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Department of Laboratory Medicine, School of Medicine, the University of Tokushima, Tokushima 770-8503, Japan
Address all correspondence and requests for reprints to: Kenji Shima, M.D., Ph.D., Department of Laboratory Medicine, School of Medicine, the University of Tokushima, Kuramotocho 3-chome, Tokushima 770-8503, Japan. E-mail: shima{at}clin.med.tokushima-u.ac.jp
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several alternate spliced isoforms (a–e, as well as others) of the OB-R have been cloned, and all of these, except for the OB-Re (soluble form), contain a single transmembrane domain (6, 7, 8, 9). Among them, the OB-Rb has the greatest capacity to perform signal transduction. Several lines of evidence suggest that the central nervous system, in particular the hypothalamus, is a direct target of leptin. The OB-Rb is highly expressed in those hypothalamic nuclei that are known to control the regulation of food intake and body weight (10, 11). The activity of the STAT3 transcription factor and fos gene expression are increased in the hypothalamus within 1 h after a single iv injection of leptin (12). Finally, the much higher potency in inducing weight loss of intracerebroventricular infusion of leptin than sc leptin (13) and the identification of leptin in cerebrospinal fluid are consistent with the idea that the main site of its action is in the central nervous system (14). However, the OB-Rs, including the OB-Rb, are expressed in a wide variety of tissues (7), including pancreatic islets (15, 16), in addition to the brain, and the number of reports on the extraneural action of leptin are increasing (15, 16, 17, 18, 19). Several laboratories have reported a direct action of leptin on the endocrine pancreas. However, conflicting results were observed in experiments using batch incubation or perifusion of isolated pancreatic islets, or perfused pancreas, in which leptin has an inhibitory, a stimulatory, or no effect on insulin release from the pancreatic islets (15, 16, 20, 21, 22, 23, 24, 25, 26). If leptin had a distinct direct action on the pancreatic endocrine functions, the results would be more or less alike, although they might differ slightly in the degree of effectiveness. These findings together with several reports demonstrating the stimulatory effect of leptin on sympathetic activities (27, 28, 29) prompted us to assume the possibility that it might indirectly act on pancreatic endocrine cells through the sympathetic nervous system, which has been well documented to modulate their functions (30, 31).
The synthesis of the uncoupling protein-1 (UCP1) (32), an important element in energy expenditure that exists in the adipocytes of the brown adipose tissue (BAT), is essentially regulated at the level of transcription by norepinephrine released at the surface of the adipocytes through stimulation of the sympathetic nervous system (33). Therefore, the UCP1 messenger RNA (mRNA) level in BAT represents a viable marker for the excitatory state of the sympathetic nervous system over a time course.
To ascertain whether leptin has an indirect action on pancreatic
endocrine functions via the sympathetic nervous system, we examined the
effects of leptin on pancreatic 
- and ß-cell functions in rats
that were surgically vagotomized and/or medically sympathectomized. The
data show that leptin indirectly suppresses glucose-induced insulin
secretion and stimulates hypoglycemia-induced glucagon secretion
through activation of the sympathetic nervous system.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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200 g), were purchased from Japan SLC
(Hamamatsu, Japan) and used for the following experiments after
acclimation for 1 week by housing them in an animal room with food and
water available ad libitum. 1) The effect of leptin on insulin secretion was studied using 70 rats. Among these, a group of 30 rats that was divided into 3 groups of 10 animals each (an intact group, a group that underwent vagotomy, and a group that underwent both vagotomy and chemical sympathectomy) was subjected to an iv glucose load. Five rats from each group received a bolus injection of leptin or a control protein (see Expression and purification of leptin and control protein below; 20 nmol/kg BW) 10 min before the administration of glucose. The other 30 rats, which underwent vagotomy, were divided into 5 groups and were also subjected to an iv glucose load. Six rats of each group received a bolus injection of leptin (0, 1, 10, 20, or 40 nmol/kg BW) 10 min before the administration of glucose. The remaining 10 rats were used in an in vitro experiment. Leptin was infused continuously at a rate of 20 nM into the perfused pancreas, in which 11.1 mM glucose-induced insulin secretion was tested.
