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Rhythmic Messenger Ribonucleic Acid Expression of Clock Genes and Adipocytokines in Mouse Visceral Adipose Tissue

Division of Clinical Pharmacology (H.A., H.Y., Y.H., Y.O., S.T., A.F.), Department of Pharmacology, Jichi Medical School, Tochigi 329-0498, Japan; and Department of Diabetes and Digestive Disease (T.T., S.K.), Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa 920-8641, Japan

Address all correspondence and requests for reprints to: Dr. Akio Fujimura, Department of Pharmacology, Jichi Medical School, Tochigi 329-0498, Japan. E-mail: akiofuji{at}jichi.ac.jp.

	Abstract

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Various peripheral tissues show circadian rhythmicity, which is generated at the cellular level by their own core oscillators that are composed of transcriptional/translational feedback loops involving a set of clock genes. Although the circulating levels of some adipocytokines, i.e. bioactive substances secreted by adipocytes, are on a 24-h rhythmic cycle, it remains to be elucidated whether the clock gene system works in adipose tissue. To address this issue, we investigated the daily mRNA expression profiles of the clock genes and adipocytokines in mouse perigonadal adipose tissues. In C57BL/6J mice, all transcript levels of the clock genes (Bmal1, Per1, Per2, Cry1, Cry2, and Dbp) and adipocytokines (adiponectin, resistin, and visfatin) clearly showed 24-h rhythms. On the other hand, the rhythmic expression of these genes was mildly attenuated in obese KK mice and greatly attenuated in more obese, diabetic KK-A^y mice. Obese diabetes also diminished the rhythmic expression of the clock genes in the liver. Interestingly, a 2-wk treatment of KK and KK-A^y mice with pioglitazone impaired the 24-h rhythmicity of the mRNA expression of the clock genes and adipocytokines despite the antidiabetic effect of the drug. In contrast, pioglitazone improved the attenuated rhythmicity in the liver. These findings suggest that the intracellular clock gene system acts in visceral adipose tissues as well as liver and is influenced by the conditions of obesity/type 2 diabetes and pioglitazone treatment.

	Introduction

Top Abstract Introduction Materials and Methods Results and Discussion References

 
VARIOUS PHYSIOLOGICAL and behavioral processes exhibit circadian rhythmicity. Recent studies have revealed that these endogenous rhythms are generated at the cellular level by circadian core oscillators, which are composed of transcriptional/translational feedback loops involving a set of clock genes (1, 2, 3). In mammals, rhythmic transcriptional enhancement by two basic helix-loop-helix PER-ARNT-SIM domain-containing transcription factors, CLOCK and brain and muscle ARNT-like protein (BMAL)1, provides the basic drive to the system; the CLOCK-BMAL1 heterodimer directly or indirectly activates the transcription of various clock-controlled genes (1, 2, 3, 4, 5). For example, the albumin D-site binding protein (Dbp), which expression is directly regulated by the CLOCK-BMAL1, is involved in the circadian transcriptional regulation of several metabolic enzymes (1, 2, 3). In parallel, the heterodimer activates the transcription of several clock genes, including period (PER) and cryptochrome (CRY) (6, 7, 8). The resultant PER and CRY proteins translocate back into the nucleus and inhibit the activity of CLOCK-BMAL1, forming the negative feedback loop (1, 2, 3, 9). Thus, these clock genes control the circadian rhythm of physiological output by regulating the expression of multiple clock-controlled genes.

The intracellular circadian clock system resides in not only the hypothalamic suprachiasmatic nucleus, which is recognized as being the mammalian central clock, but also various peripheral tissues (10, 11, 12). The suprachiasmatic nucleus is not essential for driving peripheral oscillations but rather acts as a synchronizer of peripheral oscillators (12). Therefore, the physiological rhythmicity in peripheral tissues may be controlled directly by their own clock genes.

