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1Department of Veterinary Physiology, Faculty of Agriculture, and 2Department of Basic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, Gifu 501-1193; and 3Department of Oral Physiology, School of Dentistry, Meikai University, Saitama 350p-0283, Japan
Submitted 26 December 2002; accepted in final form 5 March 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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; Graff and
Stellar 1962; Weingarten
1982). A striking characteristic of VMH lesioned rats is their
hyperreactivity to the stimulus properties of foods
(Corbit and Stellar 1964; Graff
and Stelilar 1962; Weingarten
1982). When given a relatively palatable diet including standard
laboratory chow, they eat far more than normal animals. In contrast, if the
palatability of the standard diet is reduced by the addition of quinine-HCl
(QHCl), the hyperphagic animals reduce their food intake markedly, while
normal animals maintain a relatively constant food intake. These feeding
characteristics have been represented as "finickiness."
Although alteration in taste sensitivity and preference in VMH-lesioned
rats have been well documented at the behavioral level, possible changes in
peripheral taste nerve responsiveness accounting for the behavioral
alterations are not known. In genetically diabetic db/db mice, it has
been demonstrated that responses of the chorda tympani (CT) nerve to sugars
are greater than those of lean control mice
(Ninomiya et al. 1995).
Recently, Kawai et al. (2000)
showed that leptin directly suppresses the sensitivities of taste receptor
cells to sweet substances. Thus it is rational to suppose that the enhanced
responses of the CT nerve to sugars in db/db mice are due to defects
of the suppressive effect of leptin, because these mice express a mutant
leptin receptor (Chen et al.
1996; Chua et al.
1996; Lee et al.
1996). VMH-lesioned rats exhibit hyperleptimia as in
db/db mice (Satoh et al.
1997; Suga et al.
1999,
2000), but leptin receptors in
taste receptor cells would be unaffected by VMH destruction itself. Therefore
it is of interest whether taste nerve responsiveness to sugars is elevated or
not in VMH-lesioned rats to know the direct effects of leptin on taste-sensing
mechanism more precisely.
In the present study, we recorded responses of the CT nerves of the VMH-lesioned rats to various taste stimuli including sugars. Our results showed that the VMH-lesioned rats possess greater sensitivities to sugars except for fructose but not to other taste stimuli than control rats. Additional experiments using dietary obese and streptozotocin (STZ)-induced diabetic rats indicate that some common metabolic impairments might be related to the enhanced gustatory neural responses to sugars in addition to the direct effects of leptin.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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We used female Wistar rats, weighing 180–230 g (6–7 wk old) at the time of delivery from Japan SLC (Shizuoka, Japan). They were housed individually in plastic cages at 22 ± 2°C (mean ± SD) with a 12:12-h light-dark cycle (light on 0700–1900 h) and given free access to laboratory chow (LABO MR Stock, Nihon-Nosan, Yokohama, Japan) and water. The rats were maintained in the laboratory for ≥2 wk after arrival to permit them to acclimate to their surroundings before experiments began (8–9 wk old, 250–300 g at the start of experiments).
The VMH was destroyed bilaterally by an electrolytic lesion according to
the procedure described by Saito et al.
(1985) with slight
modifications. Briefly, rats were anesthetized with pentobarbital sodium (40
mg/kg ip) and were placed in the stereotaxic instrument and positioned with
the nose bar set 5 mm above the interaural line. The electrode, consisting of
an insulated stainless steel insect pin with exposed tip, was positioned 0.6
mm lateral to the Bregma and 9.0 mm below the skull surface. A direct anodal
current of 1.2 mA for 4 s was passed through the electrode. The current pass
was repeated three times with 30-s interval. For sham controls, the same
surgical procedures were performed except that no current was passed. Only
animals that developed hyperphagia and rapid gain in body weight compared with
sham-lesioned rats were used. Sham-lesioned animals were used as controls for
possible damage to nerve fibers by the procedure. We designated the early
progressive phase of obesity as the dynamic phase (2 wk after creating VMH
lesions) and the late phase of obesity as the static phase (15–18 wk
after VMH lesions). At the end of the experiments, localization of the lesions
was verified microscopically in serial frontal sections of the brain stained
with cresyl violet.
