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Laboratory of Animal Reproduction, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan; the Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University (Y.T., N.T., I.M.), Nagoya 468-8503, Japan; and the Reproductive Sciences Program (R.C.T., D.L.F.) and the Departments of Obstetrics and Gynecology and Biology (D.L.F.), University of Michigan, Ann Arbor, Michigan 48109
Address all correspondence and requests for reprints to: Dr. Kei-ichiro Maeda, Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan. E-mail: keimaeda{at}agr.nagoya-u.ac.jp
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Introduction |
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Peripheral organs such as pancreas, fat tissue, and the gastrointestinal tract are able to sense the nutritional state and secrete specific hormones to maintain metabolic homeostasis (10). Among these tissues, ß-cells in the islets of Langerhans are known to have a glucose-sensing mechanism to secrete insulin in response to increased blood glucose levels. These cells have both a specific subtype of the glucose transporter-2 (GLUT2) and a high Km hexokinase [glucokinase (GK)] (11, 12, 13). GK is distinguished from other hexokinase by features such as its low affinity for glucose and its lack of inhibition by glucose-6-phosphate (14). GLUT2 also possesses a high Km constant for glucose (15). Because pharmacological blockade of GK with mannoheptulose, which is an inhibitor of glucose phosphorylation, suppresses the insulin secretory response to glucose in islets (16), and mice in which the GK gene is disrupted do not secrete insulin in response to the administration of glucose (17, 18, 19), GK is considered to play a critical role in sensing blood glucose levels.
As the presence of GK is a prerequisite for glucose sensing in the pancreatic ß-cells, it is reasonable to postulate that GK also plays a role in glucose sensing in the brain to monitor glucose availability. There is physiological evidence to support the idea that a glucose-sensing mechanism similar to that in pancreatic ß-cells is localized in the brain. Fourth ventricular injection of alloxan, which inhibits GK activity (20), causes feeding behavior at the low level (21) and eliminates 2-DG-induced feeding at the high level (8). However, there are few studies indicating the localization of GK in the brain.
In the present study the immunohistochemical localization of pancreatic GK was determined in the brain, with a focus on the lower brain stem. We paid much attention to the AP and NTS because of their significance in previous reports. We also characterized the GK-like immunoreactive cells in the brain using dual immunohistochemistry with reference to glucose transporters as well as specific cell-type markers. In addition, we examined the subcellular localization of GK-like immunoreactivity using confocal laser microscopy.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Antibodies
A goat antiglucokinase polyclonal antibody raised against a
peptide corresponding to amino acids 2–20 of human pancreatic
glucokinase (GKP) was used (anti-GKP antibody, 1:25 for
immunohistochemistry; Santa Cruz Biotechnology, Inc.,
Santa Cruz, CA). The rabbit polyclonal antiliver glucokinase (GKL)
antibody (1:50) was raised against purified liver GK and has been
described previously (22). The rabbit anti-GLUT2 antibody used (1:2000;
Biogenesis, New Fields, UK) was raised against a fusion
protein consisting of the C-terminal 25 amino acids of the rat GLUT2,
glutathione-S-transferase, and a synthetic 13-amino acid
C-terminal sequence of rat GLUT2. We used a rabbit polyclonal antibody
to GLUT1 (1:100; Santa Cruz Biotechnology, Inc.) and GLUT4
(1:25; Chemicon International, Inc., Temecula, CA). Other reagents used
were a mouse monoclonal antibody to the microtubule-associated
protein-2 (MAP2) that recognizes MAP2a, MAP2b, and MAP2c; protein
markers of neurons (1:500; Sigma, St. Louis, MO); a rabbit
polyclonal antibody to the glial fibrillary acidic protein (GFAP), a
protein marker of glial cells (1:10; DAKO Corp., Glostrup,
Denmark); a mouse monoclonal antibody to vimentin, a protein marker of
ependymocytes (23) (1:100; Roche Molecular Biochemicals
GmbH, Mannheim, Germany); and a rabbit polyclonal anti-serotonin
antibody (1:1,000; DiaSorin, Inc., Stillwater, MN).
The biotinylated donkey antigoat IgG (1:400), FITC-conjugated donkey antigoat IgG (1:400), Cy3-conjugated donkey antirabbit IgG (1:800), and Cy3-conjugated donkey antimouse IgG (1:800) were purchased from Jackson ImmunoResearch Laboratories, Inc. (West Grove, PA). The biotin-conjugated goat antirabbit IgG (1:200) was purchased from Vector Laboratories, Inc. (Burlingame, CA).
