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Departments of Pharmacology and Pathology, Amgen, Inc., Thousand Oaks, California 91320
Address all correspondence and requests for reprints to: Zhi-Qing Shi, M.D., Ph.D., Department of Pharmacology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, California 91320. E-mail: jshi{at}amgen.com
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Introduction |
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The objective of this study was to examine our hypothesis that leptin may have differential, tissue-specific effects on glucose utilization in vivo. This study focuses on the chronic effect of leptin on regulation of glucose transport in insulin-sensitive tissues such as muscle and adipose tissues. As the GLUT-4 glucose transporter is considered to be the primary and regulatable transporter species in these tissues (15), we have examined the effect of leptin on GLUT4 mRNA and protein expression in these tissues. Brown adipose tissue (BAT) has been identified as a major site of thermogenesis, and leptin treatment increases uncoupling protein expression and heat production (16). The effect of leptin on oxygen consumption in brown adipocytes was also studied.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-32P]UTP was obtained from Amersham
(Arlington Heights, IL). The Maxi Script SP6/T7 Transcription Kits and
the RPA II ribonuclease protection assay kits were obtained from
Ambion, Inc. (Austin, TX). D-Glucose, Somogyi
reagents, and protein A-peroxidase were purchased from Sigma Chemical Co. (St. Louis, MO). Regular pork insulin was obtained
from Eli Lilly & Co. (Indianapolis, IN).
Experimental animals
Male Sprague Dawley rats (275–350 g BW) were obtained from
Harlan Sprague Dawley, Inc. (San Diego, CA). Animals were
housed in separate cages in temperature-controlled rooms (22–24 C)
with a 12-h light, 12-h dark cycle and were fed regular rat chow. Two
experimental protocols were used. In the protocol for 2-DG uptake
measurements, rats received chronic cannulation of the left carotid
artery and right jugular vein as described previously (9). In the
meantime, Alzet osmotic pumps were implanted sc which delivered
r-Met-MuLeptin (4 mg/kg·day; n = 12) or phosphate buffer vehicle
(V; n = 8) for 5 days. Another group of rats receiving vehicle
infusion was pair-fed (PF; n = 9), with the amount of daily food
consumption matching that of leptin-treated animals. Body weight and
food intake were monitored every day. In another protocol for
determination of glucose transporter mRNA and protein expression, three
groups of rats (leptin, V, and PF) received corresponding osmotic pump
implantation 5–7 days before the ribonuclease protection assay and
Western blot analysis. Animals were killed by cervical dislocation
after a 5-h fast, and all tissues were processed at the same time in a
side by side fashion.
Measurement of glucose utilization in muscle and adipose tissues in
vivo
The in vivo glucose uptake rate in individual
tissues was determined and calculated from the measurement of 2-DG
uptake under the conditions of a hyperinsulinemic euglycemic clamp
(17, 18, 19, 20, 21, 22, 23). The experiments were carried out in unrestrained conscious
rats. Animals were fasted 5–6 h before the experiments. Contents in
the vascular cannulas were aspirated, and the cannulas were extended
with PE-50 plastic tubings and flushed with fresh heparinized (10 U/ml)
saline. Basal arterial blood samples were taken for biochemical and
hormonal assays. The right jugular venous cannula was used for infusion
of tracer, insulin, and glucose via serial Y needle connectors. A
continuous infusion of regular porcine insulin (Eli Lilly & Co.) was given at 2 mU/kg·min and maintained throughout the
experiment. An exogenous glucose infusion (30%) was given at variable
rates to maintain plasma glucose at normal basal levels, according to
instant plasma glucose measurements by a glucose oxidase method using a
Beckman Coulter, Inc. Glucose Analyzer II (Beckman Coulter, Inc., Fullerton, CA). Arterial blood was sampled every
10 min throughout the experiment to ensure that euglycemia was
maintained. A flash iv injection of 30 µCi [14C]2-DG
was given at 90 min of the glucose clamp, and blood was sampled via the
arterial catheter immediately before (0 min) and 3, 6, 10, 20, 30, and
40 min after the flash injection.
