Decreased visceral adiposity accounts for leptin effect on
hepatic but not peripheral insulin action
Nir
Barzilai1,2,
Li
She2,
Lisen
Liu2,
Jiali
Wang2,
Meizu
Hu2,
Patricia
Vuguin3, and
Luciano
Rossetti2
Divisions of 1 Geriatrics and
3 Pediatric Endocrinology,
Department of Medicine, and the
2 Diabetes Research and Training
Center, Albert Einstein College of Medicine, Bronx, New York 10461
 |
ABSTRACT |
Leptin decreases
visceral fat (VF) and increases peripheral and hepatic insulin action.
Here, we generated similar decreases in VF using leptin (Lep),
3-adrenoreceptor agonism
(
3), or food restriction (FR) and asked whether insulin action would
be equally improved. For 8 days before the in vivo study,
Sprague-Dawley rats (n = 24) were
either fed ad libitum [control (Con)], treated with Lep or
3 (CL-316,243) by implanted osmotic mini-pumps, or treated with FR.
Total VF was similarly decreased in the latter three groups (Lep, 3.11 ± 0.96 g;
3, 2.87 ± 0.48 g; and FR, 3.54 ± 0.77 g compared
with 6.91 ± 1.41 g in Con; P < 0.001) independent of total fat mass (by
3H2O)
and food intake. Insulin (3 mU · kg
1 · min
1)
clamp studies were performed to assess hepatic and peripheral insulin
sensitivity. Decreased VF resulted in similar and marked improvements
in insulin action on glucose production (GP) (Lep, 1.19 ± 0.51;
3,
1.46 ± 0.68; FR, 2.27 ±0.71 compared with 6.06 ± 0.70 mg · kg
1 · min
1
in Con; P < 0.001). By contrast,
reduction in VF by
3 and FR failed to reproduce the stimulation of
insulin-mediated glucose uptake (~60%), glycogen synthesis
(~80%), and glycolysis (~25%) observed with Lep. We conclude that
1) a moderate decrease in VF
uniformly leads to a marked increase in hepatic insulin action, but
2) the effects of leptin on
peripheral insulin action are not due to the associated changes in VF
or
3 activation.
 |
INTRODUCTION |
A MAJOR ROLE of a centripetal distribution of adiposity
in the pathophysiology of insulin resistance has been suggested by numerous epidemiological studies (9, 25). However, the covariance of
central adiposity and insulin resistance may also be due to tightly
associated hormonal or metabolic parameters. We have recently reported
that the administration of the "anorectic" fat-derived hormone,
leptin, to moderately obese rats leads to a selective decrease in
intra-abdominal adiposity and to marked improvements in both hepatic
and peripheral insulin action (7). This suggests that some of the
chronic metabolic effects of leptin might be secondary to the decrease
in visceral fat (VF).
Leptin suppresses appetite and augments energy expenditure mainly via
its interaction with hypothalamic receptors (41, 42), and it has been
postulated that some of the downstream effects of leptin are mediated
by the
3-adrenoreceptor system
(17). A mutation in this receptor is associated with insulin resistance (44), morbid obesity (10), and increased visceral adiposity (40).
Administration of
3-adrenoreceptor agonists
increases thermogenesis through their action on uncoupling protein 1. Although this action occurs mainly in brown fat,
3-adrenoreceptors are present
in a variety of white fat tissue in humans (26). Because the
administration of selective
3-adrenoreceptor agonists to rodents affects visceral more than subcutaneous fat (20), it is
possible that the selective effect of leptin on VF is due, in part, to
the activation of this neuronal pathway (12). Furthermore, important
metabolic actions of leptin on energy expenditure, substrate partitioning, insulin action, and storage of body fat have also emerged
(19, 32, 34).
In fact, whereas chronic administration of leptin improves insulin
action in animal models (7, 19, 34), recent studies have also shown
acute modulation of insulin action by leptin in vivo (22, 39, 43) and
in vitro (11). Thus insulin action may be improved before and
independently of the leptin-induced decrease in VF.
