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. Author manuscript; available in PMC: 2008 Sep 7.
Published in final edited form as: Biochem Biophys Res Commun. 2007 Jul 5;360(4):828–833. doi: 10.1016/j.bbrc.2007.06.136

Food Entrainment of Circadian Gene Expression Altered in PPARα−/− Brown Fat and Heart

Brian C Goh 1, Xiying Wu 1, Ann E Evans 2, Meagan L Johnson 2, Molly R Hill 2, Jeffrey M Gimble 1,3,4
PMCID: PMC2277508  NIHMSID: NIHMS28135  PMID: 17624301

Abstract

The circadian clock is subject to food entrainment. Since PPARα exhibits a circadian expression profile, we hypothesized that PPARα deficiency would alter the food entrainable response of adipose, cardiac, and liver tissues. Wild type and PPARα null mice were compared under ad libitum or restricted food access for the expression of circadian transcription factor-encoding mRNAs. Temporally restricted food access caused between a mean 5.8 to 11.5 hour phase shift in the expression profiles of the circadian genes Bmal1, Per3, and Rev-erbα in all tissues of control mice. In contrast, these same conditions phase shifted the circadian genes in tissues of PPARα null mice between a mean of 10.8 to 14.2 hr with amplitude attenuation. The food entrained phase shifts in the brown adipose and cardiac tissue circadian transcription factors of the PPARα null mice were prolonged significantly relative to wild type controls. Likewise, PPARα responsive genes in the livers of PPARα null mice exhibited a significantly prolonged phase shift relative to control mice. These findings confirm and extend recent observations in the literature..

Keywords: Adipose Tissue, Circadian, Cardiac, Liver, Peroxisome Proliferator Activated Receptor α

Introduction

Circadian rhythms play a major role in many, if not all, physiological processes [1]. The circadian clock, comprised of a highly conserved group of transcription factors (Clock, BMAL1, Period (Per), and Cryptochrome (Cry)), regulates the oscillatory expression profile of downstream targets including albumin D binding protein (DBP) and the orphan nuclear hormone receptors, Rev-erbα and Rev-erbβ [1, 2]. While the suprachiasmatic nucleus (SCN) within the brain acts as the core circadian oscillator, recent findings indicate that autonomous circadian clocks exist within peripheral tissues [3, 4]. When organ cultures were prepared with peripheral tissues isolated from Per2 promoter/luciferase reporter transgenic mice, their luciferase expression profile displayed circadian rhythmicity for over 20 days ex vivo [4]. Moreover, the peripheral tissues maintained their circadian rhythmicity even after SCN ablation in vivo. Thus, the circadian mechanisms throughout the body can display some degree of independence.

The circadian clock is entrained by food exposure and access in addition to photic stimuli [1, 2]. Temporal restriction of food access has been found to alter animal behavioral activities, leading to the hypothesis that a “food entrainable oscillator (FEO)” exists within the brain or some other site within the organism [5–7]. Restricted food access influences the expression profile of genes encoding the circadian transcription factors in the fat, liver, and other peripheral tissues [8–14]. When we restricted food access for AKR/J mice to the 12 hour lights on period for seven days, we observed a phase shift in the expression profile of multiple circadian transcription factors (Bmal1, Clock, Cry1–2, Npas2, Per1–3) and their immediate downstream targets (DBP, E4bp4, Id2, Rev-erbα, Rev-erbβ) in brown and white adipose tissues and liver [8]. This correlated with both a phase shift and amplitude attenuation in serum corticosterone levels [8].

Previous research has shown that the alpha isoform of peroxisome proliferators-activated receptors (PPARα) exhibits circadian rhythmicity and plays a significant role in lipid metabolism [15–17]. PPARα is known to be a major transcriptional regulator in fatty acid oxidation (FAO) through several processes such as fatty acid transport and activation of acyl-CoA esters [15, 17]. Additionally, PPARα has been shown to display patterns of expression that are in coordination with the core circadian genes’ profiles [16, 18, 19]. PPARα plays a critical metabolic role as evidenced by the hypothermia and hypoglycemia displayed by PPARα null mice relative to wild type controls under conditions of prolonged fasting [20, 21]. Based on these findings, we postulated that the circadian response to food entrainment will differ in PPARα null mice relative to their wild type controls. The current study tests this hypothesis by examining the impact of PPARα deficiency on the expression genes encoding circadian transcription factors and PPARα responsive proteins in peripheral tissues following temporally restricted food access. The results confirm and extend previous observations by Canaple et al [18].

