin, 2-DG, and NaFl on leptin (ob) mRNA and 18S
ribosomal RNA
The effects of inhibiting glucose uptake and metabolism with 2-DG
or NaFl on leptin gene expression and ribosomal 18S RNA were examined.
As shown in Fig. 7A, leptin
(ob) mRNA was detectable in adipocytes incubated for 48
h either with 1.6 nM insulin or without insulin (control).
However, the leptin mRNA signal was reduced to near undetectable levels
when adipocytes were incubated with 1.6 nM insulin and
either 2-DG (10 mg/ml) or 1.0 mM NaFl (Fig. 7A). The effect
of 2-DG and NaFl was specific, because in the same samples there was no
effect of these concentrations of 2-DG or NaFl on 18S ribosomal RNA
(Fig. 7B) or on nonspecific RNA bands (with a different mol wt than
leptin mRNA) that could be detected on the Northern blots after long
exposures (data not shown). Leptin mRNA was significantly reduced by
2-DG or NaFl regardless of whether the signal was normalized for 18S
ribosomal signal (P = 0.0174). Qualitatively similar
effects of 2-DG or NaFl were observed in cultures incubated for 96
h (P = 0.0228; data not shown).
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1.5 mmol/L) in the diluted
Matrigel. However, both the integrated AUC from 0–96 h
(P < 0.02) and the leptin concentration at 96 h
(P < 0.01) were increased by fructose (Fig. 8).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Blockade of glucose transport with 2-DG, phloretin, or cytochalasin B at concentrations at or below those typically used in adipocytes (29, 30) produced a dose-dependent decrease in leptin secretion in the presence of high physiological concentrations of insulin. The competitive inhibition produced by 2-DG could be reversed by the addition of a high concentration of glucose, suggesting that 2-DG did not inhibit leptin secretion via a nonspecific toxic effect on the adipocytes. As expected, the inhibition by phloretin was not reversed by glucose, as phloretin is not a competitive inhibitor and, therefore, produces an irreversible inhibition of glucose transport that is not readily overcome by high glucose concentrations. These experiments provide evidence that glucose uptake is required to increase leptin secretion from isolated adipocytes despite the presence of high physiological insulin concentrations.
Inhibition of glycolysis with either iodoacetate or NaFl at low concentrations (31, 32) also produced concentration-dependent inhibition of leptin secretion in the presence of insulin. When glycolysis is inhibited, glycolytic intermediates accumulate, resulting in a secondary impairment of glucose uptake. As with primary blockade of glucose uptake, during inhibition of glucose metabolism by either glycolytic inhibitor, the amount of glucose taken up over 96 h of incubation was highly correlated with the amount of leptin secreted despite the presence of insulin. These results suggest that the stimulation of leptin secretion by insulin is unlikely to be due to a direct effect of insulin per se, but is secondary to the effect of insulin to stimulate glucose uptake and metabolism in adipocytes.
We also found that inhibition of glucose transport and metabolism with
2-DG or glycolysis with NaFl markedly inhibited leptin (ob)
gene expression, as assessed by Northern blot analysis of leptin mRNA.
In the same cultures, 18S ribosomal RNA levels were unaffected by
either 2-DG or NaFl, suggesting that the decrease in leptin gene
expression was not due to a nonspecific overall effect of these
inhibitors to impair adipocyte RNA synthesis. In addition, we examined
the amount of heparin-released lipoprotein lipase (LPL) from adipocytes
cultured with the various inhibitors (data not presented). Although LPL
was modestly decreased by the inhibitors (25–50% of
insulin-stimulated levels), the suppression of leptin secretion was
significantly greater (80–90%), suggesting a relative specificity of
blocking glucose uptake and metabolism on leptin secretion
vs. that on another protein (LPL) produced by adipose
tissue. Lastly, the effects of the blockers to inhibit leptin
expression and secretion are unlikely to be due to a depletion of
adipocyte energy stores, as it is known that adipocytes can generate
energy (ATP) by oxidizing fatty acids via mitochondrial ß-oxidation
(37, 38).
Taken together, these data suggest a physiological role for glucose in the regulation of leptin expression and secretion by adipocytes. Accordingly, we hypothesize that during fasting, when circulating insulin and glucose concentrations are low and glucocorticoids are elevated, leptin secretion declines secondary to decreased glucose transport into adipose tissue. Upon refeeding, increases in circulating insulin and glucose and the resulting increases in adipose glucose uptake and metabolism stimulate leptin secretion and restores circulating leptin concentrations to prefasting levels. This model, therefore, can explain the effects of fasting and refeeding on circulating leptin in humans (2, 3, 4) and rodents (5, 6, 7). In addition, the nocturnal increase in plasma leptin observed in humans could potentially arise as a delayed consequence of increased insulin-stimulated glucose metabolism following meals (8). The effect of glucose infusions to prevent the fall of plasma leptin during fasting in human subjects may be similarly mediated (2).
Thus, leptin secretion appears to reflect the amount of glucose transported and metabolized by adipose tissue. There is convincing evidence that suggests that a significant portion of glucose entering adipose tissue is metabolized to lactate and released (34, 35). This lactate may contribute to the pool of gluconeogenic precursors during fasting. Our results show that when a smaller proportion of glucose carbon taken up by adipocytes is released as lactate, more leptin is secreted. These data are consistent with the changes in leptin secretion observed during fasting and refeeding. In addition, fructose, in the presence of low glucose concentrations, stimulates leptin secretion, demonstrating that a nonglucose substrate can induce the adipocyte to secrete leptin and suggesting that stimulation of leptin secretion by glucose metabolism occurs downstream of phosphofructokinase.
In summary, blockade of glucose transport or inhibition of glycolysis inhibits leptin secretion from and gene expression in isolated cultured adipocytes. The secretion of leptin is directly proportional to the amount of glucose taken up by the adipocytes. These results suggest that leptin secretion is linked to glucose transport and metabolism and help to explain the known effects of feeding/fasting and long term glucose and insulin administration on circulating leptin concentrations.
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Acknowledgments |
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Footnotes |
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Received July 9, 1997.
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P. Lofgren, I. Andersson, B. Adolfsson, B.-M. Leijonhufvud, K. Hertel, J. Hoffstedt, and P. Arner Long-Term Prospective and Controlled Studies Demonstrate Adipose Tissue Hypercellularity and Relative Leptin Deficiency in the Postobese State J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6207 - 6213. [Abstract] [Full Text] [PDF]
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 S.J. Adamiak, K. Mackie, R.G. Watt, R. Webb, and K.D. Sinclair Impact of Nutrition on Oocyte Quality: Cumulative Effects of Body Composition and Diet Leading to Hyperinsulinemia in Cattle Biol Reprod, November 1, 2005; 73(5): 918 - 926. |