2) The effect of leptin on glucagon secretion was studied using 30 rats, which were divided into 3 groups of 10 animals each. Two groups, an intact group and a group that underwent chemical sympathectomy, were subjected to an iv injection of insulin (0.6 U/kg BW; Novo Nordisk, Bagsvaerd, Denmark) to induce hypoglycemia. Five rats from each group received a bolus injection of leptin or a control protein (20 nmol/kg BW) 10 min before the insulin injection. The remaining group was used in an in vitro experiment. Leptin was infused continuously at a rate of 20 nM into the perfused pancreas, in which glucopenia-induced glucagon secretion was tested.
3) The effect of leptin on UCP1 mRNA expression in interscapular BAT was tested using nine rats with or without chemical sympathectomy (see UCP1 expression in BAT below).
The iv glucose load test
Four days before the following tests, catheterization of the
femoral vein (see below) and vagotomy (see below) were performed,
whereas a chemical sympathectomy (see below) was performed 48 h
before the tests. All tests were conducted while the animals were
conscious. Leptin or the control protein (20 nmol/kg BW) was injected
intravenously 10 min before the iv administration of
D-glucose (0.5 g/kg BW). Afterward, venous blood (0.2 ml)
was withdrawn from the catheter using a heparinized 1.0-ml syringe and
collected into chilled tubes, at 0, 3, 6, and 30 min for the
determination of plasma insulin levels and at 0, 3, 6, 30, 45 and 60
min for the determination of plasma glucose levels. In the experiment
to examine the dose-dependent suppressive action of leptin on insulin
secretion in the iv glucose load test (Table 1
), several doses of leptin (0, 1, 10,
20, and 40 nmol/kg BW) were injected intravenously to vagotomized rats
10 min before the administration of D-glucose (0.5 g/kg
BW). Afterward, venous blood was collected into chilled tubes at 0, 3,
and 6 min for the determination of plasma insulin levels.
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Catheterization of the femoral vein
Under anesthesia using sodium pentobarbital (50 mg/kg BW), a
silicone rubber catheter (FT-025, Bio-Medica, Osaka, Japan) was
inserted into the left femoral vein, and the line of a catheter was led
out through sc tissues to an IVH kit (Bio-Cannula, Bio-Medica). After
the operation, the rats were kept in a special IVH cage (BG-781,
Bio-Medica) and were continuously infused with physiological saline
until the test.
Vagotomy
A subdiaphragmatic vagotomy was conducted by sectioning the main
vagal trunk according to the method reported by Snowdon and Epstein
(34) just after catheterization under anesthesia. In control rats (sham
operation), laparotomy was conducted without vagotomy.
Chemical sympathectomy
6-Hydroxydopamine (6-OHDA) is known to selectively destroy
sympathetic nerve terminals. According to the method described
previously (35), 6-OHDA hydrobromide (Sigma Chemical Co., St. Louis,
MO), which was dissolved in ice-cold 0.9% saline containing ascorbic
acid (57 mM; Merck, Darmstadt, Germany), was administrated
intravenously at a dose of 0.19 mmol/kg BW 48 h before the tests.
The control group was given only the vehicle (0.9% saline containing
57 mM ascorbic acid). The dose of 6-OHDA used in this
experiment has been shown to cause a substantial reduction in the
number of adrenergic nerves in the islets of Langerhans in the mouse
(36). Moreover, we confirmed that 6-OHDA administration significantly
(P < 0.0001) reduced norepinephrine concentration in
pancreatic tissues 48 h after the administration (6-OHDA
administration, 137 ± 39 pg/g pancreatic wt; vehicle
administration, 495 ± 72 pg/g pancreatic wt).
Pancreas perfusion
Pancreata from rats that had been starved for 16 h were
perfused through the celiac artery via a catheter inserted into the
aorta, as described previously (37). The basal medium, which was used
for the perfusion, was Krebs-Ringer bicarbonate buffer (pH 7.4)
supplemented with 0.2% BSA (fraction V, Sigma Chemical Co.) and 4.5%
dextran (average mol wt, 71K; Sigma Chemical Co.). The pancreas was
perfused at a flow rate of 2.5 ml/min with medium warmed to 37 C and
equilibrated continuously with 95% O2-5% CO2.