Methods and Materials

Experimental Design

Protocols were reviewed by the OCU and/or PBRC Institutional Animal Care and Use Committees. Founders of the breeding colony at OCU were provided by Dr. F. Gonzales (NCI, NIH) [15]. Experiment 1 (March 2005) investigated differences in gene expression between ad libitum fed wild type and PPARα-null mice. Eight to ten week old C57BL/6N x Sv/129 wild-type (WT) male mice were compared against 8–10 week old C57BL/6N x Sv/129 homozygous PPARα-null male mice. Animals were acclimatized for 2 weeks to a regular chow diet (Purina 5015) with ad libitum access under a strict 12h light/ 12h dark cycle. After this period, groups of 3 animals from each genotype were sacrificed at 4 hour intervals over a 24-hour period. Liver, brown adipose tissue (BAT), epididymal adipose tissue (eWAT), and plasma were harvested, flash frozen in liquid nitrogen, and subsequently processed for total RNA isolation or cholesterol/triglyceride assay. Experiment 2 (May of 2006) examined the effect of temporally restricted feeding (RF). The study was conducted with groups of 40 wild-type and 40 PPARα-null male mice (age ranges, 7–25 weeks) acclimatized to a regular chow diet (Purina 5015) and maintained on a strict 12h light/ 12h dark cycle. The wild-type and PPARα-null mice were then sub-divided into two cohorts; an ad libitum cohort that retained free access to food and an experimental cohort whose feeding time was restricted to the 12-hour lights on period. This feeding schedule was maintained for 8 days until the time of harvest. Body weights and food intake were monitored daily both cohorts. Animals from each cohort were then sacrificed as described in Experiment 1.

Real-Time PCR (RT-PCR)

Total RNA from the selected tissues was isolated and purified using TriReagent and 1-bromo-3-chloropropane, BCP (Molecular Research Center). 2μg of RNA was then reversely transcribed using Moloney Murine Leukemia Virus Reverse Transcriptase (MMLV-RT; Promega) with Oligo dT at 42 C for 1 hour in a 20μl working volume. The cDNA was then diluted into 1:100 for the liver and 1:25 solutions for the heart and fat depots. Primers for the selected circadian and lipid metabolism genes were designed using Primer Express (Applied Biosystems) (Supplement Table 1). Real-Time PCR was then performed using the SYBR® Green PCR Master Mix (Applied Biosystems) on the 7900 Real Time PCR system (Applied Biosystems). Universal cycling conditions of 95°C for 10 min, 40 cycles of 95°C for 15 sec, and then 60°C for 1 min were used. Genes of interest were normalized against Cyclophilin B, which has been shown to maintain the consistency of expression required for a “housekeeping” control in a manner similar to actin and GAPDH [8, 22]. All RT-PCR assays were performed in triplicate and the Cyclophilin B-normalized ratio data presented in the figures represents the mean ± standard deviation.

Statistical Section

Oscillation patterns and periodicity of the qRT-PCR and serum data were evaluated using Time Series Analysis-Single Cosinor v. 6.0 software (Expert Soft Technologie) [23]. Comparisons between groups were performed using a one tailed Students t-test. Analyses with p values <0.05 were considered significant.

Results

Circadian core oscillator gene expression in wild type and PPARα-null mice with ad libitum food access

We examined RNA expression patterns in peripheral tissues harvested from wild-type and PPARα-null mice with ad libitum food access. Figure 1 displays 24 hour profiles of liver, BAT, and eWAT gene expression as a function of Zeitgeber Time (ZT) where ZT0 corresponds to the initiation of the 12-hour lights-on period. The positive circadian transcriptional regulators, Bmal1 and Npas2, displayed similar expression profiles and amplitudes in all three tissues of wild type and PPARα-null mice. The profile of Bmal1 and Npas2 mRNA levels, normalized to Cyclophilin B, displayed mean acrophase values of ZT 20.9 and 21.7, respectively. The expression profile of the negative circadian transcriptional regulators, Per1 and Per3, displayed mean acrophases of ZT11.4 and ZT10.6, respectively, reflecting an ~10 hr time difference relative to Bmal1 and Npas2. The amplitudes of Per1 and Per3 were similar between wild type and PPARα-null mice in all tissues except eWAT. DBP, Rev-erbα, and Rev-erbβ, downstream transcriptional targets of Bmal1 and Npas2, exhibited mean acrophases of ZT8.5, ZT 5.6, and ZT8.2 in all three tissues. The circadian rhythmicity of all genes in all tissues was statistically significant (p < 0.05) based on Cosinor analysis.