After the last blood sample, the rats were killed by cervical dislocation. Soleus muscle (SM), extensor digitorum longus muscle (EDL), white epididymal adipose tissue (WAT), interscapular BAT, and liver were excised and frozen in liquid nitrogen. The above tissues were digested by NaOH and deproteinated by either 6% HClO4 or the Somogyi procedure. The supernatant from the deproteinated samples were mixed with scintillation cocktail, and 14C radioactivity was quantitated (21, 22). After the plasma samples were deproteinated using the Somogyi procedure, an aliquot of the supernatant was evaporated overnight and then mixed with scintillation cocktail for determination of [14C]2-DG with a liquid scintillation counter. The rate of glucose uptake in individual tissues was calculated according to Kraegen’s method (23).
Western blot analysis
The isolated adipose tissues from both epididymal WAT and
interscapular BAT were homogenized in 10 vol ice-cold buffer containing
25 mM HEPES, 250 mM sucrose, 4 mM
EDTA, aprotinin (40 µg/ml), 25 mM benzamidine, 0.2
mM phenylmethylsulfonylfluoride, 1 µM
leupeptin, and 1 µM pepstatin, pH 7.4. Homogenates from
adipose tissue were centrifuged at 5,000 x g for 5 min
at 4°C. The supernatant was then centrifuged at 150,000 xg for 2 h at 4°C to obtain the membrane fraction (24). The
muscle tissues were homogenized in homogenization buffer (pH 7.4)
containing 10 mM NaHCO3, 0.25 M
sucrose, and 5 mM NaN3 at 4°C. Homogenates
were centrifuged at 1,200 x g for 10 min at 4°C. The
first and second supernatants were combined and centrifuged at
9,000 x g for 10 min at 4°C. The resultant
supernatant was centrifuged at 200,000 x g for 90 min
at 4°C. The pellet was resuspended and stored at -80°C before
Western blot analysis (24, 25). Protein content in both muscle and
adipose tissues was determined by a modification of the Lowry method,
with BSA as a reference standard (26). Equivalent amounts of protein
homogenates (30 µg) were separated in 10% SDS-polyacrylamide gel and
electrophoretically transferred to a nitrocellulose membrane
(polyvinylidene difluoride, Schleicher & Schuell, Inc.,
Keene, NH). The filters were blocked by incubation for 1 h in PBS
with 5% nonfat milk. Blots were then washed in PBS-Tween and incubated
with a rabbit polyclonal antiserum (1:1,000) raised against a peptide
corresponding to the GLUT4 COOH-terminus (27). Blots were washed and
incubated with a goat antirabbit secondary antiserum (1:2,000 dilution)
conjugated to horseradish peroxidase (Sigma Chemical Co.).
Detection of immune complex was accomplished using the enhanced
chemiluminescent reagent (ECL, Amersham, Arlington
Heights, IL). The filters were then exposed to Kodak XAR films
(Eastman Kodak, Rochester, NY) and subjected to laser
scanning densitometry (Molecular Dynamics, Inc.,
Sunnyvale, CA) to quantitate the results.
Ribonuclease protection assay
Animals were killed after 5 h of fasting on day 5 of leptin
treatment. The STAT-60 reagent was used to extract total RNA from EDL,
SM, interscapular BAT, and epididymal WAT. A segment of the rat GLUT4
sequence (Gb:D28561, nucleotides 1445–1629) was generated by RT-PCR
from rat muscle RNA and cloned into the transcription vector pGEM-T
(Promega Corp., Madison, WI). Radiolabeled antisense
transcripts were synthesized from linearized plasmid templates using T7
RNA polymerase (Boehringer Mannheim, Indianapolis, IN) and
[32P]rat UTP (800 Ci/mol; Amersham).
A 103-bp rat cyclophilin probe (Ambion, Inc. Austin, TX)
was used as an internal control. The ribonuclease protection assay was
performed using the RPA II kit (Ambion, Inc.) and 5 µg
total RNA from each sample. Quantitation was performed with a
PhosphorImager and ImageQuant software (Molecular Dynamics, Inc., Sunnyvale, CA). The ratio of the integrated volume of the
GLUT4 band vs. the cyclophilin (housekeeping control) band
was calculated, and the results were expressed as the mean ±
SEM of the values in each group.
Measurement of oxygen consumption
After 5 h of fasting, animals were killed by cervical
dislocation, and interscapular BAT was immediately excised from each
group of rats. Brown adipocytes were isolated using the method
described by Nedergaard et al. (28). The 1.4-ml cell
suspension (2–3 x 106 cell/ml) in Kreb-Ringer buffer
was added to a magnetically stirred chamber at 37 C. Oxygen consumption
was measured polarographically using a Clark style oxygen electrode
(4004 Clark oxygen probe, YSI, Inc., Yellow Springs, OH).
