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Diurnal Variation in Rat Liver Thyroid Hormone Receptor (TR)- Messenger Ribonucleic Acid (mRNA) Is Dependent on the Biological Clock in the Suprachiasmatic Nucleus, whereas Diurnal Variation of TRß1 mRNA Is Modified by Food Intake

Department of Endocrinology and Metabolism (B.Z.D., M.P.-T.S., E.F., O.B., W.M.W.), Academic Medical Center, University of Amsterdam, and Department of Hypothalamic Integration Mechanisms (A.K.), Netherlands Institute for Brain Research, 1105 AZ Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: O. Bakker, Department of Endocrinology and Metabolism, F5-171, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: o.bakker{at}amc.uva.nl.

	Abstract

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Previous studies have shown a diurnal variation of certain isoforms of thyroid hormone receptors (TR) in rat liver. The genesis of these diurnal changes is still unknown. To clarify whether the biological clock, located in the hypothalamic suprachiasmatic nucleus (SCN), is involved, we made selective SCN lesions. Rats with an SCN lesion lost their circadian rhythm of plasma corticosterone and TSH when compared with intact animals. TR1 and TR2 mRNA expression of control rats was higher in the light period than in the dark period; changes that were abolished in the rats with SCN lesions. In contrast, liver TRß1 mRNA of intact rats showed a diurnal variation that failed to reach statistical significance. To evaluate whether these effects could be explained indirectly by the disappearance of rhythmic feeding behavior in rats with SCN lesions, we performed a second experiment in which otherwise intact animals were subjected to a regular feeding (RF) schedule, with one meal every 4 h. When compared with rats with free access to food, RF only affected TRß1 mRNA expression and had no effect on the diurnal changes in TR1 and TR2. We conclude that liver TRß1 expression is most clearly affected by food intake. Diurnal changes in liver TR1 and TR2 are controlled by the biological clock in the SCN but not via changes in the daily rhythm of food intake. The findings may have physiological relevance for diurnal variation of T₃-dependent gene expression, which is supported by a diurnal variation in the expression of the 5'-deiodinase gene.

	Introduction

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CIRCADIAN RHYTHMS ARE mainly driven by the biological clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Input from the environment into this oscillator is primarily via the eyes (1). The SCN clock regulates many rhythmic processes that may include the rhythmic expression of genes in, for instance, the liver. Some liver genes that show a rhythmic expression include thyroid hormone-dependent genes such as cholesterol 7--hydroxylase (CYP7A), phosphoenolpyruvate carboxykinase, glucose 6-phosphate dehydrogenase, glutamine synthetase, and Spot 14 (2, 3, 4, 5, 6, 7). Thyroid hormones influence the expression of these genes via thyroid hormone receptors (TR), which belong to the nuclear receptor superfamily and act mainly as transcription factors. They are encoded by two separate genes: c-erbA-, which encodes TR1 and TR2 isoforms, and c-erbA-ß, which encodes TRß1, TRß2, and TRß3 isoforms. The TR2 splice variant, which is only found in mammalians, cannot bind T₃ but can act as a constitutive repressor of TR action (8, 9). Although TRß1 is the predominant TR in the liver, TR1 and TR2 are expressed in this tissue as well (TR1 about 4-fold less) (10) and, like TRß1, in a zonal fashion, as we have shown recently (5, 11). In these studies, we found that the protein expression of these receptors also shows a diurnal variation. A higher expression of TRß1 protein was observed at the beginning of the dark period when the rats are nutritionally active, whereas a higher expression of TR2 protein was found during the light period when the animals are resting.

In our previous studies, we were not able to determine the origin of the diurnal variations in TR isoform expression. To determine whether the diurnal variation is derived from a direct effect of the SCN or an indirect effect via SCN-controlled feeding behavior, we performed two sets of experiments. In the first experiment, we compared the diurnal variations of TR mRNA expression in livers of rats whose circadian clock was lacerated with the diurnal variations in intact animals. In the second experiment, we examined the diurnal variations of TR mRNA expression in livers of animals that had been accustomed to a regular feeding (RF) schedule (i.e. one meal every 4 h), whereas the control animals had free access to food.