Figure 1. Circadian Gene Expression Profiles in Metabolic Tissues of Wild Type and PPARα Null Mice.

Figure 1

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The mRNA expression profile of “positive” (Npas2, Bmal1) and “negative” (Per1, Per3) circadian transcriptional regulators and their immediate downstream targets (DBP, Rev-erbα, Rev-erbβ) are displayed over a 24-hour period in brown adipose tissue (BAT), liver, and epididymal white adipose tissue (eWAT) mRNAs pooled from groups of n = 3 mice per time point. In this and all subsequent figures, the 24-hour expression profile has been duplicated to visually display evidence of circadian rhythmicity. The qRT-PCR values (mean ± S.D. of triplicate determinations) were normalized relative to Cyclophilin B. Cosinor analysis documented p values < 0.05 for all measurements in all tissues with the exception of Per1 (wild type and PPARα null BAT and wild type eWAT) and Per3 (wild type BAT) (Supplement Table 2).

Effect of temporally restricted food access on the circadian gene expression profiles in wild type and PPARα-null mice

In Experiment 2, all cohorts displayed comparable body weights at the initiation of the study. During the first two days, the wild type and PPARα-null mice with temporally restricted food access exhibited reduced food intake relative to their ad libitum fed counterparts; however, by day 3, all cohorts displayed comparable food intake and body weights in all cohorts were comparable at the conclusion of the study (data not shown). The PPARα mRNA levels displayed a statistically significant circadian profile in all tissues in wild type mice under ad libitum conditions (Supplement Figure 1).

Under conditions of ad libitum food access, the amplitudes and acrophase for representative circadian gene markers (Bmal1, Per3, Rev-erbα) were similar in the BAT and cardiac tissue of wild type and PPARα-null mice (Figure 2). When food access was temporally restricted, the wild type mice shifted the acrophase of circadian gene expression by means (±S.D.) of 5.8±2.0 hrs (heart) and 7.1±.8 hrs (BAT) relative to the ad libitum state.. In contrast, with temporally restricted food access, the PPARα-null mice shifted the acrophase of circadian gene expression between 14.2±2.5 hrs (heart) and 11.4±1.2 hrs (BAT); relative to the wild type controls, these values were statistically significant. In BAT, temporally restricted food access reduced the amplitude of circadian gene expression in both wild type and PPARα-null mice (Figure 2). In cardiac tissue, temporally restricted food access reduced the amplitude of wild type Bmal1 and PPARα-null Rev-erbα expression and only increased this parameter for PPARα-null Bmal1 (Figure 2).

Figure 2. Circadian Gene Expression in Brown Adipose and Cardiac Tissue of Wild Type and PPARα Null Mice under Ad Libitum and Temporally Restricted Food Access.

Figure 2

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The mRNA expression of Bmal1, Per3, and Rev-erbα was determined in brown adipose tissue (BAT) and heart isolated from wild type (solid line) and PPARα null (dotted line) mice with either ad libitum (ad lib) or temporally restricted (RF) food access. Values are the mean ± S.D. of triplicate qRT-PCR assays conducted using mRNA pools from n=3 animals per time point and normalized relative to Cyclophilin B. Cosinor analysis documented p values < 0.05 for all measurements in both tissues (Supplement Table 3).

Temporal restriction of food access shifted the acrophase of circadian gene expression in eWAT by 8.7±1.6 hrs in wild type mice and 10.8±2.2 hrs in PPARα-null mice (p =0.176); this was associated with a change in amplitude in some but not all genes. (Figure 3 and Supplement Tables 4 and 5) In liver, temporal restriction of food shifted the acrophase of circadian gene expression by 11.5±0.8 hrs in wild type mice and 13.2±0.5 hrs in PPARα-null mice (p =0.075) (Figure 3). The amplitude of gene expression under temporal restricted food access was not significantly changed relative to the ad libitum state for either wild type or PPARα-null mice. In all tissues, the period of circadian gene expression ranged between 23.0 to 25.1 hours and achieved statistically significant rhythmicity in nearly all instances. The one exception was Rev-erbα expression in the liver of wild type mice with temporally restricted food access; this displayed a statistically significant ultradian period of 12.2 hours (Supplement Tables 4 and 5).

Figure 3. Circadian Gene Expression in Liver and Epididymal White Adipose Tissue of Wild Type and PPARα Null Mice under Ad Libitum and Temporally Restricted Food Access.