Fixation
Ten animals were perfused transcardially with 50 ml 0.05
M PBS (pH 7.5) at room temperature followed by 100 ml
ice-cold 4% paraformaldehyde in 0.05 M phosphate buffer
(PB; pH 7.5) under deep pentobarbital anesthesia. The brain, liver, and
pancreas were removed, postfixed by the same fixative overnight at 4 C,
and cryoprotected with 30% sucrose in 0.05 M PB for 2–3
days at 4 C. The brain and liver were sectioned at 30-µm thickness
with a cryostat. The sections were stored in a cryoprotectant at -20 C
until stained. The pancreas was sectioned at 20-µm thickness,
thaw-mounted on glass slides, dried, and preserved at -30 C.
The fourth cerebroventricular area collected from five rats was used for whole mount immunostaining. The brain was removed immediately after the decapitation. The dorsal portion of the medulla oblongata including the AP and the NTS was removed under a dissecting microscope. The excised tissues were fixed with 4% paraformaldehyde in 0.05 M PB at 4 C overnight and were rinsed four times for 15 min each time in 0.05 M PBS.
Immunohistochemistry
The localization of the target proteins was determined by
immunoperoxidase histochemistry or fluorescence immunohistochemistry.
All incubations were carried out at 4 C, and the sections were rinsed
four times for 15 min each time with 0.05 M PBS between
each step unless otherwise indicated. For immunoperoxidase
histochemistry, free floating sections or glass slide-mounted sections
were 1) incubated with 0.05 M PBS containing 0.6%
H2O2 at room temperature
for 30 min to eliminate endogenous peroxidase activity, 2) incubated
with the paper-filtrated 10% skim milk in 0.05 M PBS
containing 0.05% Triton X-100 for 60 min at room temperature to block
nonspecific binding of antibodies, 3) incubated for 4 days under
constant shaking with primary antibodies diluted in the same solution
used for blocking nonspecific binding of antibodies as described above,
4) incubated with biotinylated secondary antibody for 60 min at room
temperature with constant shaking, 5) incubated with the
streptavidin-biotin complex solution (Vector Elite ABC kit,
Vector Laboratories, Inc.) for 60 min at room temperature.
The 4-day incubation period was chosen to lower the background level of
immunostaining. Sections were rinsed four times for 15 min each time in
0.1 M Tris-HCl buffer (pH 7.5). The immunoreactivities were
visualized by 0.1% 3,3'-diaminobenzidine (Sigma) and
0.02% H2O2 solution
containing 0.25% NiCl2 in 0.1 M
Tris-HCl buffer in the dark. Free floating sections were mounted on the
gelatin-coated glass slides, and all sections were observed under a
light microscope (Eclipse E800, Nikon, Tokyo, Japan). The
images were directly digitized by a CCD camera (PA-160,
Nikon) and printed on a Fuji Pictrography
3000 (Fuji Photo Film Co., Ltd., Tokyo, Japan).
For fluorescence immunohistochemistry, sections were incubated in the same blocking solution used in immunoperoxidase histochemistry after rinsing four times for 15 min each time in 0.05 M PBS. Then, sections were incubated in the primary antibody for 4 days with constant shaking. In dual immunohistochemistry, sections were incubated with a mixture of two primary antibodies. The sections were then rinsed four times for 15 min each time in 0.05 M PBS and incubated with the fluorescence-conjugated secondary antibodies for 2 h in the dark at room temperature. After incubation of the secondary antibody, free floating sections were mounted on glass slides, and all sections were coverslipped with Fluorogard antifade reagent (Bio-Rad Laboratories, Inc., Hercules, CA). They were examined under a confocal laser scanning microscope (MRC 1024, Bio-Rad Laboratories, Inc.).
For whole mount preparations, tissues were incubated in 0.05 M PBS containing 0.5% Triton X-100 overnight to enhance the permeability of antibodies. The sections were immersed in the same blocking solution used in the immunoperoxidase histochemistry overnight. After blocking nonspecific binding, tissues were transferred to the primary antibody solution containing rabbit anti-GLUT2 antibody for 4 days. Tissues were then washed four times for 15 min each time in 0.05 M PBS and incubated with the solution containing Cy3-conjugated donkey antirabbit IgG overnight. After rinsing four times for 15 min each time in 0.05 M PBS, they were mounted on glass slides and covered with Fluorogard and a coverslip. The dorsal view of the three-dimensional digital image was constructed from 100 pieces of sections scanned at 2-µm intervals with a confocal laser scanning microscope.