To delineate the contribution of the leptin-induced changes in VF to
the potent effects of leptin on in vivo insulin action, in the current
study we generated similar decreases in VF by alternative means and
compared their impact on hepatic and peripheral insulin action. We
utilized the
3-adrenoreceptor
agonist CL-316,243, which caused decreased VF (by ~60%) with no
changes in food intake and modest decline in total fat mass (~10%)
(20), and caloric restriction designed to achieve a similar decrease in VF.
We hypothesize that if decreased VF is solely responsible for the
leptin-induced improvement in insulin action, the latter will be
independent of the modality by which VF is decreased. Alternatively,
leptin may play a direct role in the modulation of peripheral or
hepatic insulin action.
 |
MATERIALS AND METHODS |
Experimental animals.
Four groups of male Sprague-Dawley rats (Charles River Laboratories,
Wilmington, MA) received the following treatment by osmotic minipumps
for 8 days: 1) Con
(n = 6), saline;
2) Lep
(n = 6), recombinant mouse leptin at
the rate of ~0.5
mg · kg
1 · day
1
(Amgen, Thousand Oaks, CA; >95% pure by SDS-PAGE);
3)
3
(n = 6), a
3-adrenoreceptor agonist, at
the rate of ~0.1
mg · kg
1 · day
1
(CL-316,243 provided by Wyeth-Ayrest Research); and
4) FR
(n = 6), saline and food restriction
at the physiological level of 17 kcal/day. Data obtained from four of
the six Lep rats were included in a previous publication (7) and are
reported here solely to facilitate comparison with
3 and FR. These
rats were selected on the basis of their VF to match that obtained with the alternative interventions. Food intake and body weights were measured every 24 h during the 8-day infusion period. Rats were housed
in individual cages and subjected to a standard light (6 AM to 6 PM)-dark (6 PM to 6 AM) cycle. Eight days before the in vivo study,
rats were anesthetized with an intraperitoneal injection of
pentobarbital sodium (50 mg/kg body wt), the osmotic minipumps were
placed in the subcutaneous interscapular area, and indwelling catheters
were inserted in the right internal jugular vein and in the left
carotid artery (4, 5, 7, 38, 39). The venous catheter was extended to
the level of the right atrium, and the arterial catheter was advanced
to the level of the aortic arch.
Body composition.
Body composition was assessed as in Refs. 3, 5, and 7. Briefly, rats
received an intra-arterial bolus injection of 20 µCi of
tritiated-labeled water
(3H2O;
New England Nuclear, Boston, MA), and plasma samples were obtained at
30-min intervals for 3 h. Steady-state conditions for plasma
3H2O
specific activity were achieved within 45 min in all studies. Five
plasma samples obtained between 1 and 3 h were used in the calculation of the whole body distribution space of water. VF (i.e.,
epididymal, perinephric, and mesenteric fat depots) was dissected and
weighed at the end of each experiment.
Measurements of in vivo glucose kinetics.
Measurements were performed as in Refs. 7 and 39. Briefly, a
primed-continuous infusion of HPLC-purified
[3-3H]glucose (New
England Nuclear; 40 µCi bolus, 0.4 µCi/min) was administered for
the duration of the study. Two hours after the basal period, a
primed-continuous infusion of somatostatin (1.5 µg · kg
1 · min
1)
and regular insulin (3 mU · kg
1 · min
1)
were administered, and a variable infusion of a 25% glucose solution
was started at time 0 and periodically
adjusted to clamp the plasma glucose concentration at ~7.5 mM for the
rest of the studies. Samples for determination of
[3H]glucose specific
activity were obtained every 10 min, and plasma samples for
determination of plasma insulin, glycerol, and free fatty acid (FFA)
concentrations were obtained every 30 min during the study. At the end
of the infusions, rats were anesthetized (pentobarbital, 60 mg/kg body
wt iv), the abdomen was quickly opened, portal vein blood was obtained,
and muscle and liver were freeze-clamped in situ with aluminum tongs
precooled in liquid nitrogen.