Recent advances in the understanding of adipocyte biology have indicated that adipose tissue not only serves as an energy-storing tissue but also performs a secretory function by producing a variety of bioactive substances, including adiponectin, resistin, and leptin, thus acting as endocrine tissue (13). Because some of these so-called adipocytokines greatly influence insulin sensitivity, glucose metabolism, and atherosclerosis, they may provide a molecular link between the increased adiposity and development of type 2 diabetes and/or metabolic syndrome (14). Among these adipocytokines, the circulating level of leptin exhibits a clear diurnal variation in animals (15, 16, 17) and humans (18, 19, 20). Moreover, plasma adiponectin concentrations in nonobese subjects show a 24-h rhythmic cycle, which is absent in obese subjects (19, 20). In addition, altered expression of the clock genes Per2 and Bmal1 has been reported in the livers of db/db mice, which serve as a model of severe, obese diabetes (21). Therefore, it is possible that clock genes in adipose tissue regulate the expression and/or secretion of adipocytokines and that obesity leading to insulin resistance and type 2 diabetes dampens the regulation of the clock genes. However, it remains to be elucidated whether the expression of clock genes exhibits rhythmicity and whether clock genes play a role in adipose tissue. To address these issues, we investigated 24-h changes in the mRNA levels of the clock genes and adipocytokines in C57BL/6J mouse adipose tissue. Moreover, we examined whether obesity linked to insulin resistance and type 2 diabetes alters the daily rhythms of the mRNA expression, using KK and KK-A^y mice, which are models of mild and severe, spontaneous obese diabetes, respectively.

	Materials and Methods

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Mice
In a preliminary study, we found that the mRNA levels of adiponectin and resistin exhibited 24-h rhythmicity in female, but not male, C57BL/6J mice (data not shown). Therefore, only female mice were used in this study. C57BL/6J (Charles River Japan, Yokohama, Japan), KK/Ta, and KK-A^y/Ta mice (CLEA Japan, Tokyo, Japan) were obtained at 8 wk of age and maintained under a specific pathogen-free condition with controlled temperature and humidity and a 12-h light (0700–1900 h), 12-h dark (1900–0700 h) cycle. Mice were housed individually and given a standard laboratory diet (CE-2; CLEA Japan) and water ad libitum. Half of the KK and KK-A^y mice were fed CE-2 with 0.02% pioglitazone. After 2 wk, animals were killed to obtain blood, liver, and perigonadal fat samples at the following zeitgeber times (ZTs): 0, 6, 12, and 18, in which ZT 0 is defined as lights on and ZT 12 as lights off. All animal procedures were preformed in accordance with the Guidelines for Animal Research at the Jichi Medical School, Japan.

Measurement of circulating glucose and insulin concentrations
The blood glucose concentration was measured using a Glutest Ace R (Sanwa Kagaku Kenkyusyo, Nagoya, Japan). The RIA for serum insulin was performed using kits purchased from Linco Research (St. Charles, MO). The intra- and interassay coefficients of variation were less than 10%.

RNA extraction and real-time quantitative PCR
The isolation of total RNA was achieved using the RNeasy lipid tissue minikit or the RNeasy minikit according to the manufacturer’s instructions (QIAGEN, Valencia, CA). Reverse transcription was performed with 1.2 µg total RNA, random hexamer primer, and RevertAid M-MuLV reverse transcriptase (Fermentas, Hanover, MD). The gene expression was analyzed by real-time quantitative PCR, performed with the ABI Prism 7700 sequence detection system (Applied Biosystems, Foster City, CA), as previously described (22, 23). All specific sets of primers and TaqMan probes were obtained from Applied Biosystems [TaqMan gene expression assays and TaqMan rodent glyceraldehyde-3-phosphate dehydrogenase (GAPDH) control reagents]. The GenBank accession codes were NM_016974 for Dbp, NM_011065 for Per1, NM_011066 for Per2, NM_007489 for Bmal1, NM_007771 for Cry1, NM_009963 for Cry2, NM_009605 for adiponectin, NM_022984 for resistin, NM_021524 for visfatin, and NM_008493 for leptin. All of the primer sets, except for the TaqMan rodent GAPDH control reagents, were designed to be located in two exons to avoid the amplification of potentially contaminating genomic DNA. To control the variation in the amount of DNA available for PCR in the different samples, the gene expression of the target sequence was normalized in relation to the expression of an endogenous control, GAPDH. The data were analyzed using the comparative threshold cycle method because the efficiency of the target amplification was approximately equal to that of the GAPDH amplification (24).