Dietary obese rats and insulin-deficient diabetic rats have been also prepared to provide a comparison with VMH-lesioned rats. To induce dietary obesity, some rats were maintained on a high-fat diet for 18–20 wk. The high-fat diet contained the following (g/kg): 330 lard (Oriental Yeast, Tokyo), 50 corn oil (Oriental Yeast), 200 casein (Oriental Yeast), 225 corn starch (Oriental Yeast), 100 sucrose (Oriental Yeast), 50 cellulose (Oriental Yeast), 35 minerals (AIN76 mineral mixture; Oriental Yeast), and 10 vitamins (AIN76 vitamin mixture; Oriental Yeast). Control animals were given a standard laboratory chow (MR stock; Japan SLC, Shizuoka, Japan). Diabetic rats were made with a single-bolus intraperitoneal injection of STZ (60 mg/kg; Sigma, St. Louis, MO) dissolved in 0.1 M citric buffer (pH 4.2). The diabetic animals with fasting blood glucose concentrations of >300 mg/dl were remained untreated throughout the duration of the study.
Neural recording procedure
The CT nerve responses to various taste stimuli were recorded as previously
described (Shimizu and Tonosaki
1999). The electrical activity of the whole CT nerve was fed to an
AC amplifier and integrated with a time constant 1.0 s. The integrated
electrical activity was led to and analyzed with PowerLab software
(ADInstruments, Mountain View, CA). The height of steady-state responses of
the integrated CT nerve activity, which were measured at 10 s after the onset
of stimuli, were normalized to means of responses to 0.1 M NH4Cl
being taken as unity (1.0). A series of taste stimulations was repeated at
least three times, and the reproducible responses were considered to be the
real responses of the respective rats.
Solutions used as chemical stimuli were (in M) 0.5 sucrose, 0.5 glucose,
0.5 fructose, 0.5 maltose, 0.05 NaCl, 0.01 HCl, 0.01 QHCl, and 0.05 monosodium
glutamate (MSG). All of the test solutions were made fresh each week and
refrigerated when not in use. The details of chemical stimulation procedures
were described previously (Ogiso et al.
2000; Shimizu and Tonosaki
1999).
Measurements
Blood samples were obtained after a 6-h fast (9:00 AM to 3:00 PM). Plasma glucose levels were determined by the glucose oxidase method (Glucose B-test, Wako Pure Pharmaceutical, Osaka, Japan). Plasma insulin and leptin concentrations were determined by ELISA kits (Morinaga, Yokohama, Japan).
Statistical analysis
All values were presented as means ± SE. Statistical significance was examined by an ANOVA, with post hoc testing by means of Duncan's multiple range test. Comparisons between groups were made by Student's t-test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Figure 1 shows integrated responses of the CT nerve to various taste stimuli in sham-operated and VMH-lesioned rats. In the dynamic phase (2 wk after creating VMH lesions), there was no significant difference in the nerve responses to any taste stimulus between sham-operated and VMH-lesioned rats (Fig. 1A). In contrast, the magnitude of response to sucrose in the static phase (15–18 wk after VMH lesions) was prominently greater than that in age-matched control (Fig. 1B). Magnitudes of responses to NaCl, HCl, QHCl, and MSG were unchanged even in the static phase (Fig. 1B).
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In addition to sucrose, maltose, glucose, and fructose were also used as taste stimuli to see whether the enhancement of the CT nerve responsiveness is specific for sucrose or generalized for other sugars. As shown in Fig. 2A, the nerve responses to the four sugars were similar in both VMH-lesioned rats in the dynamic phase and their age-match sham-operated animals. In the static phase, relative magnitudes of responses to maltose and glucose, in addition to sucrose, were significantly larger than that in control animals, although no such difference was evident in response to fructose (Fig. 2B).