Figure 3

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The mRNA expression of Bmal1, Per3, and Rev-erbα was determined in liver and epididymal white adipose tissue (eWAT) isolated from wild type (solid line) and PPARα null (dotted line) mice with either ad libitum (ad lib) or temporally restricted (RF) food access. Values are the mean ± S.D. of triplicate qRT-PCR assays conducted using mRNA pools from n=3 animals per time point and normalized relative to Cyclophilin B. Cosinor analysis documented p values < 0.05 for all measurements in both tissues with the exception of Rev-erbα in wild type liver RF (p = 0.112) and wild type eWAT ad lib (p = 0.081) and RF (p = 0.072) (Supplement Table 3).

Circadian oscillations in hepatic expression of PPARα downstream target genes

The circadian expression profile of representative genes regulated by PPARα were evaluated in the liver of wild type and PPARα-null mice (Figure 4). The mRNAs of the lipid metabolic enzymes acyl Co-A oxidase (ACOX1), fatty acid desaturase 2 (FADS2), and elongation of very long chain fatty acid 5 (Elovl5) displayed statistically significant circadian oscillations in wild type and PPARα-null mice; however, the amplitude of ACOX1 was markedly attenuated in the PPARα-null mice. With restricted feeding, the mean shift acrophase shift in these three genes was significantly greater in PPARα-null (12.6±2.8 hrs) relative to wild type mice (6.7±4.1 hrs) (Supplement Tables 4 and 5).

Figure 4. Circadian expression profile of hepatic genes regulated by PPARα.

Figure 4

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The mRNA level of ACOX-1, Elovl-5, and FASD2 were determined in the liver of wild type (solid line) and PPARα null (dotted line) mice under ad libitum and restricted feeding conditions. Cosinor analyses documented statistically significant rhythms (p <0.05) for all expression profiles except for WT-ad lib ACOX1 (p = 0.32) and FADS2 (p = 0.96) and KO-restricted feeding ACOX1 (p = 0.53) (Supplement Table 3).

Discussion

Temporally restricted food access entrains a phase shift in circadian transcription factor gene expression profiles in peripheral tissues of wild type mice [8–14]. The current work reports that PPARα deficiency significantly modulates this phenomenon in BAT and cardiac muscle, shifting the acrophase of circadian gene expression by up to an additional 8 hrs. While eWAT and liver displayed a prolonged food entrained acrophase shift of 1.5–2 hrs of circadian gene expression in the PPARα null mice relative to wild type controls, these differences did not achieve statistical significance. However, the expression of PPARα responsive genes in the liver showed evidence of a prolonged food entrained acrophase shift in the PPARα null mice relative to controls with some degree of amplitude attenuation.

In general, our results confirm those reported by Canaple et al. [18]. Both studies show food entrainment of circadian transcription factor gene expression in the liver of both the wild type and PPAR α null mice and of the PPAR α mRNA level in the liver of wild type mice. Both studies demonstrate a comparable shift in the hepatic expression of Per 3 and Rev-erbα between daytime and nighttime fed PPARα null and wild type mice [18]. Likewise, independent studies by Satoh et al. have demonstrated that murine energy metabolism and hepatic circadian transcription factor mRNA expression profiles acclimated within six days to a similar time-restricted feeding regimens [24].

Mice deficient in PPARα display altered cardiac tissue metabolism, relying primarily on glycolysis rather than fatty acid oxidation, resulting in decreased energy reserves and reduced contractile function under stress [20, 25, 26]. With prolonged fasting, PPARα null mice are prone to hypothermia, consistent with altered BAT function [20, 21]. These findings may be linked to the current observation that BAT and cardiac tissue of PPARα null mice show altered food entrainable circadian transcription factor gene expression. However, further studies will be necessary to define the mechanism connecting circadian transcription factors and PPARα in these peripheral tissues. Nevertheless, analyses of the circadian profile of PPARα null mice have increased significance in light of recent observations that mice deficient in the genes encoding PPAR gamma co-activator 1 (PGC1)α and β, co-activators of both PPAR α and γ [27], also exhibit a disrupted circadian rhythm and altered metabolic function [28, 29].

Supplementary Material

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Acknowledgments

The authors wish to acknowledge support from the Pennington Biomedical Research Foundation (B.C.G., X.W., J.M.G.) and the Clinical Nutrition Research Center (NIH grant DK072476) (J.M.G.); their colleagues Drs. Andrew Butler, Z. Elizabeth Floyd, Randall L. Mynatt, and Sanjin Zvonic for their critical discussions and review of the manuscript; Gail Kilroy for discussions and technical support.

Footnotes

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