	Materials and Methods

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Experimental animals
Male Wistar rats were obtained from Harlan (Horst, The Netherlands) and housed in a temperature-controlled environment (20–22 C) on a 12-h light, 12-h dark schedule (lights on at 0700 h). In the first experiment, the animals were divided into intact and suprachiasmatic lesion (SCNx) groups. In the second experiment, the animals were divided into a RF group and a control group, which had free access to food ad libitum. Before the start of the experiment, animals were allowed to acclimatize to the light-dark cycle for several weeks with four animals in a cage. At least 1 wk before the start of the experiments, animals were placed into individual cages (38 x 26 x 16 cm). Water was always available ad libitum. In both groups, there were six rats per time point. Our local animal welfare committee approved all studies.

SCN lesions (experiment 1)
Rats were anesthetized with Hypnorm (Duphar, Weesp, The Netherlands; 0.6 ml/kg, im), mounted with their heads in a David Kopf Stereotact (David Kopf Instruments, Tujunga, CA) with the toothbar set at +5.0 mm, and subjected to a bilateral SCN lesion (coordinates: 1.4 mm rostral to bregma; 1.1 mm lateral to the midline; 8.3 mm below the brain surface) using bilateral lesion electrodes, 0.2 mm in diameter, with temperature set at 85 C for 1 min (lesion generator; Radionics, Burlington, MA). This temperature was found empirically to result in lesions large enough to eliminate the SCN bilaterally but small enough to leave surrounding hypothalamic brain structures, such as the paraventricular and supraoptic nuclei intact (12). A drawback of this restricted lesion size is the limited yield of animals in which the lesion is complete (i.e. ±30%). To check the effectiveness of the lesion, daily water intake was measured, after a rest period of 2 wk to recover from anesthesia and brain trauma, during the middle 8 h of the light period. Only animals showing a daytime water intake of more than 30% of the total daily intake (in intact control animals this value is typically <10%) were assumed to have complete lesions of the SCN and were allowed to enter the experiment. After the experiments, the presence and extent of the SCN lesion was checked by immunocytochemical staining of hypothalamic sections for the presence of vasopressin and/or vasoactive intestinal polypeptide-containing cell bodies or fibers. If animals had cell bodies that stained positively for either vasopressin or vasoactive intestinal polypeptide at the border of the lesion or for immunoreactive fibers in SCN target areas such as the paraventricular nuclei, they were excluded from the analysis. The rats were killed at Zeitgeber time (ZT) 6, ZT10, ZT18, and ZT22 (ZT12 being defined as the onset of the dark period). One animal was excluded from further analysis because of a very low body weight.

RF (experiment 2)
Rats were trained at least 3 wk before the experiment on a six 10-min meals per day feeding schedule spaced equally over the light-dark cycle (RF group). Food pellets were available in metal food hoppers to which access could be prevented by a sliding door situated in front of it. Door opening and closing were activated by an electrical motor and controlled by a clock. Food became available at ZT2, ZT6, ZT10, ZT14, ZT18, and ZT22. Door opening time was determined empirically in previous experiments (13). Animals did not save food for consumption during the 4-h intermeal period. Adaptation was considered completed when animals had learned to consume approximately 3 g at every meal. Despite the equally distributed feeding activity, general (locomotor) activity still showed a clear light-dark rhythm, with the major part of activity occurring during the dark period. During the light period, animals would wake up, eat, and resume sleeping. In the experiment, rats were killed at ZT0.5, ZT6.5, ZT12.5, and ZT18.5. During final sampling, three animals were excluded from further analysis because of very low body weight (RF group ZT0.5) or severe brain damage (one each in ad libitum groups ZT6.5 and ZT12.5).

Analysis of hormone data
Plasma concentration of T₃ was determined with an in-house RIA (14) of TSH by a chemiluminescent enzyme immunoassay (Immulite; detection limit 0.4 ng/ml; Diagnostic Products Corp., Los Angeles, CA), and plasma corticosterone was determined using a RIA (detection limit 1 ng /ml; ICN Biochemicals, Inc., Costa Mesa, CA).

