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1Brown Foundation Institute of Molecular Medicine and 2School of Public Health, Human Genetics Center, University of Texas Health Science Center at Houston; and 3United States Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030
Submitted 30 April 2004 ; accepted in final form 26 July 2004
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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(PPAR). We hypothesized that cardiac and skeletal muscle alter their responsiveness to fatty acids over the course of the day, allowing optimal adaptation when availability of this substrate increases. In the current study, pyruvate dehydrogenase kinase 4 (pdk4) was utilized as a representative PPAR-regulated gene. Opposing diurnal variations in pdk4 expression were observed in cardiac and skeletal muscle isolated from the ad libitum-fed rat; pdk4 expression peaked in the middle of the dark and light phases, respectively. Elevation of circulating fatty acid levels by high-fat feeding, fasting, and streptozotocin-induced diabetes increased pdk4 expression in both heart and soleus muscle. Highest levels of induction were observed during the dark phase, regardless of muscle type or intervention. Specific activation of PPAR with WY-14643 rapidly induced pdk4 expression in heart and soleus muscle. Highest levels of induction were again observed during the dark phase. The same pattern of induction was observed for the PPAR-regulated genes malonyl-CoA decarboxylase and uncoupling protein 3. Investigation into the potential mechanism(s) for these observations exposed a coordinated upregulation of transcriptional activators of the PPAR system during the night, with a concomitant downregulation of transcriptional repressors in both muscle types. In conclusion, responsiveness of cardiac and skeletal muscle to fatty acids exhibits a marked diurnal variation. These observations have important physiological and pathophysiological implications, ranging from experimental design to pharmacological treatment of patients.
diabetes; fasting; high-fat feeding; peroxisome proliferator-activated receptor-; pyruvate dehydrogenase kinase 4
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(PPAR). PPAR, in association with its heterodimerization partner retinoid X receptor (RXR), binds to the fatty acid response element (FARE) located within promoters of various target genes, many of which encode for key regulators of both fatty acid and carbohydrate oxidation (2, 14, 22). These genes include those encoding for malonyl-CoA decarboxylase (mcd), pyruvate dehydrogenase kinase 4 (pdk4), and uncoupling protein 3 (ucp3) (3, 18, 20, 23). Transcriptional activity of the PPAR/RXR heterodimer is increased through ligand binding. The natural ligand for PPAR appears to be either fatty acids themselves or a fatty acid derivative (7). Thus fatty acids act in a feed-forward manner, inducing the expression of those enzymes that promote fatty acid oxidation (e.g., mcd, ucp3) as well as those that repress carbohydrate oxidation (e.g., pdk4). PPAR is a key mediator of metabolic adaptation in response to increased fatty acid availability (e.g., high-fat feeding, fasting, uncontrolled type 1 diabetes mellitus) for tissues such as cardiac and skeletal muscle (2, 15, 22). Conversely, for situations in which increased reliance on carbohydrate as a fuel is required (e.g., cardiac hypertrophy, hypoxia), downregulation of PPAR activity appears essential for metabolic switching (1, 12, 21).