Rates of glycolysis and glycogen synthesis were estimated as in Refs. 7
and 37. Rates of hepatic glucose fluxes were determined as in Refs. 7,
36, and 38. Gene expression of phosphoenolpyruvate carboxykinase
(PEPCK) and glucose-6-phosphatase (G-6-Pase) by RT-PCR were determined
as in Ref. 29.
Analytic procedures.
Plasma glucose was measured by the glucose oxidase method (Glucose
Analyzer II, Beckman Instruments, Palo Alto, CA). Plasma corticosterone
and insulin (with rat and porcine insulin standards) were measured by
radioimmunoassay. Plasma glucagon and leptin (RIA kit, Linco Research,
St. Charles, MO) concentrations were measured by radioimmunoassay. The
plasma concentration of FFA was determined by an automated kit
according to the manufacturer's specifications (Waco Pure Chemical
Industries, Osaka, Japan). Plasma
[3H]glucose
radioactivity was measured in duplicates in the supernatants of
Ba(OH)2 and
ZnSO4 precipitates of plasma
samples (20 µl) after evaporation to dryness to eliminate tritiated
water. UDP-glucose and PEP concentrations and specific activities in
the liver were obtained through two sequential chromatographic
separations, as previously reported (7, 36, 38).
 |
RESULTS |
Caloric intake, body weight, and fat distribution.
Because our design required matching VF by various experimental means,
rats had to be preselected for assignment to each study group according
to their body weights. Marked decreases in body weight were anticipated
after 8 days of Lep and FR; thus rats were weighed before initiation of
treatment. Con and
3 rats weighed 303 ± 19 and 288 ± 18 g, whereas Lep and FR rats weighed 351 ± 3 and 338 ± 6 g. As
expected, administration of exogenous leptin decreased food intake by
~50%, and administration of CL-316,243 (
3) resulted in similar
food intake as Con (Table 1). Because we
had previously shown that pair-feeding to Lep was not sufficient to
reproduce the effect of Lep on total abdominal fat (7), in this study
FR rats received approximately one-half the caloric consumption of Lep.
After these protocols, similar body weight and lean body mass (LBM)
were achieved in all groups (Table 1, Fig.
1A),
and epididymal, perinephric, and mesenteric fat depots were similarly
decreased by all interventions (Table 1, Fig. 1C). Thus the remaining differences
in body composition among the groups were due to variations in the
amount of total fat mass (Fig. 1B).
However, the latter was significantly lower in Lep (34 ± 8 g),
3
(28 ± 9 g), and FR (17 ± 8 g) compared with Con (54 ± 4 g).

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Fig. 1.
Body composition. Lean body mass (LBM,
A), total fat mass
(B), and total epididymal,
perinephric, and mesenteric visceral fat (VF,
C) obtained at end of 8-day infusion
of interventions from rats treated with saline (Con), leptin (Lep),
3-adrenoreceptor agonist
CL-316,243 ( 3), or food restriction (FR). Fat mass was calculated
from whole body volume of distribution of water, estimated by
3H20
bolus injection in each experimental rat. See detail in
MATERIALS AND METHODS. Total VF was
similar for all intervention groups vs. Con.
* P < 0.001 vs. Con;
** P < 0.001 vs. Con and
leptin.
|
|
Decreasing VF per se markedly enhances hepatic insulin sensitivity.