For the insulin secretion test, perfusion with the basal medium
supplemented with 3.3 mM D-glucose was
performed during the first 10 min, followed by perfusion with the
medium supplemented with 11.1 mM D-glucose for
20 min, and then perfusion with the medium supplemented with 3.3
mM D-glucose was performed again for the final
10 min. For the glucagon secretion test, perfusion with the basal
medium supplemented with 5.6 mM D-glucose was
performed during the first 10 min, followed by perfusion with the
medium supplemented with 1.7 mM D-glucose for
26 min. A 15-min equilibration period preceded each perfusion
experiment. Leptin was dissolved at a concentration of 500
nM in the basal medium supplemented with 3.3 mM
D-glucose and was infused laterally through a three-way
tube at a flow rate of 0.1 ml/min. Therefore, the concentration of
leptin in the perfusion medium was approximately 20 nM.
Leptin or the solution without leptin (vehicle) was infused throughout
the experiment. The effluent was collected at 2-min intervals in
chilled tubes, which contained both aprotinin (500 kallikrein units)
and EDTA disodium salt (5 mg) for the glucagon secretion test.
UCP1 expression in BAT
Four days before killing the rats, catheterization of the
femoral vein was performed, whereas chemical sympathectomy was
performed 48 h before killing the rats. From 24 h before
killing the rats, leptin (0.31 µmol/day) or vehicle [solvent for
leptin (PBS) diluted with saline] was continuously infused
intravenously into the catheter using a disposable infusion pump
(Surefuser-A, Nipro Co., Osaka, Japan) at a rate of 0.7 ml/h. After
killing the rats, interscapular BAT was excised, and total RNAs were
prepared by the guanidine thiocyanate-cesium chloride centrifugation
method (38) (Fig. 2A) or by two extractions against Isogen (Nippon Gene
Co., Toyama, Japan; Fig. 2B). RNAs (8 µg) were denatured in 50%
formamide-2.2 M formaldehyde at 65 C for 10 min, and
electrophoresed on a 1% agarose gel containing 2.2 M
formaldehyde. The gel was blotted onto a Hybond-N nylon hybridization
membrane (Amersham International, Aylesbury, UK). The membrane was then
hybridized with the [-32P]deoxy-CTP random priming
labeled rat UCP1 complementary DNA probe (32) (provided by Dr. Daniel
Ricquier, Centre National de la Recherche Scientifique, Meudon,
France), washed at a stringency of 0.5 x standard saline
citrate (SSC; 1 x SSC is 150 mM sodium chloride and
15 mM sodium citrate)-0.1% SDS at 65 C, and exposed to
x-ray film, as described previously (39). The amount of intact RNA in
each lane of the gel was judged to be constant by ethidium bromide
fluorescence, which showed ribosomal RNA bands of 18S and 28S directly
in the gel and after transfer of the RNA to the nylon hybridization
membrane. A Bio-Image analyzer (BAS-1500Mac, Fuji Photo Film Co.,
Tokyo, Japan) (40) was used for quantification.
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To rule out the possibility that some impurities in our recombinant leptin might affect pancreatic functions, a control protein was used in a control experiment in place of the recombinant leptin in the experiments with the iv glucose load test and the hypoglycemia-induced glucagon secretion test. This protein was a portion of the intracellular domain (from amino acid 980 to 1129) of the rat leptin receptor (OB-Rb) (9), which was expressed, purified, refolded, and dialyzed in exactly the same manner as the recombinant leptin.
Assays
Levels of plasma glucose were determined by the glucose oxidase
method using Antsense II (Bayer-Sankyo Co., Tokyo, Japan). Levels of
insulin immunoreactivity were measured with a commercial kit (Eiken
Chemical Co., Tokyo, Japan) with rat insulin as a standard (Novo
Nordisk) (37). RIA of glucagon immunoreactivity was performed with
antiserum OAL123 (Otsuka Pharmaceutical Co., Tokyo, Japan) (42), which
is directed toward the C-terminal portion of glucagon and recognizes
glucagon, but not glicentin or oxyntomodulin. Norepinephrine
concentrations in pancreatic tissues were analyzed using the postlabel
fluorogenic method with diphenylethylenediamine (Tosoh Corp., Tokyo,
Japan) as described previously (43). Briefly, total pancreatic tissue
from each rat was homogenized in 0.4 N perchloric acid
containing 5 mM EDTA and 0.1 mM
L-ascorbic acid and centrifuged at 10,000 x
g for 20 min at 4 C, and the supernatant was then used for
the analysis.