These electrodes were connected to the biological oxygen monitor (YSI
model 5300, YSI, Inc.), providing simultaneous recording
of both the total O2 concentration and the rate of
O2 consumption in the chamber (29, 30).
Calculation and statistical analysis
The rate of tissue glucose uptake (defined as the glucose
metabolic index, Rg) was calculated as follows: Rg (µmol/100 g·min)
= Cp Cm1(45)/
045 Cp1(t) dt, where Cp is the
steady state plasma glucose concentration over the 45-min period of
observation (millimoles per liter), Cm1 is the tissue accumulation of
[14C]2-DG-6-phosphate per unit mass at 45 min
(disintegrations per min/mg·wet wt), Cp1(t) is the plasma
[14C]2-DG concentration (disintegrations per min/ml), and
the tracer bolus is administered at time zero. All data are expressed
as the mean ± SEM. Two-way ANOVA or unpaired
t test was used to determine the statistical differences
among the three groups or between two groups, respectively.
Significance is assumed at P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
The baseline body weight for the experimental rats was about 275
g. There was a significant progressive reduction (5%) in the body
weight of leptin-treated rats (P < 0.05 vs.
V and PF), whereas the V control rats increased body weight (6%)
during the study. A slight body weight loss was observed in PF rats on
days 2 and 3, after which their body weight was slowly increased in a
pattern similar to that of V rats. Leptin significantly reduced food
intake (11.5 ± 0.4 g/day) compared with that of the vehicle
control rats (16.8 ± 1.5 g/day; P < 0.05). The
pair-fed animals received an amount of food equal to that consumed by
the leptin-treated rats.
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,
the plasma insulin level was decreased and the leptin level was
increased in the leptin group compared with those in both V and PF
control rats. The plasma T4 level was increased in the
leptin-treated group compared with that in the V control group, but did
not significantly differ from that in PF rats. Plasma glucagon and
corticosterone levels did not change after leptin treatment. The plasma
triglyceride concentration was significantly reduced in leptin-treated
rats compared with that in both V and PF control rats. The plasma
glucose level was also reduced in leptin-treated rats compared with
that in the V control group, but did not differ from that in PF rats.
Plasma ß-hydroxybutyrate was increased in the leptin-treated group
compared with levels in the other two groups.
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. The basal plasma glucose level was
reduced in the leptin group (115.6 ± 3.8 mg/dl) compared with
those in the V (126.7 ± 4.2 mg/dl) and PF (128.5 ± 2.9
mg/dl) groups. The plasma glucose levels were clamped at the respective
baseline values during the glucose clamp. During the last 60 min, the
glucose infusion rate required to maintain the clamp was 16.5 ±
0.3 mg/kg·min in the leptin group, 8.8 ± 0.6 mg/kg·min in the
V group, and 13.0 ± 0.1 mg/kg·min in the PF group. There was a
significant difference in the glucose infusion rate among the three
groups of animals (P < 0.05).
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. 2-DG
uptake was examined in SM, EDL, interscapular BAT, epididymal WAT, and
liver. The Rg (micromoles of glucose per 100 g tissue/min) is a
glucose metabolic index calculated from tissue
[14C]2-DG-6-phosphate accumulation and parameters derived
from plasma glucose and [14C]2-DG data. A small, but
significant, increase in the Rg value was observed in EDL and SM
muscles in the leptin-treated group compared with those in V and PF
groups. In BAT, 2-DG uptake in the leptin-treated group was
significantly elevated and was 3-fold that in the V control group and
70% greater than that in the PF group. Intriguingly, 2-DG uptake in
WAT was significantly reduced by leptin treatment, with a Rg value 50%
less than those in the V and PF groups. No difference was found in 2-DG
uptake by the liver among the three groups.
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shows
the results from Western blot analysis. In BAT, GLUT4 protein levels
were markedly increased in the leptin-treated group compared with those
in the V and PF groups. No significant difference was observed in
muscle tissues among the three groups. However, levels of GLUT4 protein
were markedly reduced in WAT of leptin-treated rats compared with that
of V and PF animals.
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, leptin treatment significantly
increased GLUT4 mRNA expression in BAT compared with that in both
control groups. The ribonuclease protection assay result shows a very
significant decrease in GLUT4 mRNA expression in WAT of leptin-treated
animals, which is in agreement with the Western blot assay. No
significant difference in GLUT4 mRNA expression in muscle tissues was
observed between the leptin-treated and control (V and PF) groups.