Specificity of immunostaining
To test the specificity of the anti-GKP, 60 µl antibody
solution containing 1.2 µg antibodies were incubated at 4 C overnight
with 60 µg of the synthetic antigen peptide (Santa Cruz Biotechnology, Inc.). To examine the specificity of anti-GLUT2
antibody, the antibody was adsorbed with the solution containing the
rough plasma membrane fraction prepared from rat liver, because the
membrane fraction of the liver is rich with GLUT2 (24). Five grams of
the rat liver were homogenated in 20 ml 1 mM
NaHCO3 (pH7.5), filtrated, and diluted with 480
ml 1 mM NaHCO3. The homogenate was
centrifuged at 1500 x g for 10 min, and 210 ml 1
mM NaHCO3 was added to the
resultant precipitate. The mixture was centrifuged at 100 x
g for 5 min and at 1000 x g for 10 min
again. The fluffy layer was removed, diluted with 105 ml 1
mM NaHCO3, and used as a
rough membrane fraction. The protein concentration in this solution
(3.61 mg/ml) was measured by the Bio-Rad Laboratories, Inc., protein assay kit in accordance with the Bradford method
(25). The 200 µl anti-GLUT2 solution containing 0.02 µg antibodies
were incubated with 5 µl plasma membrane solution at 4 C overnight,
and then used for immunohistochemistry.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). In addition, cells
surrounding the third and lateral ventricles in the forebrain
were also stained by anti-GKP antibody (data not shown). Double
staining with anti-GKP and antivimentin antibodies revealed that
GKP-like immunoreactive cells on the ventricular walls, such as the
central canal (Fig. 1A, white), the fourth ventricle (Fig. 1B, white), and the third ventricle (Fig. 1C, white), were immunoreactive to vimentin. In the dorsal and
ventral ends of the central canal (Fig. 1A, right) and the
intermediate part of the third ventricle on dorsoventral axis around
the hypothalamus (Fig. 1C, right), the tapering processes of
ependymocytes were stained with anti-vimentin antibody, but lacked the
GKP-like immunoreactivity (Fig. 1, A and C, left). There was
no GKP immunoreactivity in the ventral one third of the third
ventricular wall (data not shown), an area known to be comprised of
ependymal tanycytes (26).
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, A and B, black), the raphe
pallidus (Fig. 2, A and C, black), the raphe magnus, and the
raphe pontis (data not shown). This immunoreactivity was localized
within both soma and dendrite-like processes. Clusters of the GKP-like
immunoreactive cells were also located around the ventrolateral
medullary surface (Fig. 2, A and D, black) and fourth
ventricle (data not shown). Figure 2D shows immunopositive processes
that appear adjacent to a blood vessel in the ventrolateral medulla
(arrowheads). No immunopositive cells were located in the AP
and the NTS (data not shown). In the hypothalamus, no immunoreactivity
of GKP was found, except for the ependymocytes and a few small cells
near the third ventricle (data not shown). Dual immunostaining with
anti-GKP and either anti-MAP2 or anti-GFAP antibodies in the raphe
obscurus (Fig. 2, E and F) and the dorsal raphe nucleus (Fig. 2, G and
H) identified cells that contain both MAP2-like (E, right,
or G, lower) and GKP-like (E, left, or G,
upper) immunoreactivities in the cytoplasm and the processes
of the cells in both nuclei. On the contrary, GFAP (F,
right, or H, lower) immunoreactivity was not
colocalized with GKP-like (F, left, or H, upper)
immunoreactivity (Fig. 2, F and H). Colocalization of GKP and MAP2 was
also found in other raphe nuclei, including the raphe pallidus (Fig. 2I). Figure 2J represents a high magnification image of colocalization
of the MAP2- and GKP-like immunoreactivities in the raphe obscurus.
Vimentin immunoreactivity was not found in the cells of the raphe
nuclei (data not shown). These results strongly suggest that these
GK-like immunoreactive cells in raphe nuclei are most likely
neurons.
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) and hypothalamus (data not shown) were
also stained with anti-GKP antibody (green). GLUT1-like
immunoreactivity (red) surrounded the wall of microvessels,
whereas GKP-like immunoreactivity was seen in the cytoplasm of the
cells. These data suggest that the GKP-like immunoreactive cells
adjacent to the blood vessels are most likely endothelial cells.