Over the course of a normal day, fatty acid availability fluctuates, with generally higher circulating fatty acids when the animal is asleep (8). We hypothesized that cardiac and skeletal muscle exhibit diurnal variations in responsiveness to fatty acids in synchronization with diurnal variations in fatty acid availability, thereby allowing optimal adaptation at the appropriate time of day. Somewhat unexpectedly, the present studies expose a lack of synchronization between diurnal variations in the stimulus (i.e., fatty acids) and responsiveness of the PPAR system in cardiac and skeletal muscle of the ad libitum-fed rat.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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agonist studies) or at the Animal Care Center of the Children's Nutrition Research Center at Baylor (high-fat feeding and fasting studies). All animals were housed under controlled conditions (23 ± 1°C, 12:12-h light-dark cycle) and received standard laboratory chow and water ad libitum unless otherwise stated. Ten days before they were killed, animals were housed in a separate environment-controlled room in which a strict 12:12-h light-dark cycle regime was enforced [lights on at 7:00 AM; zeitgeber time (ZT) 0]. On the day of the experiment, animals were killed at 3-h intervals. To ensure reproducibility of gene expression cycles, at least two control and two intervention animals were killed at each time point on three separate days. After administration of pentobarbital sodium (100 mg/kg ip), hearts and soleus muscles were isolated, freeze clamped in liquid nitrogen, and stored at –80°C before RNA extraction. Dietary manipulations. Animals were fed either standard laboratory chow (Purina Mills, St. Louis, MO), a low-fat diet (LFD; Research Diets, New Brunswick, NJ), or a high-fat diet (HFD; Research Diets). The LFD and HFD were isocaloric and varied only in the proportion of energy obtained from carbohydrate and fat. The contributions of carbohydrate, fat, and protein to total energy available were 70%, 10%, and 20% for the LFD and 20%, 60%, and 20% for the HFD, respectively. The source of carbohydrate was a combination of corn starch, maltodexrin, and sucrose, while the fat source was a combination of soybean oil and lard.
High-fat feeding. Rats were fed either the LFD or the HFD for 4 wk. Beginning at ZT0 on the day of the experiment, hearts and soleus muscles were isolated from LFD and HFD rats at 3-h intervals for a 24-h period. A total of 97 animals were studied, of which 48 were fed the LFD and 49 were fed the HFD.
Fasting. Rats were divided into two groups randomly: fed and fasted. At ZT6 on the day of the experiment, access to standard laboratory chow was withdrawn from rats in the fasted group only. Hearts and soleus muscles were isolated from fed and fasted rats at 3-h intervals for a 24-h period, beginning at ZT6. A total of 104 animals were studied, of which 54 were fed controls and 48 were fasted.
Induction of diabetes.
Type 1 diabetes mellitus was induced by a single tail vein injection of the pancreatic 
-cell toxin streptozotocin (STZ; 65 mg/kg) 4 wk before muscle isolation. Control animals were injected with vehicle only (Hanks' buffer; 4 ml/kg). Animals were considered diabetic if their blood glucose level was >300 mg/dl. Beginning at ZT0 on the day of the experiment, hearts and soleus muscles were isolated from vehicle/control and diabetic rats at 3-h intervals for a 24-h period. A total of 123 animals were studied, of which 62 were controls and 61 were diabetic.
Specific PPAR activation.
To specifically activate the PPAR system, WY-14643 (50 mg/kg) was administered by a single injection (ip) exactly 4 h before muscle isolation. Control animals were injected with vehicle only (1:1 vol/vol DMSO-saline). Beginning at ZT0 on the day of the experiment, hearts and soleus muscles were isolated from vehicle/control and WY-14643-treated rats at 3-h intervals for a 24-h period. A total of 96 animals were studied, of which 48 were vehicle controls and 48 were WY-14643 treated.
RNA extraction and quantitative RT-PCR.
RNA extraction and quantitative RT-PCR of samples were performed using previously described methods (4, 9, 10). Specific quantitative assays were designed from rat sequences available in GenBank (Table 1). Standard RNA was made for all assays by the T7 polymerase method (Ambion, Austin, Texas) with the use of total RNA isolated from rat hearts. The correlation between the number of PCR cycles required for the fluorescent signal to reach a detection threshold (Ct) and the amount of standard was linear over at least a five-log range of RNA for all assays (data not shown). The level of transcripts for the constitutive housekeeping gene products -actin and cyclophilin were quantitatively measured in each sample to control for sample-to-sample differences in RNA concentration. PCR data are reported as the number of transcripts per number of -actin molecules, with the exception of the fasting studies. Here, data are reported as the number of transcripts per number of cyclophilin molecules (as -actin expression significantly decreased by 33% in hearts and soleus muscles isolated from fasted group; data not shown). Expression of -actin did not change with the other experimental interventions in rodent hearts and soleus muscles (data not shown). Data reported as fold change from trough value (see Fig. 7) allow for direct comparison of heart and soleus muscle diurnal variations on the same figure.