Statistical analysis
Data were analyzed using an ANOVA with a post hoc test of Fisher’s protected least significant differences (PLSD). The values are presented as the means ± SEM, and P < 0.05 was considered significant. All calculations were performed using StatView (version 5.0; SAS Institute, Cary, NC).

	Results and Discussion

Top Abstract Introduction Materials and Methods Results and Discussion References

 
Rhythmic mRNA expression of clock genes and adipocytokines in visceral adipose tissue of C57BL/6J mice
To investigate whether the mRNA expression of clock genes and adipocytokines shows daily rhythms in visceral adipose tissue, perigonadal fat samples were obtained from 10-wk-old C57BL/6J mice every 6 h throughout a single 24-h period. As shown in Fig. 1, A and B, all clock genes examined (Dbp, Per1, Per2, Bmal1, Cry1, and Cry2) exhibited 24-h rhythmicity (F = 6.6–32.6, each P < 0.01, one-way ANOVA to test rhythmicity of each gene). In a manner that was consistent with previous observations (10, 11, 12, 25) in other peripheral tissues, including the heart, liver, spleen, and kidney, the transcript levels of Dbp, Per1, and Per2 peaked in the latter half of the light phase. On the other hand, the Bmal1 mRNA dropped to near trough levels at the same time. Additionally, the Cry1 and Cry2 mRNA levels peaked at ZT 18 and 12, respectively. These results suggest that an intracellular circadian clock system operates in the visceral adipose tissue as well as in other peripheral tissues.

View larger version (41K): [in this window] [in a new window]   FIG. 1. Daily mRNA expression profiles of the clock genes (A and B) and adipocytokines (C) in the visceral adipose tissues of C57BL/6J, KK, and KK-Ay mice. Female mice were maintained under a 12-h light, 12-h dark cycle and fed a standard diet with (—) or without (—) 0.02% pioglitazone for 2 wk. Thereafter, perigonadal fat samples were obtained at ZT 0, 6, 12, and 18. Transcript levels of the target genes were determined by real-time quantitative RT-PCR. D, mRNA levels of the representative gene (Dbp, Per2, or Cry1) at the time that its level peaked in C57BL/6J mice were compared among groups using an ANOVA with a post hoc test of Fisher’s PLSD. All data are means and SEM of five mice at each time point and are expressed as relative values to the lowest values in C57BL/6J mice for each gene. *, P < 0.05; , P < 0.01 vs. untreated KK mice; , P < 0.05 vs. untreated KK-Ay mice.

Alterations in the daily mRNA expression profiles of clock genes and adipocytokines in the visceral adipose tissue of obese diabetic mice
In the last decade, it has become evident that various adipocytokines are closely associated with the development of type 2 diabetes, metabolic syndrome, and/or atherosclerosis (13, 14). The plasma concentrations of several adipocytokines, including adiponectin and leptin, have been correlated with visceral fat accumulation (13, 14, 18, 19, 20). Moreover, obesity blunts the diurnal rhythm of plasma adiponectin concentration (19, 20). Thus, it can be speculated that obesity may affect not only adipocytokine but also clock gene expression. To verify this hypothesis, we investigated the daily profiles of mRNA levels for the clock genes and adipocytokines in perigonadal fat of 10-wk-old KK and KK-A^y mice. The KK strain models mild, obese diabetes, whereas the introduction of the A^y allele (KK-A^y) exacerbates the pathophysiological condition with consequent overt diabetes (28). As shown in Table 1, KK mice were significantly heavier than C57BL/6J mice, and obesity was more severe in KK-A^y mice. In addition, obvious hyperglycemia and hyperinsulinemia were detected in KK-A^y but not in KK mice.