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, A–E). A three-dimensional image of
whole mount preparation constructed from the confocal laser scanning
microscopic sections revealed that GLUT2-like immunoreactivities were
located along the wall of the fourth ventricle (Fig. 3F, white), but not on the dorsal surface of the AP. GLUT2-like
immunoreactivities were located on the cilia (Fig. 3G, black), whereas GKP-like immunoreactivities were located in
the cytoplasmic area (Fig. 3, A–E). GLUT2-like immunoreactivity was
eliminated when the antibody was preincubated with the plasma membrane
fraction of rat liver, which are known to be rich with GLUT2 (Fig. 3H).
Similar to the distribution of GLUT2-like immunoreactivity, GLUT1-like
immunoreactivity (red) was also found in the cilia of the
ependymocytes surrounding the central canal, fourth ventricle, third
ventricle (data not shown), and lateral ventricle (Fig. 3I). The
cytoplasmic area of ependymocyte was dually stained with anti-GKP
(green) and anti-GLUT4 (red) in both the lower
brain stem (Fig. 3K) and the forebrain (data not shown). Slight
GLUT4-like immunoreactivities were also found in the plasma membrane,
but not in the cilia or the tapering processes of ependymocytes. The
subcellular localization of GLUT4 in ependymocytes is similar to that
in skeletal and cardiac muscle fibers, in which the immunoreactivities
are located in both the cytoplasmic area and the plasma membrane (data
not shown).
Neurons in the raphe nuclei
Results from dual immunohistochemistry using anti-GKP and
antiserotonin antibodies in raphe nuclei confirmed that serotonin
immunoreactivities were identified in all GKP-like immunoreactive
neurons in the raphe nuclei (Fig. 4). This
colocalization includes the raphe obscurus, the raphe pallidus (data
not shown), the dorsal raphe nucleus (Fig. 4A, white), the
median raphe nucleus (Fig. 4B, white), the raphe magnus, and
the raphe pontis (data not shown). The GK-like immunopositive neurons
in the ventrolateral part of medulla oblongata also displayed serotonin
immunoreactivity (Fig. 4C, arrowheads). Serotonin
immunoreactivity was expressed in both the cytoplasm and processes of
these neurons. GK-like immunoreactivity was not found in fine
serotonin-immunoreactive fibers, which might be axons. None of these
serotonergic neurons was positively stained with anti-GLUT1,
anti-GLUT2, or anti-GLUT4 antibodies (data not shown).
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, white). By contrast, no pancreatic GK-like immunoreactivity
was found in the liver (Fig. 5B). Using an anti-GK antibody raised
against liver type-GK (anti-GKL) on liver tissue sections, cell nuclei
of hepatocytes were intensely fluorescent (Fig. 5C, white).
These subcellular localizations of GK in the islets of Langerhans and
hepatocytes are similar to those reported previously (13, 22, 27),
indicating that the anti-GKP antibody used in the
present study recognizes the pancreatic-type GK, but not the liver-type
GK. Positive immunoreactivities observed in the ependymocytes were
eliminated by the preadsorption of the anti-GKP antibody with the
synthetic peptide derived from the N-terminus of GK of pancreatic type
as described in Materials and Methods (Fig. 5D, white). No positive immunoreactivity was found in these
regions using rabbit anti-GKL raised against the liver-type GK (data
not shown). The positive immunoreactivity found in neurons of the raphe
nuclei eliminated with preadsorption using the synthesized peptide
comprised of the N-terminus of pancreatic-type GK (Fig. 5E, white).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Ciliated ependymocytes also
contain specific types of glucose transporter immunoreactivities,
i.e. GLUT2 and GLUT1 on cilia and GLUT4 predominantly in
the cytoplasmic area. In the pancreas, GK is thought to play an
important role in glucose sensing, as point mutations in the
glucokinase gene produces mice that lack normal insulin secretory
responses (17, 18). Further, homozygous GK null mice cannot survive
after birth (19). GK due to its comparatively lower affinity for
glucose creates an intracellular ATP/ADP ratio based upon intercellular
glucose levels (11). It is a change in ATP concentrations in response
to increased glucose that is thought to alter the
K+-ATP channel, which, in turn, stimulates
insulin secretion from the ß-cells (28). In this context, the
GKP-like immunoreactive cells in the brain, i.e.
ependymocytes, serotonergic neurons, and endothelial cells, may
represent components of another glucose-sensing system similar to that
seen in pancreatic ß-cells.