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Statistical analysis. Two-way analysis of variance (ANOVA) was conducted to investigate the main effects of group (tissue or experimental condition) and time. The general linear model procedure in SAS software, version 8.2, was used for this analysis (SAS Institute, Cary, NC). A full model including second-order interactions was conducted for each experiment. Significant differences were determined using Type III sums of squares. Tukey's post hoc test was conducted for all significant two-way ANOVAs. The null hypothesis of no model effects was rejected at P < 0.05. Repeated measures analysis was not utilized, as the samples at each time period were from different animals.
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RESULTS |
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-regulated gene pdk4 were next characterized in heart and soleus muscle isolated from the ad libitum-fed rat. Previous studies have characterized pdk4 as a typical PPAR-regulated gene, the expression of which is induced in cardiac and skeletal muscle in response to increased fatty acid availability. Striking differences were observed in the rhythms of this gene between the two muscle types (Fig. 2). Expression of cardiac pdk4 was 2.5-fold higher during the dark phase, whereas soleus muscle pdk4 expression was 2.1-fold higher during the light phase (Fig. 2).
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-regulated gene were observed during the dark phase for both muscle types (Fig. 3). Feeding rats the HFD also increased plasma NEFA levels in a circadian-dependent manner (Fig. 3A). Similar to the expression of pdk4, greater differences in plasma NEFA levels between LFD- and HFD-fed rats were observed during the dark phase (Fig. 3).
Withdrawal of food access caused a rapid induction of pdk4 in both heart and soleus muscle (Fig. 4). Induction reached a peak 
15 h after the initiation of the fast (i.e., ZT21) for both muscle types, after which time expression of this PPAR-regulated gene began to decline (Fig. 4). Plasma NEFA levels also increased rapidly after initiation of the fast, reaching a peak within 12 h (i.e., ZT18; Fig. 4A). However, in contrast to muscle pdk4 expression, plasma NEFA levels plateaued, remaining elevated thereafter (Fig. 4).
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Diurnal variations in responsiveness to PPAR activation.
The data presented in Figs. 3–5 suggest that both cardiac and skeletal muscle exhibit increased responsiveness to fatty acids during the dark phase. We next tested more specifically the hypothesis that responsiveness of the PPAR system within cardiac and skeletal muscle exhibits diurnal variations. Acute treatment (4 h) of rats with the specific PPAR agonist WY-14643 resulted in a marked induction of pdk4 in both heart and soleus muscle (Fig. 6, A and B). Consistent with our previous observations, greatest levels of induction (compared to control rats) were observed during the dark phase, peaking between ZT18 and ZT21 for both heart and soleus muscle (Fig. 6, A and B). Similar results were obtained for mcd and ucp3 expression (Fig. 6, C-F). Greatest levels of induction of these PPAR-regulated genes were again observed during the dark phase in both muscle types (Fig. 6, C-F).
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system in cardiac and skeletal muscle.