With regard to the daily profiles of adipocytokine mRNAs (Fig. 1C), the rhythmic expression of adiponectin and resistin was not detected in either KK or KK-A^y mice. Additionally, in agreement with previous results (14), the peak levels of adiponectin and resistin were significantly lower (each P < 0.01, Fisher’s PLSD) in KK mice than in the C57BL/6J mice, and their levels were even lower in KK-A^y mice than KK mice (P < 0.05 for adiponectin and P < 0.01 for resistin). The visfatin mRNA levels were also lower in KK and KK-A^y mice than in C57BL6J mice (each P < 0.01), which is contrary to the previous observations in male KK-A^y mice (27). Because a recent study has reported that the visfatin transcript level is not associated with obesity/metabolic syndrome in rats (29), further studies are needed to elucidate how obesity affects visfatin gene expression in rodents. Unlike adiponectin and resistin, visfatin still showed mild rhythmicity in KK and KK-A^y mice (F = 4.2 and 5.1, respectively, each P < 0.05, one-way ANOVA). Its transcript levels in both strains as well as C57BL/6J mice rose at ZT 6, remained at higher levels during the first half of the dark phase, and dropped to near trough levels by ZT 24. Moreover, leptin exhibited daily rhythms with a peak at ZT 18 and a trough at ZT 0 in KK (F = 3.4, P < 0.05) and KK-A^y mice (F = 3.9, P < 0.05). Thus, the daily mRNA expression rhythms of adipocytokines do not seem to be equally affected by obesity and/or type 2 diabetes. These results suggest that not only clock genes but also some other factors influence the diurnal variations in the transcript levels of adipocytokines to varying degrees.

Effects of pioglitazone on the daily mRNA expression profiles of clock genes and adipocytokines in the visceral adipose tissue of obese diabetic mice
Recent studies have suggested that thiazolidinediones, a class of oral antidiabetic agents, act as insulin sensitizers by at least partly regulating the expression of adipocytokines (14, 30). Therefore, we speculated that thiazolidinediones might correct the daily mRNA expression rhythms of clock genes and adipocytokines in obese diabetic mice. As shown in Table 1, a 2-wk treatment with pioglitazone significantly decreased both circulating glucose and insulin concentrations in KK-A^y mice. Pioglitazone treatment also affected the daily profiles of all investigated clock genes, except Cry1, in both KK and KK-A^y mice (Fig. 1, A and B; F = 7.6–46.2, each P < 0.01, two-way ANOVA). However, contrary to our expectations, pioglitazone did not improve, but rather worsened, the peak levels of the clock genes, which were diminished in association with obesity/type 2 diabetes (Fig. 1, A, B, and D). Moreover, the rhythmic mRNA expression of leptin detected in untreated mice disappeared in both pioglitazone-treated groups (Fig. 1C). Furthermore, visfatin, adiponectin, and resistin did not show any daily rhythmicity in pioglitazone-treated KK-A^y mice. On the other hand, as previously reported (14, 30), pioglitazone significantly increased the mRNA levels of adiponectin and decreased those of resistin and leptin in KK-A^y mice (Fig. 1C; F = 24.8, 60.6 and 82.9, respectively, each P < 0.01, two-way ANOVA). In addition, this treatment also increased visfatin levels (F = 24.3, P < 0.01). Thus, pioglitazone affected the gene expression levels of adipocytokines without the improvement of the clock gene system. These results support the view that some other factors, as well as clock genes, regulate the daily rhythms in mRNA levels for adipocytokines.