Plasma leptin levels were markedly increased in Lep (39 ± 8 ng/ml)
compared with
3, FR, and Con (2 ± 1, 3 ± 1, and 4 ± 1 ng/ml,
respectively). During the insulin clamp studies, the plasma glucagon
(116 ± 11, 96 ± 18, 125 ± 12, and 102 ± 9 pg/ml) and corticosterone (154 ± 22, 126 ± 28, 168 ± 21, and 186 ± 25 ng/ml in Con, Lep,
3, and FR, respectively) concentrations were
similar in all groups. Table 2 displays the
basal biochemical parameters in all experimental groups. Postabsorptive
(6 h of fasting) plasma glucose concentrations were similar in all
groups. However, plasma insulin levels were markedly decreased by
interventions and were significantly lower in Lep compared with all
other groups. Basal plasma FFA and glycerol levels were similar at
basal in all groups. At basal, glucose production (GP, Fig.
2A) was
similar in all groups (11.2 ± 0.9, 12.2 ± 1.0, 11.5 ± 0.9, and
12.4 ± 1.3 mg · kg
1 · min
1
in Con, Lep,
3, and FR, respectively). During the insulin clamp, plasma insulin levels increased to similar levels, and plasma FFA and
glycerol levels decreased similarly in all groups (Table 2). Although
GP (Fig. 2B) was decreased from
basal in all groups, it was about threefold lower (and similar) in all
intervention groups (6.1 ± 0.7, 1.2 ± 0.5, 1.5 ± 0.7, and 2.3 ± 0.7 mg · kg
1 · min
1
in Con, Lep,
3, and FR, respectively).

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Fig. 2.
Hepatic insulin sensitivity. Basal glucose production (GP,
A), GP during insulin infusion (3 mU · kg 1 · min 1,
B), and percent (%) contribution of
gluconeogenesis to GP in Con, Lep, 3, and FR. Although basal GP was
similar in all groups, insulin inhibited GP to a greater extent in the
3 intervention groups. Gluconeogenesis increased more in Lep than in FR
and 3. * P < 0.001 vs. all
others.
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|
Effect of decreasing VF with Lep,
3, or FR on
gluconeogenesis and glycogenolysis.
The direct contribution of plasma glucose to the hepatic glucose
6-phophate (G-6-P) pool was
calculated from the specific activities of UDP-glucose and plasma
glucose (Table 3), and it was similar in
all groups. Thus decreased VF resulted in similar decreases (to <30%
of Con) in the rates of GP, flux through G-6-Pase or total glucose
output (TGO), and glucose cycling (GC) in response to physiological
hyperinsulinemia. Lep and FR increased the percentage of hepatic
G-6-P pool that is derived from
PEP-gluconeogenesis (GN), but the rate of GN was similar in all
intervention groups (Table 4). In a net
sense, the major contribution to the decreased GP in all intervention
groups was due to a marked decrease in glycogenolysis (to <20% of
Con).
Effect of decreasing VF with Lep,
3, or FR on PEPCK
and G-6-Pase gene expression.
Multiple densitometric scanning of PCR products (examples shown in Fig.
3A)
shows that when the hepatic G-6-Pase and PEPCK mRNA levels were
compared with those of Con, they were increased by approximately
twofold in Lep and more modestly in FR, but not in
3.

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Fig. 3.
Gene expression of hepatic glucose-6-phosphatase (Glc-6-Pase) and
phosphoenolpyruvate carboxykinase
(PEPCK). Individual livers from each of the rats were rapidly obtained,
clamp-frozen with liquid nitrogen, and stored in 80°C for
subsequent analysis. RT-PCR analysis for Glc-6-Pase, PEPCK, and
-actin is described in text. A:
example of RT-PCR analysis from Con, Lep, 3, and FR.
B: analysis of all RT-PCR data
obtained from all rats, corrected for intensity of -actin, and
presented in arbitrary units.
* P < 0.01 vs. Con and 3.
|
|
Leptin, but not decreased VF per se, augments insulin action on
glucose uptake, glycogen synthesis, and glycolysis.
During the insulin clamp studies, glucose uptake
(Rd, Fig.