Analysis of mRNA expression
mRNA was isolated from each liver sample using a MagnaPure (Roche Molecular Biochemicals, Mannheim, Germany) according to the manufacturer’s protocol. Thereafter, cDNA was synthesized using the First Strand cDNA synthesis kit with random primers (Roche Molecular Biochemicals). Real-time PCRs were performed in a LightCycler (Roche Molecular Biochemicals). TR1 and TR2 were simultaneously detected using sequence-specific hybridization probes and the LightCycler-FastStart DNA Master hybridization probes kit (Roche Molecular Biochemicals, Mannheim, Germany); probes, primers, and program have been previously described (15). To measure TRß1 and 5'-deiodinase mRNAs, we used the DNA Master Sybergreen kit (Roche Molecular Biochemicals), and for the housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), we used the LightCycler-FastStart DNA Master Sybergreen kit. The primers used for TRß1 were sense: 5'-TGGGCGAGCTCTATATTCCA-3'; and antisense: 5'-ACAGGTGATGCAGCGATAGT-3 (185-bp product according to GenBank accession no. NM 012672). The primers used for 5'-deiodinase were sense: 5'-CCTCCACAGCTGACTTCCTC-3'; and antisense: 5'-TAGAGCCTCTCAGGCAGAGC-3 (215-bp product according to GenBank accession no. X57999). The primers used for GAPDH were sense: 5'-AACCACGAGAAATATGACAAC-3'; and antisense: 5'-CATCCTGGGCTACACTGAG-3' (430-bp product according to GenBank accession no. XM 234405). For each mRNA assayed, a standard was generated and used in the range of 3 pg to 0.3 fg per 20 µl reaction mix. All results were normalized to the amount of GAPDH for each liver.

Statistical analysis
One-way ANOVA was applied to evaluate the differences between time points within groups. Two-way ANOVA was used to analyze differences between groups and time and their interaction. ANOVA was followed by Student’s t test (unpaired, two tailed) to establish which time points differed significantly from trough values or at which time points groups differed from one another. Due to their nonuniform distribution, TR mRNA values were normalized by logarithmic transformation of the relative mRNA concentrations. A difference was considered significant at P < 0.05. All data were evaluated using SPSS version 11 (SPSS, Inc., Chicago, IL).

	Results

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Effect of a SCN lesion on diurnal variation of hormone and TR isoform levels
One-way ANOVA indicated the existence of diurnal variation in intact animals in plasma corticosterone and TSH but not in T₃. Ablation of the biological clock (SCNx) resulted in loss of the diurnal variation of both corticosterone and TSH (Table 1 and Fig. 1). Although the daily mean of plasma corticosterone levels did not differ between intact and SCNx rats, we found an interaction between groups and time. Post hoc analyses indicated that plasma corticosterone levels were significantly higher at ZT10 in control animals (P = 0.02) and significantly lower at ZT22 in control animals (P = 0.03). The daily mean of both T₃ and TSH levels was higher in intact rats compared with SCNx rats. Post hoc analysis indicated lower plasma T₃ levels at ZT6 (P = 0.006) and lower plasma TSH levels at ZT10 (P = 0.04) and ZT18 (P = 0.046).

View this table: [in this window] [in a new window]   TABLE 1. Analysis of diurnal variations of plasma corticosterone, TSH, and T3 and relative expression of liver mRNA of TRß1, TR1, and TR2 in intact and SCNx groups

View larger version (18K): [in this window] [in a new window]   FIG. 1. Diurnal changes of plasma corticosterone, TSH, T3, and liver TR mRNA isoforms in intact (white circles) and SCNx (black circles) rats. The light and dark periods are shown as white and black bars, respectively, above the graph. Data are expressed as mean ± SEM.

View larger version (9K): [in this window] [in a new window]   FIG. 2. Diurnal changes of liver 5'-deiodinase mRNA. A, Changes in control (white circles) and SCN-lesioned (black circles) rats are shown. The light and dark periods are shown as white and black bars, respectively, above the graph. Data are expressed as mean ± SEM. B, Changes in control (white circles) and RF (black circles) rats are shown. The light and dark periods are shown as white and black bars, respectively, above the graph. Data are expressed as mean ± SEM.