Calculations and statistical analysis
All results are presented as the mean ± SD.
Statistical significance was determined using Student’s t
test for individual comparison of means. The data presented in Table 1
were analyzed at each time point between groups by one-way ANOVA using
the StatView computer software program (Abacus Concepts, Berkeley, CA).
When ANOVA showed significant differences, post-hoc analysis
was performed with Scheffé’s test. Significance was accepted as
P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(Intact). On the contrary, leptin
significantly suppressed an increase in plasma insulin concentrations
while causing a rise in plasma glucose levels after an iv glucose
injection in the vagotomized rats (Fig. 1, Vagotomy). In these rats,
significant differences in plasma insulin levels at 3, 6, and 30 min
were observed, and significant differences in plasma glucose levels
were seen at 30, 45, and 60 min between the leptin-treated and the
control protein-treated groups. However, in rats that underwent both
vagotomy and sympathectomy, the effects of leptin on responses of both
plasma insulin and plasma glucose to iv glucose, which were observed in
vagotomized rats, were not observed (Fig. 1, Vagotomy and
Sympathectomy). Chemical sympathectomy alone had no significant effect
on the plasma insulin or glucose response to iv glucose (data not
shown). As shown in Table 1, leptin at a dose as low as 10 nmol/kg BW,
significantly (P < 0.05) suppressed the plasma insulin
response to iv glucose in vagotomized rats. The suppressive effects of
leptin on an increase in plasma insulin concentrations 6 min after an
iv glucose load appeared to be dose dependent.
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shows changes in the mean
levels of insulin in the effluents from perfused rat pancreas with the
perfusate supplemented with 3.3 and 11.1 mM
D-glucose in the presence or absence of leptin. The rise in
the D-glucose concentration provoked a biphasic stimulation
of insulin secretion. In the absence of leptin, mean insulin secretion
increased from a basal level of 0.9 ± 0.3 pmol/min at 10 min
(just before perfusion with 11.1 mM D-glucose)
to the first peak level of 4.9 ± 2.3 pmol/min at 14 min (4 min
after changing to a perfusate with 11.1 mM
D-glucose) and decreased gradually thereafter, with the
second peak at 30 min (just before termination of perfusion with 11.1
mM D-glucose). After perfusion with 3.3
mM D-glucose, the mean levels of insulin in the
effluent decreased gradually and reached the basal level at 40 min. With leptin, the mean level of insulin in the effluents during the basal glucose condition (3.3 mM D-glucose; until 10 min) was significantly (P < 0.05) suppressed compared with that without leptin. Over the entire period after changing to perfusate with 11.1 mM D-glucose, except for near the peaks and at 40 min (10 min after changing to perfusate with 3.3 mM D-glucose; the last fraction of this experiment), the mean levels of insulin were also significantly (P < 0.05) lower with leptin than without leptin. Leptin (20 nM) suppressed the secretion of insulin from the perfused pancreas.
Effect of leptin on plasma glucagon response to insulin-induced
hypoglycemia in rats with or without pretreatment with 6-OHDA
Figure 3 shows changes in
concentration of plasma glucose and plasma glucagon after an iv bolus
injection of insulin (0.6 U/kg BW). After the injection of insulin to
intact rats that received an injection of the control peptide 10 min
before this, the plasma glucose level decreased from 4.6 ± 0.9
mM (0 min) to a minimum of 2.1 ± 0.4 mM
at 30 min and then rose gradually thereafter, reaching a level of
4.3 ± 1.2 mM at 90 min, the end of the experiment
(Fig. 3A, Intact). With the administration of leptin 10 min before the
experiment (Fig. 3A, Intact), the plasma glucose level decreased to a
minimum of 2.1 ± 0.3 mM at 15 min, similar to that in
the control protein-treated rats, but increased thereafter to higher
levels at 45 and 90 min compared with those in the control
protein-treated rats.