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Several lines of evidence suggest that ependymocytes play a role in transporting nutrients from the cerebrospinal fluid (CSF) to the underlying neuropil. GKP-like immunoreactivities in ependymocytes in the wall of third cerebroventricle have been described briefly (29), like our observation in third cerebroventricle. Due to the presence of monocarboxylate transporter-1 and -2, ependymocytes appear capable of transporting lactate and other monocarboxylates (30, 31). Further, GLUT1- and GLUT2-like immunoreactivities and GLUT4 messenger RNA expression have been identified in ependymocytes (Refs. 32, 33 and the present results). The presence of GLUT1- and GLUT2-like immunoreactivities on cilia of these ependymocytes, documented in the present study, suggests that these transporters are localized to cell surfaces where efficient transport of glucose would take place. On the other hand, GKP-like immunoreactivity was found in the cytoplasm of GLUT1- or GLUT2-positive ependymocytes as in pancreatic ß-cells (24). Given this anatomical localization of glucose transporters and GK, it seems reasonable to propose that glucose would be converted to glucose-6-phosphate (the rate-limiting conversion of glucose to ATP) soon after its entry into the ependymocytes. Taken together, it is possible that ciliated ependymocytes detect metabolic alternations in nutrients in CSF per se. It has been shown that glucose passes from blood to CSF at low affinity with a concentration gradient (34). The brain, therefore, could monitor the CSF glucose levels to detect the changes in blood glucose levels. The present study also demonstrated that GLUT4-like immunoreactivity was found within the cytoplasm of ependymocytes in ad libitum-fed rats. It is well established that GLUT4 is located in skeletal muscle and adipose tissue and translocates from cytoplasm to plasma membrane in response to insulin (35), whereas pancreatic ß-cells and hepatocytes do not have GLUT4 (24). Although the precise function of GLUT4 remains to be fully elucidated, it is tempting to speculate that this GLUT4 plays an important role in the transport of glucose from the CSF to the neuropil when insulin concentrations in blood are high and composes part of the insulin-dependent glucose-sensing mechanism.
If ependymocytes serve to sense nutrients in the CSF, how is this system regulated? Some possible counterregulatory processes come from previous evidence demonstrating that particular growth factors suggested to be satiety factors (36, 37) increase in the CSF after feeding or glucose administration (38). Importantly, fibroblast growth factor I (FGF-I) and FGF-I messenger RNA have been detected in ependymocytes after glucose treatments (38). Perhaps the ependymocytes send nutritional information to other cells through secretion of specific peptides such as FGF-I.
The present study found that serotonergic neurons in the raphe nuclei contain GK-like immunoreactivities. The serotonergic system is known to be involved in the regulation of feeding behavior. Serotonin-1B and -2C receptor agonists suppress food intake in rats (39), and mice lacking serotonin-2C receptor display overweight (40). Furthermore, some reports have suggested that particular raphe nuclei are related to glucose sensing: Dinh et al. demonstrated that food intake increases after a local injection of 5-thioglucose into the ventral medulla in which the raphe obscurus and the raphe pallidus is located (41). Blood insulin increases when the raphe obscurus is chemically stimulated (42). Leurope et al. found GLUT2 immunoreactivity in the raphe obscurus (43). These findings emphasize the importance of raphe obscurus as a glucose-sensing area. On the other hand, peripheral nutritional information might be relayed by the serotonergic neurons in the dorsal raphe nucleus, because the dorsal raphe nucleus has been reported to contain receptors for the fat hormone, leptin (44). These considerations together with the present results raise the possibility that specific populations of serotonergic neurons are equipped with a glucose-sensing mechanism and therefore may be capable of relaying nutritional information. In the present study a large number of GK-like immunoreactive processes were found closely associated with the blood vessels. In addition, numerous serotonergic fibers have been found to be in contact with CSF and ependymocytes (45), reinforcing the idea that serotonergic neurons could receive nutritional signals from both blood and CSF.
In conclusion, GK-like immunoreactivity is located in three types of cells in the brain, namely ciliated ependymocytes, serotonergic neurons, and endothelial cells. Ciliated ependymocytes also displayed GLUT2- and GLUT1-like immunoreactivities on the cilia and GLUT4-like immunoreactivity in the cytoplasm. Overall, the present study provides strong evidence for pancreatic GK-like immunoreactivity in the brain being closely associated with glucose-sensing mechanisms.
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Acknowledgments |
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Footnotes |
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Received May 12, 1999.
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S. Ohkura, T. Tanaka, S. Nagatani, D. C. Bucholtz, H. Tsukamura, K.-I. Maeda, and D. L. Foster Central, But Not Peripheral, Glucose-Sensing Mechanisms Mediate Glucoprivic Suppression of Pulsatile Luteinizing Hormone Secretion in the Sheep Endocrinology, December 1, 2000; 141(12): 4472 - 4480. [Abstract] [Full Text] [PDF]
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