4A) was
increased by 63% (P < 0.001) in Lep
(17.5 ± 1.1, 28.6 ± 1.3, 19.2 ± 1.3, and 20.7 ± 1.3 mg · kg
1 · min
1
in Con, Lep,
3, and FR; respectively). This improvement in
peripheral insulin action was accounted for by a twofold increase in
the rate of glycogen synthesis (Fig.
4B; 5.6 ± 0.9, 11.6 ± 1.2, 8.7 ± 1.3, and 9.7 ± 1.1 mg · kg
1 · min
1
in Con, Lep,
3, and FR; P < 0.001) and by a 26% increase in glycolysis (11.9 ± 1.6, 15.0 ± 1.2, 10.0 ± 1.2, and 11.2 ± 0.3 mg · kg
1 · min
1
in Con, Lep,
3, and FR; P < 0.01).

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Fig. 4.
Peripheral insulin sensitivity. Glucose uptake
(Rd,
A), glycogen synthesis (GS,
B), and glycolysis (C)
during insulin infusion (3 mU · kg 1 · min 1).
Glycolysis was determined by conversion rate of
[3-3H]glucose to
3H2O,
and GS was determined as the difference between
Rd and glycolysis.
Rd was increased by contribution
from both GS and glycolysis. * P < 0.001 vs. all others; ** P < 0.01 vs. all others.
|
|
 |
DISCUSSION |
In this study we attempted to delineate whether the potent effects of
leptin on in vivo insulin action are secondary to the associated
changes in body composition. Decreasing VF led to a striking
improvement in hepatic insulin sensitivity that was independent of
total fat mass (FM) and of the modalities used to achieve the "target" VF. This observation provides support for a cause-effect relationship between intra-abdominal deposition of fat and hepatic insulin resistance. Conversely, the marked stimulation of
insulin-mediated glucose uptake, glycolysis, and glycogen synthesis
induced by leptin treatment could not be reproduced by decreasing VF by
alternative means. The latter finding indicates that, at least within
the time frame of the present study, the effects of leptin on
peripheral insulin action are not likely to be solely mediated via
decreased VF and/or activation of the
3-adrenoreceptor system.
Furthermore, rapid changes in VF modulate hepatic much more than
peripheral insulin action.
"Manipulating" body composition.
It is well established that weight loss is commonly associated with
decreased plasma insulin concentrations and increased insulin
sensitivity (8, 13, 15, 16, 27). Early studies in obese mice reported
marked improvements in glucose tolerance after leptin treatment (19,
34). However, whereas some reports suggested that the improvement in
glucose tolerance may precede the decline in body weight and total fat
mass (34, 41), it has been difficult to discern the relative
contribution of the associated changes in body composition to the
improved glucose tolerance observed with leptin treatment (19, 34).
Furthermore, although pair-feeding vehicle-treated rats to the level of
leptin-treated rats resulted in similar decreases in body weight and
FM, leptin caused a selective and marked decrease in visceral adiposity
(7). The latter observation further complicates the interpretation of
potential effects of leptin treatment on in vivo insulin action.
Administration of
3-adrenoreceptor agonists
causes marked decreases in circulating leptin concentrations (18, 28,
30); however, consistent with previous reports (20), in the present study food intake was not decreased compared with Con (Table 1). Despite similar caloric intake,
3 rats gained less weight and their
FM was significantly lower than Con rats. This may be due to increased
energy expenditure and thermogenesis in this group (20).
To generate similar VF with FR it was necessary to further decrease the
caloric intake by ~50%; this intervention resulted in much lower FM
than in the other groups. This finding is a dramatic confirmation of
the selective effects of Lep and
3 on intra-abdominal adiposity.
This model is also different from the administration of leptin and
3-adrenoreceptor agonists,
because energy expenditure is expected to be markedly decreased. Thus
similar declines and final mass of VF were obtained in the three
intervention groups despite differences in food consumption, weight
gain, energy expenditure, food intake, and whole body adiposity.