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Plasma glucose, insulin, and leptin concentrations in dynamic and static phase of VMH-lesioned rats
Table 1 shows plasma glucose, insulin, and leptin concentrations in the dynamic and the static phases of VMH-lesioned rats. Plasma glucose levels did not significantly change in the dynamic phase, whereas it prominently increased in the static phase. VMH-lesioned rats in the dynamic phase had a 3-fold higher plasma insulin concentration and a 4.5-fold higher plasma leptin concentration than those in controls. These levels were further increased in the static phase. In sham-operated rats, plasma glucose and insulin levels were comparable at 2 and 15–18 wk after operation, but plasma leptin levels were significantly increased during this period.
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Chorda tympani nerve responses to various taste stimuli in diet-induced obese rats and STZ-diabetic rats
The representative recordings of the CT nerve responses to various taste stimuli from rats maintained by high-fat diet and STZ-diabetic rats are shown in Figs. 3 and 4, respectively. As was observed in VMH-lesioned obese rats, high-fat diet-induced obese rats showed greater CT nerve response to sucrose than control rats, although such a difference was not evident in response to NaCl, HCl, QHCl and MSG (Fig. 3). In STZ-diabetic rats, there was no notable change in the CT nerve responses to any stimuli used, when the nerve responses were recorded 2 wk after STZ injection (data not shown). However, in rats maintained for 4 wk after STZ injection, the magnitude of response to sucrose was specifically increased as compared with vehicle-injected control (Fig. 4).
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Relative magnitudes of responses to sucrose, maltose, glucose, and fructose in diet-induced obese and STZ-induced diabetic rats were shown in Fig. 5, A and B, respectively. Similar to VMH-lesioned rats in the static phase, responses to maltose and glucose were also significantly larger than those in control animals, although no such difference was observed in response to fructose.
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Plasma glucose, insulin, and leptin concentrations in diet-induced obese rats and STZ-diabetic rats
Table 2 represents plasma
glucose, insulin, and leptin concentrations in diet-induced obese and
STZ-induced diabetic rats. In high-fat diet fed rats, these plasma parameters
were significantly higher when compared with control rats that were maintained
on a standard diet (Table 2,
left). As expected, STZ-diabetic rats had fourfold higher plasma
glucose concentration with a marked reduction of insulin levels (
15% of
mean control values) when compared with control animals
(Table 2, right).
Plasma leptin was <0.5 ng/ml in all STZ-diabetic rats
(Table 2, right).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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,
2002), our results suggest
some common metabolic impairments might be related to the enhanced CT nerve
responses to sugars in addition to the direct effects of leptin.
Recently, it has been demonstrated that taste cells express the leptin
receptor and that leptin directly increases K+ conductance,
resulting in hyperpolarization and reduction of cell excitability
(Kawai et al. 2000).
Considering that db/db mice express a defective leptin receptor
(Chen et al. 1996;
Chua et al. 1996;
Lee et al. 1996), it is
reasonable to suppose that the enhancement of CT response to sugars is due to
the lack of the suppressive effect of leptin. In accordance with this,
intraperitoneal injection of leptin to db/db mice does not affect the
CT nerve responses to sweeteners, whereas leptin substantially reduces those
in lean control animals (Kawai et al.
2000). In the present study, we observed that the CT nerve
responses to sugars in VMH-lesioned obese rats were greater than those in
control rats. Similarly, high-fat diet-induced obese rats have greater
responses to sugars as compared with rats maintained with a standard
laboratory chow. These results conflict with the suppressive effect of leptin
on taste reactivity to sugar because plasma leptin concentration of these rats
is elevated as in db/db mice, but leptin receptors in taste cells are
intact in contrast to db/db mice. This apparent discrepancy could be
reconciled by supposing that leptin resistance is induced in taste cells. In
fact, the early progressive phase of obesity was not accompanied by changes in
CT nerve responses, suggesting that the enhancement of CT nerve responses to
sugars is established on a time scale of several months. It is generally
considered that a major mechanism for leptin resistance is a defect in the
blood-brain-barrier transport system that delivers leptin to the sites of
action in the hypothalamus (Caro et al.