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, Intact). The effect of leptin on
plasma glucose and plasma glucagon responses to an iv bolus insulin
injection in rats pretreated with 6-OHDA are also shown in Fig. 3
(Sympathectomy). In the rats that had been pretreated with 6-OHDA, the
plasma glucose concentrations in both groups changed in the same way
after insulin injection regardless of administration of leptin or the
control protein (Fig. 3A, Sympathectomy). The same was true for changes
in plasma glucagon level after insulin injection (Fig. 3B, Sympathectomy).
Effect of leptin on glucagon secretion from perfused rat
pancreas
Figure 4 shows changes in the mean
levels of glucagon in the effluents from perfused rat pancreas with the
perfusate supplemented with 5.6 and 1.7 mM
D-glucose in the presence or absence of leptin. Without
leptin, the mean glucagon levels increased from a basal level of
35 ± 8 fmol/min to a peak level of 219 ± 137 fmol/min 12
min after changing to the perfusate with 1.7 mM
D-glucose and essentially remained at this level thereafter
until it decreased, several minutes before the end of the experiment.
With the addition of leptin to the perfusate, changes in mean glucagon
secretion during perfusion with 1.7 mM
D-glucose were quite similar to those in the experiment
without leptin. Throughout the experiment, no significant differences
in the corresponding glucagon secretion between the two groups were
observed.
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, lane 1 vs. lanes 2 and 3;
Fig. 5B, lane 1 vs. lane 6). The injection of 6-OHDA 48
h before the excision of BAT (24 h before the start of continuous
infusion of leptin) completely abolished the enhancement of UCP1 mRNA
expression by leptin (Fig. 5B, lanes 4 and 5 vs. lane 6).
6-OHDA injection to rats without leptin infusion had no effect on the
expression levels of UCP1 mRNA (Fig. 5B, lanes 1 vs. lane 2
and 3).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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These results along with the well documented findings that alterations in sympathetic tone affect basal (30) and glucose-stimulated insulin secretion (31) suggest that leptin may modulate pancreatic endocrine functions through its stimulative activity of the sympathetic nerves ending around the pancreatic endocrine cells. It is, however, difficult to explain why leptin administration suppressed glucose-stimulated insulin secretion in vagotomized, but not in intact, rats. However, it can be reasonably presumed that leptin-induced sympathetic activity might be exaggerated in the former due to the lack of counteraction by the parasympathetic nerve, whereas it might be counterbalanced in the latter by activation of a parasympathetic system, which per se augments glucose-stimulated insulin secretion. Hisatomi et al. (45) reported that the depletion of norepinephrine from sympathetic nerve endings by treatment with 6-OHDA lowered the pancreatic norepinephrine content, which was confirmed in our experiments. Therefore, the leptin-induced suppression of insulin secretion would be expected to be abolished in rats that underwent both vagotomy and chemical sympathectomy. This was, in fact, observed, thus supporting the idea that leptin-induced suppression of insulin secretion is mediated through its adrenergic stimulation. However, we found no significant effect of the pretreatment with 6-OHDA on plasma insulin and glucose responses to iv glucose. It can be assumed that the chemical sympathectomy alone could not enhance insulin secretion in response to hyperglycemia.
To our knowledge, this study represents the first investigation of the
effect of leptin on glucopenia-induced glucagon secretion from the
perfused rat pancreas, although its effect on the glucose-induced
suppression of glucagon secretion has been reported (20, 26). Leptin,
when tested at a concentration of 20 nM, failed to affect
the stimulative action of glucopenia on glucagon secretion from the
perfused rat pancreas. Moreover, we were unable to detect any
significant effect of 80 nM leptin on glucopenia-induced
glucagon secretion from cultured pancreatic islets (unpublished
observation). Judging from our data together with Leclercq-Meyer’s
finding (20, 26) of the failure of 10 nM leptin to
counteract the effects of glucose on glucagon secretion in the perfused
rat pancreas, it is likely that leptin per se, at the dose
used here, does not significantly affect glucagon secretion from
pancreatic -cells. It has been reported (45) that in the isolated
rat pancreas, adrenergic mediation accounts for most of the glucagon
response to glucopenia, which is controlled within the pancreas,
possibly through a direct enhancement by glucopenia of norepinephrine
release from nerve endings. Hypoglycemia-induced glucagon secretion has
also been reported to be accompanied by pancreatic norepinephrine
spillover in the conscious dog (46), suggesting that neural signaling
to pancreatic -cells is responsive to changes in the glucose level.