VF and hepatic insulin sensitivity.
All interventions that decreased VF resulted in similar fasting plasma
glucose levels despite lower plasma insulin levels compared with Con
rats, suggesting an improvement in postabsorptive hepatic insulin
sensitivity. To directly test whether hepatic insulin sensitivity was
improved by decreasing VF, we performed low-dose insulin clamp studies
in combination with somatostatin infusions. The plasma glucose, FFA,
glycerol, and insulin concentrations during the insulin clamp studies
were similar in all groups (Table 2). This procedure also erased the
portal-venous insulin gradient, matching peripheral and hepatic insulin
levels in all groups. Decreasing VF resulted in a marked decrease in GP
during the insulin infusion, indicating heightened hepatic insulin
sensitivity (Fig. 2B). This
improvement in insulin action was independent of the modalities by
which decreased VF was achieved, and it is consistent with other animal
models, such as the calorie-restricted "old" rats (2) and rats
with surgical removal of VF (6). Although the mechanism(s) whereby VF
regulates insulin sensitivity remain to be delineated, it is evident
that the impacts of changes in VF on hepatic glucose fluxes are
remarkable. It has been suggested that the unique metabolic
characteristics of the intra-abdominal fat depots that concern the
turnover of glycerol, FFA, and lactate play a role through a "portal
effect" (9), i.e., the hepatic load of FFA, lactate, and glycerol
can modulate liver glucose metabolism (31, 35). However, it should be
noted that, in this experimental model, the peripheral concentrations
of these substrates were unchanged during the basal and insulin clamp
periods. Although potential effects of long-term differences in plasma FFA, lactate, or glycerol levels on hepatic enzymes cannot be excluded,
alternative hypotheses should also be considered for the
"cross-talk" between intra-abdominal fat depots and the liver. For example, a fat-derived and secreted peptide, tumor necrosis factor-
(TNF-
), causes peripheral and hepatic insulin resistance via its antagonism of early insulin signaling (14, 21).
Consistent with the lower GP, the rates of TGO and GC were also
markedly decreased in parallel with the changes in VF. This suggests a
marked decrease in the in vivo flux through G-6-Pase. In a net sense,
the decreased GP in the intervention groups was mainly the result of a
marked suppression of hepatic glycogenolysis, which was most pronounced
in the group treated with leptin (Table 2). Overall, whereas hepatic
insulin sensitivity improved similarly with all interventions designed
to decrease VF, there were some changes in the intraheptic distribution
of hepatic glucose flux and in the gene expression of key hepatic
enzymes that appear to be treatment specific. For example, the percent
contribution of GN to TGO was increased by Lep
FR
3 (Fig. 2C). This is supported by
the increased expression of hepatic PEPCK in Lep and FR. Although
leptin has similar effects on PEPCK mRNA when administered acutely via
a peripheral vein (39) or in a cerebral ventricle (29), it should be
pointed out that the decline in plasma insulin concentrations might
also contribute to the upregulation of this gene. By contrast, it is
noteworthy that acute and chronic stimulation of the
-adrenergic
systems has frequently divergent effects. We have previously shown that
the acute (6-h) administration of the same
3-adrenoreceptor agonist
increased the gene expression of G-6-Pase and PEPCK, perhaps via
activation of hypothalamic efferent pathway(s) (29). The waning of this
effect after more prolonged exposure to the agonist may be due to
either the associated marked decline in leptin levels and/or central or
peripheral downregulation of the
-adrenoreceptor system. This also
suggests that the stimulation of the
3-adrenoreceptor system is not
likely to mediate the effects of chronic leptin administration on
hepatic gene expression.
Unique effects of leptin on peripheral insulin sensitivity.