1996; Schwartz et al.
1996; Van Heek et al.
1997). However, in addition to the defect in leptin access, it has
been demonstrated that a signaling defect also exists in leptin-responsive
hypothalamic neurons in the mice fed high fat diet
(El-Haschimi et al. 2000). In
addition, it has been shown recently that skeletal muscle become resistant to
the direct effects of leptin, such as increase in lipid oxidation and
triglycerol breakdown, during the development of obesity
(Steinberg and Dyck 2000;
Steinberg et al. 2002). It is
thus possible that the leptin signaling pathway in the taste cells is
down-regulated by prolonged hyperleptinemia in high-fat diet-induced obese
rats as well as in VMH-lesioned obese rats.
We found that STZ-induced diabetic rats have higher CT nerve responses to
sugars as in VMH-lesioned obese rats. This result seems to conflict with that
reported by Ninomiya et al.
(1995), who have demonstrated
that STZ-induced diabetic mice show no significant difference in CT nerve
responses to sugars compared with the control mice. This difference is
probably derived from the difference in duration of diabetic state. In fact,
we failed to observe significant changes in CT nerve responses to sugars 2 wk
after STZ injection, whereas the enhancement of sugar responses of CT became
evident after 4 wk of STZ injection. It should be noted, however, that the
plasma leptin was reduced much by 2 wk after STZ injection
(Table 2)
(Havel et al. 1998). If leptin
exerts a tonic inhibitory effect on sweet taste sensing mechanism in taste
cells under the normal conditions, the reduction of circulating leptin may
result in an increased sensitivity of taste cells immediately. The evidence
that the time course of increase in CT responses to sugars does not coincide
with a reduction of serum leptin level suggests that some chronic factors,
including lowered leptin levels, alters the taste-sensing mechanism under the
diabetic and obese conditions.
At present, the putative chronic factors that affect the sugar-sensing
system in taste cells are not known. We speculate, however, that a chronic
increase in plasma glucose and reduction of insulin action are likely to
underlie the altered sensitivity of CT responses to sugars. Under the diabetic
condition, tissue glucose utilization may be limited because of insulin
deficiency or insulin resistance. Furthermore, persistent hyperglycemia has
been known to reduce the brain blood flow and the glucose transport across the
blood-brain barrier (Gjedde and Crone
1981; Harik and LaManna
1988; Matthaei et al.
1986; Pardridge et al.
1990), both of which would result in a lowered supply of glucose
to the brain. Thus these conditions can be recognized as an insufficiency of
intracellular glucose, in spite of the presence of excess extracellular
glucose. Considering that enhancement of sugar responsiveness of CT is
correlated with an increase in sugar intake behavior (Ninomiya et al.
1995,
2002), the enhancement of CT
nerve responses to sugars in diabetic rats is inferred to be an adaptive
change to satisfy the demand for glucose of brain and peripheral tissues. In
accordance with this, we found that VMH-lesioned obese rats showed a strong
preference for starch, which is a source of glucose but possesses different
taste quality than sugars (Y. Shimizu, T. Takewaki, and K. Tonosaki,
unpublished observation).