Effects of type 2 diabetes and pioglitazone on the daily mRNA expression profiles of clock genes in the liver
To elucidate whether the above-mentioned findings are specific to the visceral adipose tissue, we further determined daily mRNA expression profiles of the clock genes in the liver (Fig. 2). Consistent with the effect detected in the adipose tissue, overt obesity/type 2 diabetes significantly dampened the peaks of all investigated clock genes. On the other hand, mild obesity might not affect the clock gene system because the peak levels of clock genes in KK mice were not lower than those in C57BL/6J mice. Interestingly, contrary to the findings in the adipose tissue, pioglitazone treatment improved the rhythmicity of the mRNA expression of the clock genes in KK-A^y mice. These results further support the view that pathophysiological condition of obese type 2 diabetes is related to the impaired clock gene system in peripheral tissues.

View larger version (30K): [in this window] [in a new window]   FIG. 2. A and B, Daily mRNA expression profiles of the clock genes in the liver of C57BL/6J, KK, and KK-Ay mice after being fed a regular diet with (—) or without (—) pioglitazone for 2 wk. C, mRNA levels of the representative gene (Dbp, Per1, or Cry1) at the time when its level peaked in C57BL/6J mice were compared among groups using an ANOVA with a post hoc test of Fisher’s PLSD. All data are means and SEM of four mice at each time point and are expressed as relative values to the lowest values in C57BL/6J mice for each gene. , P < 0.01 vs. untreated KK mice; , P < 0.05; **, P < 0.01 vs. untreated KK-Ay mice.

Turek et al. (34) recently reported that homozygous Clock mutant mice are hyperphagic and obese and that they develop a metabolic syndrome of hyperleptinemia, hyperglycemia, and hyperlipidemia. The Clock mutant mice have a severely disturbed diurnal feeding rhythm accompanying the attenuated mRNA expression of hypothalamic peptides involved in energy balance. In contrast, neither obese diabetes nor pioglitazone treatment affected the daily feeding rhythms of mice in our study (Fig. 3), although feeding is a dominant zeitgeber (timing cue) for peripheral clocks (21, 35, 36). Therefore, it is still possible that obesity, namely adipocyte hypertrophy, directly causes the alteration of the circadian clock system in adipose tissue, even if the central clock system is affected in obese diabetic mice. Actually, BMAL1 has been recently shown to play essential roles in the regulation of adipocyte differentiation and lipogenesis (37). The Rev-Erb also promotes PPAR-induced adipocyte differentiation (32). Moreover, inactivation of BMAL1 or CLOCK suppresses the diurnal variation in glucose and triglycerides and abolishes gluconeogenesis in mice (38). Thus, the clock gene system appears to be involved in the development of type 2 diabetes at least via the regulation of adipocyte differentiation and gluconeogenesis.

View larger version (15K): [in this window] [in a new window]   FIG. 3. Daily profiles of food intake in C57BL/6J, KK, and KK-Ay mice after being fed a regular diet with (—) or without (—) pioglitazone for 2 wk. Data are means ± SEM of five mice in each group and are expressed as percentages of total food intake.

In conclusion, we found that mRNA expression of the clock genes and adipocytokines shows significant 24-h rhythmicity in mouse visceral adipose tissue. Moreover, spontaneous obese diabetes attenuated this rhythmic expression in most of the clock and adipocytokine genes investigated. Likewise, obese diabetes impaired the rhythmic expression of the clock genes in the liver. Interestingly, pioglitazone treatment improved the attenuated rhythmicity in the liver but not the adipose tissue. Further studies are needed to clarify whether impairment of the clock gene system in visceral adipose tissue and liver is involved in the development of type 2 diabetes and/or metabolic syndrome.

	Footnotes

 
First Published Online September 15, 2005

Abbreviations: BMAL, Brain and muscle ARNT-like protein; CRY, cryptochrome; Dbp, albumin D-site binding protein; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PER, period; PLSD, protected least significant differences; PPAR, peroxisome proliferators-activated receptor; ZT, zeitgeber time.

Received June 24, 2005.

Accepted for publication September 8, 2005.

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