Effect of RF on the diurnal variation of hormone and TR isoform levels
A diurnal variation was found for plasma corticosterone, T₃, and TSH in the control groups (Fig. 3 and Table 2). The diurnal variation of corticosterone remained present in the RF group, although it was associated with higher peak corticosterone levels. The daily mean of plasma TSH and T₃ was similar between control and RF rats, but RF dampened the diurnal variation in the case of TSH, whereas the diurnal variation in T₃ disappeared (Table 2). Two-way ANOVA showed a significant effect of time for plasma T₃ and TSH but no significant group effects. For plasma TSH levels, the RF regimen resulted in a shift of the peak value to another time point (in control animals at ZT18.5 vs. RF animals at ZT6.5; Fig. 3).

View larger version (17K): [in this window] [in a new window]   FIG. 3. Diurnal changes of plasma corticosterone, TSH, T3, and liver TR mRNA isoforms in control (white circles) and RF (black circles) rats. The light and dark periods are shown as white and black bars, respectively, above the graph. Data are expressed as mean ± SEM.

View this table: [in this window] [in a new window]   TABLE 2. Analysis of diurnal variations of plasma corticosterone, TSH, and T3 and relative expression of liver mRNA of TRß1, TR1, and TR2 in control and RF groups

For TR2, a diurnal variation was observed in both control and RF groups. Two-way ANOVA revealed significant effects of time and a significant interaction. Post hoc analysis showed that TR2 mRNA expression was higher during the dark period (at ZT12.5; P = 0.043) and lower during the light period (at ZT6.5; P = 0.005).

We also found a diurnal rhythm in the expression of 5'-deiodinase (two-way ANOVA, P = 0.03; Fig. 2B). No difference was found in the diurnal expression pattern as a result of RF when compared with controls (two-way ANOVA, P = 0.86, group effect; Fig. 2B), but as in the case of TRß1, the level was lower at ZT18.5.

In conclusion, RF does not abolish diurnal variation in plasma corticosterone, TSH, TRß1, TR2, or 5'-deiodinase mRNA levels, although it does affect the amplitude of the diurnal variations in TR1 and TR2, and interestingly, the diurnal variation in the TRß1 mRNA appears to be reinforced. Furthermore, it would appear that the expression pattern of the 5'-deiodinase mRNA follows that of the TRß1.

	Discussion

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To our knowledge, this is the first study to show diurnal variation of TR1, TR2, and TRß1 mRNA in rat liver in relation to biological clock and feeding behavior. We reported earlier that a diurnal variation in TRß1 protein expression exists in rat liver (5), which peaks at ZT12.5, a time point when the rodents become nutritionally active. The present study was undertaken to determine whether this variation in TR isoform expression is the result of a direct action of the biological clock. To clarify whether the biological clock in the hypothalamus is involved, we destroyed the SCN by thermoablation. As a control for the effectiveness, we looked at hormone levels for corticosterone representing the hypothalamic-pituitary-adrenal axis and for TSH and T₃ representing the hypothalamic-pituitary-thyroid axis. In accordance with previous studies, SCN ablation removed diurnal variations in corticosterone, TSH, and T₃ (12). SCN ablation did not affect mean daily levels of corticosterone but had a lowering effect on mean TSH and T₃, as previously reported. The mean daily levels of the TR isoforms were not affected, but the clearly present diurnal variation in TR1 and TR2 mRNA was abolished by the SCN lesion. Thus, the SCN seems to be the major force in regulating the diurnal variation of TR isoform mRNAs in liver, which therefore can be viewed as a real circadian rhythm. Because the TR gene was probably present earlier during the evolution than the TRß gene (16), it can be postulated that TR, being the first, is involved in the main overall thyroid hormone-dependent daily housekeeping tasks in the tissues and, therefore, has to be under regulation of the central biological clock. Identification of the output of the SCN, which is responsible for the rhythm, is not possible from our data. However, evidence has been presented recently implicating both neuroendocrine factors (17) and the autonomic nervous system (18) in the control of daily rhythms in the liver. Another interesting possibility can be inferred from the observation that T₃ itself can influence the splicing direction of the TR pre-mRNA (19), which, when combined with the fact that plasma thyroid hormone levels themselves show a diurnal rhythm, could be part of an explanation.