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shows the effect of leptin
on oxygen consumption in isolated brown adipocytes. After 7 days of
treatment with leptin or vehicle, oxygen consumption was measured in
freshly isolated BAT during a 30-min incubation. The upper
panel of Fig. 6 shows the oxygen consumption rates (nanomoles of
O2 per 106 cells) over the 30-min time course
in the leptin- and vehicle-treated rats. The mean oxygen consumption
rates per min are displayed in the lower panel. Oxygen
consumption was significantly increased (32 ± 7%) in BAT
(139 ± 8 nmol O2/30 min·106 cells) of
leptin-treated rats vs. V control rats (105 ± 7
nmol/30 min·106 cells).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Decreases in food intake and body weight in the leptin-treated rats have been common findings in many studies. The observation that the loss of body weight in the PF rats was much less than that in leptin-treated rats despite the same amount of daily food consumption suggests that leptin also induced an increase in energy expenditure, which is indeed evidenced by the current study.
BAT appears to play an important role in regulation of adiposity and energy expenditure, as brown fat deficiency in a transgenic mouse model produces severe leptin resistance (31). Our study demonstrated that chronic sc leptin treatment in the rat induced an increase in glucose uptake rate in BAT. Leptin also induced an increase in GLUT4 glucose transporter mRNA and protein expression in BAT. As GLUT4 mRNA and protein levels in BAT of PF animals were not affected, the effect of leptin must be independent of food restriction. The enhancement in GLUT4 mRNA and protein expression in BAT may directly contribute to the observed increase in glucose uptake in BAT of leptin-treated rats, because the GLUT4 glucose transporter is the main regulatable element in the glucose transport system in these insulin-sensitive tissues. It was recently shown that glucose uptake in BAT is increased 5 h after iv administration of leptin in the mouse (6). The same results were achieved after intracerebroventricular leptin administration, suggesting a central mechanism of leptin actions (6). Similar to the results found with acute iv injection, chronic iv administration of leptin for 4 days increased glucose utilization in BAT (32). However, in the same study, leptin given intracerebroventricularly had no effect (32). The researchers thus suggested a direct action mechanism of leptin in the BAT. It is thus unresolved whether such an increase in glucose uptake is mediated by leptin’s actions directly on BAT or indirectly, via an efferent pathway from the central nervous system. However, leptin given ip to intact mice was able to stimulate the release of norepinephrine from the sympathetic nerve endings in BAT (33). Leptin infusion to anesthetized rats increased BAT sympathetic nerve activity measured by direct recording from nerves innervating interscapular brown fat (34). These studies point to a possible mechanistic association that connects the leptin hormonal signal to the central nervous system and a sympathetic efferent output.
Thermogenesis in BAT may be an important mechanism by which leptin regulates body fat content. It has been shown that leptin increased uncoupling protein and lipoprotein lipase mRNA expression in BAT (35). If cellular respiration is directly coupled to the oxidative metabolism to a significant extent in BAT, then the rate of oxygen consumption in brown adipocytes would be expected to correlate with the rate of glucose uptake. This possibility is verified by our current data that demonstrated significant increases in oxygen consumption in brown adipocytes isolated from leptin-treated rats.
An intriguing finding in this study is that 2-DG uptake was significantly reduced in WAT of leptin-treated animals. This is in sharp contrast with the results in BAT. In addition, we found substantially reduced GLUT4 mRNA and protein levels in WAT in leptin-treated rats, and this effect of leptin again appears independent of food restriction. Our findings in WAT bear certain clinical importance in terms of energy storage. Fat cells require glucose to generate glycerol-3-phosphate, rather than using intracellular glycerol, for the synthesis of triglyceride, which is the major energy storage form. In this process, uptake of glucose from extracellular sources is an important step in lipogenesis in adipocytes. Therefore, a decrease in glucose transport into the WAT may lead to a reduced triglyceride store in white adipocytes. In our previous study, chronic leptin treatment also resulted in a significant diminution in hepatic triglyceride production (36). Assuming that therapeutic hyperleptinemia in humans could result in a similar reduction in glucose uptake in white adipocytes, the resultant suppression in lipogenesis could be an important part of the leptin action mechanism in the reduction of adiposity. Leptin has been shown to impair the effect of insulin on glucose transport in isolated white adipocytes in vitro (12). Our present study is the first report that leptin decreases glucose uptake and down-regulates GLUT4 mRNA and protein expression in WAT in vivo. It is apparent from our current results that glucose uptake in individual tissues is distinctly regulated and that leptin treatment produces a tissue-specific effect on glucose utilization and oxygen consumption.