One of the characteristics observed commonly among VMH-lesioned obese rats,
high-fat diet-induced obese rats and STZ-diabetic rats is that CT nerve
responses to fructose were unchanged in contrast to those to glucose, sucrose,
and maltose. Several lines of evidences have suggested that there are multiple
receptor sites for sugars in taste cells
(Beidler and Tonosaki 1985;
Jakinovich 1976;
Jakinovich and Goldstein 1976;
Tonosaki and Funakoshi 1984,
1989). Recently, receptors for
sweet taste stimuli including sugars were identified as T1Rs
(Li et al. 2002;
Margolskee 2002;
Nelson et al. 2001). However,
in contrast to bitter taste receptors T2Rs that constitute a large multigene
family (Adler et al. 2000;
Chandrashekar et al. 2000;
Matsunami et al. 2000), T1Rs
family is small and the only one form of functional sweet receptor is known to
be a heterodimer of T1R2 and T1R3 (Li et
al. 2002; Nelson et al.
2001). Available data have suggested that the heterodimer of T1R2
and T1R3 can be activated by most of sweet-tasting substances including
fructose, glucose, sucrose, and maltose
(Li et al. 2002). Thus the
molecular basis for the multiple receptor sites for sugars is not so far
established. Since several G protein 
-subunits have been identified in
taste receptor cells (Kusakabe et al.
1998; McLaughlin et al.
1992; Ruiz-Avila et al.
1995), it is possible that coupling patterns of the T1Rs and G
proteins is related to the sweet taste specificity. In fact, co-expression
experiments of T1R2/T1R3 complex with various G15 chimeras in which the
five-residue C-terminal tail was replaced by those of other G proteins showed
that sucrose induced an increase in intracellular calcium when some specific
chimeras were present (Li et al.
2002). Although the precise mechanism for the fructose-sensing
system is not clear, it may be separate from other sugar receptors, and the
factors that promote enhancement of responsiveness for glucose, sucrose, and
maltose are ineffective for this putative fructose-sensing mechanism. In
support of this notion, it has been reported that preabsorptive recognition of
fructose and glucose in small intestine is made in a different manners (Mei
1978,
1985).
Physiological significance of the differences of the responses between
fructose and other sugars are not known. It has been demonstrated that
fructose ingestion induces insulin resistance and hyperlipidemia in rats
(Elliott et al. 2002). This
disadvantage of fructose as an energy source may be related to the lack of
adaptive changes in taste sensing system for fructose. In accordance with
this, our preliminary experiments with two-bottle preference tests (glucose
vs. fructose) show that the relative preference of glucose solution was
increased day by day, and the rats become to drink glucose solution
exclusively within a week (Y. Shimizu, T. Takewaki, and K. Tonosaki,
unpublished observation).
One of the striking characteristics of VMH-lesioned rats is their
hyperreactivity to QHCl adulterated in foods
(Corbit and Stellar 1964; Graff
and Stelilar 1962; Weingarten
1982). We failed to detect changes in CT nerve responses to QHCl
in VMH-lesioned rats. It should be mentioned, however, that changes in
ingestive behavior are not necessarily accompanied by the corresponding
changes in taste nerve reactivity. Accordingly, it seems likely that
hyperreactive behavior to QHCl in VMH-lesioned rats depends on the
differential responsiveness of higher centers that receive taste information.
Further study is needed to establish the neurophysiological bases for
finickiness of VMH-lesioned obese rats.
In summary, the present study shows that the responsiveness of the CT nerve to sugars is enhanced during the development of diabetes and obesity. Although leptin is established as an important regulator of the sweet-taste-sensing system, our results have suggested that some chronic factors, including high blood glucose, inefficiency of insulin action, or leptin resistance may be related to the enhancement of CT nerve responses to sugars.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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Address for reprint requests: Correspondence to be sent to: Prof. Tadashi Takewaki, Department of Veterinary Physiology, Faculty of Agriculture, Gifu University, Gifu 501-1193, Japan Tel: (81)58–293-2940 Fax: (81)58–293-2940 E mail: tt{at}cc.gifu-u.ac.jp
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A. Hajnal, M. Covasa, and N. T. Bello Altered taste sensitivity in obese, prediabetic OLETF rats lacking CCK-1 receptors Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1675 - R1686. [Abstract] [Full Text] [PDF]
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