To evaluate whether these effects could be indirectly explained by alterations in feeding behavior in the SCNx rats, we performed a second experiment in which, otherwise intact, animals were subjected to RF every 4 h. RF resulted in a higher daily mean in corticosterone levels, which is in accordance with previous studies that have shown that (mild) food deprivation enhances the activity of the hypothalamic-pituitary-adrenal axis (13, 20, 21, 22, 23). RF caused a shift in the daily peak for TSH, which is in accordance with observations in rats receiving their food spread over several meals abolishing the diurnal variation of T₃ (24). When we looked at TR mRNA expression in liver, we found differential regulation of TR mRNA as a result of the RF regimen. RF enhanced the rhythm in TRß1 mRNA expression, but the diurnal variation in the expression of TR2 and TR1 mRNAs was reduced.

In summary, we show that diurnal variations of TR1and TR2 mRNA levels are dependent on the biological clock in the SCN, although feeding activity may modify the amplitude. In this study, we looked at TR expression at the mRNA level because circadian regulation of gene expression is primarily a result of a rapid increase of mRNA levels (25, 26, 27). However, it is important to mention two limitations of the present study that are due to the experimental conditions, namely the limited sample size and the difference in time points between the two experiments. The limited sample size could explain the absence of a statistically significant diurnal variation in TRß1 mRNA in our control rats due to the high variability at ZT0.5. We did demonstrate, however, that the highest expression of TRß1 is observed at ZT12.5 in both control and RF rats, which is in accordance with the results we obtained on the TRß1 protein in our previous study (5). Furthermore, due to the limited number of sampling points, we may have missed the highest and lowest expression of TRß1 mRNA. Therefore, we cannot completely rule out a central regulation of TRß1 mRNA in addition to regulation by food intake.

What would be the physiological relevance of the diurnal rhythms we have found in the expression of the TR isoforms? As stated above, it can be postulated that TR, being the first isoform, is involved in the main, overall, thyroid hormone-dependent daily housekeeping tasks in the tissues. TRß1, having developed later, could be thought to be more involved in the fine-tuning of hepatic gene expression (for instance, in response to feeding activity). Our data clearly demonstrate that the expression of liver 5'-deiodinase mRNA shows a diurnal rhythm, which, because the liver is the major source of circulating T₃ through the action of 5'-deiodinase, may explain the often-observed second (i.e. nocturnal) peak in plasma T₃ (12). Furthermore, the 5'-deiodinase expression appears to follow that of TRß1 in our experiments, which may well be possible because the expression patterns of the 5'-deiodinase and TRß1 proteins in rat liver overlap (5) and because it has been shown recently that TRß1 is the TR responsible for the regulation of the liver 5'-deiodinase gene (28). Another example could be the case of the TRß1-dependent CYP7A gene (29), in which it was shown that restricted feeding does shift the pattern of CYP7A expression independent of the central clock (30, 31).

We have recently shown that the TR2 protein shows the highest expression level at the end of the light period when the animals mostly rest. Because it has been suggested from knockout animal studies that the lack of TR2, which can act as an antagonist of T₃-dependent gene expression, increases the sensitivity for thyroid hormone (32, 33), this increase at a time of rest may well be physiologically relevant because it will dampen any catabolic effects of T₃.

In conclusion, our study shows that the biological clock in the SCN has a predominant role in regulation of TR gene expression as opposed to the feeding regimen, which influences TRß1 expression.

	Footnotes

 
This work was supported by Grant 903-40-194 from The Netherlands Organization for Scientific Research.

Abbreviations: CYP7A, Cholesterol 7--hydroxylase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; RF, regular feeding; SCN, suprachiasmatic nucleus; SCNx, suprachiasmatic lesion; TR, thyroid hormone receptor; ZT, Zeitgeber time.

Received June 25, 2003.

Accepted for publication November 21, 2003.

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