The muscle tissue is the major site of insulin-mediated glucose disposal in vivo. Our data show that leptin treatment increased glucose uptake in the EDL (a glycolytic muscle type) and the SM (an oxidative muscle type) in leptin-treated animals. The increase in glucose uptake in muscle tissues may largely reflect the whole body glucose utilization, and these results are in agreement with those of a study in mice (6). However, the chronic leptin infusion did not appear to alter GLUT4 mRNA and protein expression in skeletal muscles tested in this study. Thus, the mechanism by which leptin affects muscle insulin sensitivity is still unclear. A recent glucose clamp study performed in anesthetized rats demonstrated that a 4-day intracerebroventricular leptin treatment resulted in significant increments in insulin-mediated systemic glucose disposal and 2-DG uptake in various muscle types (37). However, similar changes were induced by pair-feeding in the control rats, suggesting that negative energy balance plays a role in enhancing insulin-mediated glucose metabolism (37). Kamohara et al. studied the effect of intracerebroventricular leptin on glucose uptake in denervated and intact EDL and SM in the same animal and found that leptin-stimulated glucose uptake was lower in the denervated leg than that in the intact muscle (6). This suggests that leptin may affect muscle insulin sensitivity through the central nervous system. In our recent study in unrestrained conscious rats, intracerebroventricular infusion of leptin, given either as one overnight bolus or a 1-week infusion, resulted in significant increases in whole body glucose utilization (9). These results collectively argue for a central mechanism of action rather than a direct leptin action on peripheral tissues. However, it has been shown that leptin affected muscle lipid metabolism, which leads to a decrease in muscle triglyceride content (38). The reduction in muscle triglyceride levels appears to be associated with increased insulin sensitivity in muscle (39, 40). These data seem to indicate a direct effect of leptin on peripheral tissue. The mechanism by which leptin may enhance insulin sensitivity without altering glucose transporter mRNA and protein expression in skeletal muscle remains to be identified. It is possible that changes in glucose transport activities is mediated by altered translocation and/or intrinsic activity of the glucose transporter(s) (41).
The decreases in plasma insulin, triglyceride, and glucose levels after sc leptin infusion are in agreement with the findings of recent studies by us and others (7, 9, 42). Leptin has been shown to enhance systemic insulin action in stimulating whole body glucose disposal and reducing hepatic glucose production under glucose clamp conditions (7, 9, 42). The decreased basal plasma glucose levels in the study may be associated with both a reduced hepatic glucose production and an increased glucose utilization. Plasma ß-hydroxybutyrate was elevated after leptin treatment for 7 days, indicating an accelerated rate of FFA oxidation, which, again, contributes to the overall effect of leptin in reducing adiposity. The elevated T4 levels suggest a possible involvement of thyroid hormones in the systemic actions of leptin, especially relating to calorigenic metabolism.
In summary, chronic sc leptin treatment produced a tissue-specific effect on glucose utilization in individual tissues in normal rats. Glucose uptake increases in BAT and muscle, but decreases in WAT. GLUT4 glucose transporter mRNA and protein expression were up-regulated in BAT, but down-regulated in WAT, by leptin, without a significant change in muscle tissues. The differential effects of leptin on tissue glucose utilization appear to be independent of food restriction and circulating insulin levels. The above results suggest that a marked reduction in adiposity induced by leptin is associated with both enhanced energy consumption in BAT and muscle and an attenuation in energy storage in WAT.
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Acknowledgments |
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Footnotes |
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Received September 3, 1998.
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G. R. Steinberg, A. Bonen, and D. J. Dyck Fatty acid oxidation and triacylglycerol hydrolysis are enhanced after chronic leptin treatment in rats Am J Physiol Endocrinol Metab, March 1, 2002; 282(3): E593 - E600. [Abstract] [Full Text] [PDF]
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M. Taouis, C. Dagou, C. Ster, G. Durand, M. Pinault, and J. Delarue N-3 Polyunsaturated fatty acids prevent the defect of insulin receptor signaling in muscle Am J Physiol Endocrinol Metab, March 1, 2002; 282(3): E664 - E671. [Abstract] [Full Text] [PDF]
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