A major effect of insulin in vivo is to stimulate the disposal of
glucose into peripheral tissues (mostly in skeletal muscle). During
physiological hyperinsulinemia, the rate of tissue glucose uptake in
Lep was improved by >60%, whereas only a mild increase in peripheral
glucose uptake was noted in the other intervention groups. This
improvement in peripheral insulin action was accounted for by about a
twofold increase in the rate of glycogen synthesis and by an ~25%
increase in the rate of whole body glycolysis. On the basis of
epidemiological evidence correlating insulin resistance and
hyperinsulinemia with intra-abdominal adiposity (9, 25), it has been
suggested that decreasing VF should lead to a marked improvement in the
action of insulin on peripheral glucose disposal. Indeed, modest
increases in the rates of insulin-mediated glucose uptake and glycogen
synthesis were detected when VF was markedly decreased using caloric
restriction or
3-adrenergic
agonism. However, this improvement could only account for a small
fraction (up to 30%) of the effects of leptin on glucose uptake. Thus
8-day leptin administration exerts potent effects on peripheral insulin action, which are largely independent of the associated decrease in VF.
Several mechanism(s) may be invoked to account for the enhanced muscle
insulin sensitivity in rats treated with leptin. Leptin has been shown
to increase skeletal muscle glucose uptake quite rapidly in some rodent
studies (22, 43), and activation of early insulin signaling by leptin
has been demonstrated in a muscle cell line (23) and in a preliminary
report in rats (24). However, acute exposure of skeletal muscle and
adipose cells to leptin, with and without insulin, failed to alter the glucose transport system in some studies (46). Thus leptin may augment
muscle insulin signaling via a direct action on local receptors or via
hypothalamic efferent pathways. An additional explanation may be found
in the "lipopenic" effects of leptin (32) and in the close
correlation between intramyocellular lipid levels and insulin
sensitivity (33). In fact, leptin enhances lipid oxidation and depletes
triglyceride stores in preadipocytes, pancreatic
-cells, and muscle
(1, 32, 45). The latter effects may be mediated in part via decreased
gene expression of acetyl-CoA carboxylase.
Taken together with the hepatic actions of leptin, the above data
suggest that a prolonged elevation in circulating leptin favors the
storage of energy into glycogen rather than into lipid stores. The
latter metabolic adaptation may represent a response to signals
generated by leptin in the hypothalamic "lipostat" and/or the
results of peripheral actions of the hormone.
In conclusion, decreasing intra-abdominal adiposity by ~60% via
three different means results in a dramatic increase in hepatic insulin
sensitivity. Conversely, the potent effect of leptin administration on
peripheral insulin action cannot be solely explained on the basis of the associated decrease in VF mass. Understanding the biochemical mechanism(s) that are responsible for the specific action
of leptin on skeletal muscle glucose disposal should help to clarify
the link between nutrient excess, weight gain, and insulin resistance.
 |
ACKNOWLEDGEMENTS |
We thank Jie Wu, Robin Squeglia, and Rong Liu for expert technical
assistance, and Drs. Michael McCaleb and Nancy Levin (Amgen, Thousand
Oaks, CA) for providing recombinant mouse leptin.
 |
FOOTNOTES |
This work was supported by grants from the National Institutes of
Health (KO8-AG-00639 and R29-AG-15003 to N. Barzilai, R01-DK-45024 and
ROI-DK-48321 to L. Rossetti), the American Diabetes Association, and
the Core Laboratories of the Albert Einstein Diabetes Research and
Training Center (DK-20541). Dr. Barzilai is a recipient of the Paul
Beeson Physician Faculty Scholar in Aging Award. Dr. Rossetti is the
recipient of a Career Scientist Award from the Irma T. Hirschl Trust.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: N. Barzilai,
Divisions of Geriatrics and Endocrinology, Dept. of Medicine, Belfer
Bld. #701, Albert Einstein College of Medicine, 1300 Morris Park Ave.,
Bronx, NY 10461 (E-mail: barzilai{at}aecom.yu.edu).
Received 20 January 1999; accepted in final form 8 April 1999.
 |
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