Leptin administration may increase glucopenia-induced norepinephrine
release from nerve endings and bring about an augmented plasma glucagon
response to hypoglycemia in intact rats. The fact that the
leptin-induced augmentation of the plasma glucagon response to
hypoglycemia was abolished in rats that had been treated with 6-OHDA is
compatible with the idea that the effects of leptin on glucagon
secretion are mediated by the autonomic nervous system. The findings of
others appear to be inconsistent with ours, in that leptin affected the
levels of neither plasma glucose, insulin, nor glucagon in intact
animals when given by iv (28, 47) or intracerebroventricular (29, 47)
injection. However, this is not the case. In our experiments, no effect
of leptin on insulin secretion were detected in intact rats. The
suppressive effect of leptin on insulin secretion and the augmented
effect on plasma glucose levels were observed only after an iv glucose
load into vagotomized rats. Furthermore, the stimulative effect of
leptin on glucagon secretion was detected only in response to
hypoglycemia.
At present, we have no data on the sites where iv administrated leptin acts, i.e. the central nervous system or nerve endings in the pancreas. The findings that intracerebroventricular administration of leptin stimulated sympathetic activity (29) and that the OB-Rb, which performs the highest signaling activities among the leptin receptors, are most abundant in the brain, especially the hypothalamus (10, 11), suggest that the observed effects of peripheral leptin on pancreatic endocrine functions are probably the result of transport into the central nervous system by a specific transport process (48, 49) and subsequent interaction with receptors there. However, the possibility cannot be excluded that the iv administrated leptin activates afferent nerve terminals, as reported by Wang et al. (50), which transmit signals to the central nervous system, resulting in stimulation of the sympathetic nerves.
In summary, iv administration of leptin suppressed plasma insulin and
augmented plasma glucose responses to an iv glucose load in vagotomized
rats, whereas these effects of leptin were not observed in intact rats
or rats that underwent both vagotomy and chemical sympathectomy. An iv
administration of leptin augmented the plasma glucagon response to
insulin-induced hypoglycemia in intact rats. However, this effect of
leptin on pancreatic -cells was absent in chemically
sympathectomized rats. In an experiment with perfused rat pancreas,
leptin showed a suppressive effect on insulin secretion, but showed no
significant effect on glucopenia-induced glucagon secretion. An iv
infusion of leptin augmented UCP1 mRNA expression in BAT in the intact
rat, whereas no such effect of leptin on UCP1 mRNA expression was
observed in BAT in chemically sympathectomized rats. These findings
suggest that leptin, when administrated intravenously, affects
pancreatic endocrine functions, probably through its stimulatory effect
on the sympathetic nervous system.
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Acknowledgments |
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Footnotes |
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2 Both authors contributed equally to this work.
Received January 22, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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proline) of
the leptin receptor (OB-R) cDNA is the only mutation found in the
Zucker fatty (fa/fa) rat. Biochem Biophys Res Commun 224:597–604[CrossRef][Medline]
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 S. P. Commins, P. M. Watson, N. Levin, R. J. Beiler, and T. W. Gettys Central Leptin Regulates the UCP1 and ob Genes in Brown and White Adipose Tissue via Different beta -Adrenoceptor Subtypes J. Biol. Chem., October 13, 2000; 275(42): 33059 - 33067. [Abstract] [Full Text] [PDF]
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) on basal (3.3 mM glucose) and glucose-induced
(11.1 mM glucose) insulin secretion from perfused rat
pancreas. Data are expressed as the mean ± SD insulin
secretion per min (n = 5 in each group with leptin or vehicle). *,
P < 0.05; §, P < 0.01
(vs. vehicle).