In an attempt to gain insight into the molecular mechanisms responsible for increased sensitivity of cardiac and skeletal muscle to PPAR activation, we measured diurnal variations in various positive (ppar, rxr, pgc1, p300) and negative (rev-erba) components of the PPAR system in these muscle types. Messenger RNA encoding for ppar exhibits identical diurnal variations in both heart and soleus muscle, with higher levels of expression observed during the dark phase (Fig. 7A). Diurnal variations in cardiac rxr expression were similar to those of its heterodimeration partner ppar, with a peak in expression at ZT18 (Fig. 7B). In contrast, rxr expression exhibited a less dramatic diurnal variation in soleus muscle, fluctuating only 1.2-fold over the course of the day (Fig. 7B). Differences in the amplitude of diurnal variations between heart and soleus muscle were also observed for the coactivator pgc1 (Fig. 7C). Levels of soleus muscle pgc1 mRNA were twofold higher at ZT15 compared with trough values (ZT6; Fig. 7C). Although cardiac pgc1 expression peaked at the same time of the day as soleus muscle pgc1, the fold change was less striking (1.4-fold; Fig. 7C). The main histone acetylase utilized by the PPAR system, p300, again exhibited diurnal variations in both heart and soleus muscle, with peak levels of expression during the dark phase (Fig. 7D). In contrast to diurnal variations in the positive components of the PPAR system (i.e., ppar, rxr, pgc1, and p300), greater levels of expression of the transcriptional repressor rev-erba were observed during the light phase in both heart and soleus muscle (13.7- and 9.1-fold respectively; Fig. 7E). |
DISCUSSION |
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system in both cardiac and skeletal muscle. In the normal ad libitum-fed rat, circulating fatty acids were higher during the light phase, when this animal is less active. Diurnal variations in the responsiveness of cardiac and skeletal muscle to fatty acids were investigated by increasing fatty acid availability through high-fat feeding, fasting, and STZ-induced diabetes. Regardless of the intervention, greater induction of the PPAR-regulated gene pdk4 was observed during the dark phase in both cardiac and skeletal muscle. Specific activation of PPAR through WY-14643 administration also resulted in greater pdk4 induction during the dark phase in both muscle types. Similar results were obtained for the PPAR-regulated genes mcd and ucp3. From these data, we are able to conclude that responsiveness of cardiac and skeletal muscle to fatty acids is greatest during the dark phase. This may be due in part to increased expression of positive components of the PPAR system (ppar, rxr, pgc1, p300), in combination with a concomitant downregulation of rev-erba (a negative component of this system), during the dark phase. These observations have important physiological and pathophysiological implications, ranging from experimental design to the timing of pharmacological treatment of patients.
Diurnal variations in responsiveness to fatty acids.
We initially hypothesized that diurnal variations in responsiveness of cardiac and skeletal muscle to fatty acids would be synchronized with diurnal variations in fatty acid availability in the ad libitum-fed rat. Circulating plasma NEFA levels exhibit a clear diurnal variation, with elevated levels during the light phase (Fig. 2A). This is likely due to changes in lipolysis, as circulating insulin levels decline while the animal is at rest (although a contribution by increased fatty acid utilization during the dark phase cannot be ruled out presently). Given the diurnal variations in plasma NEFA levels, we predicted that cardiac and skeletal muscle would exhibit increased responsiveness to fatty acids during the light phase. This hypothesis was challenged by increasing fatty acid availability through three separate interventions in vivo (high-fat feeding, fasting, and STZ-induced diabetes) and determining the effects on diurnal variations in expression of the PPAR-regulated gene pdk4. Somewhat unexpectedly, the results expose an increased responsiveness of cardiac and skeletal muscle to fatty acids during the dark phase.
Feeding rats an HFD significantly increased the expression of cardiac and skeletal muscle pdk4 expression, with highest levels of induction during the dark phase (Fig. 3). However, this experiment was not able to distinguish between diurnal variations in the level of the stimulus (i.e., fatty acids) and the responsiveness of the system, as high-fat feeding also increased plasma NEFA levels in a circadian-dependent manner (Fig. 3A). Unlike the high-fat feeding experiments, fasting rats caused a sustained elevation in plasma NEFA levels (Fig. 4A). Despite maintenance of the level of the stimulus, the level of induction of pdk4 declined at the light-to-dark phase transition (Fig. 4). Although the observations presented in Fig. 4 are consistent with increased sensitivity of cardiac and skeletal muscle to fatty acids during the dark phase, this experiment cannot discount the possibility that the PPAR system becomes downregulated after stimulation for >15 h (i.e., stimulus-induced downregulation of the receptor system). We therefore chronically elevated circulating fatty acid levels through STZ-induced diabetes mellitus. Four weeks of uncontrolled diabetes caused a circadian-independent elevation in circulating NEFA levels (Fig. 5A), thereby overcoming the limitations of the high-fat feeding and fasting experiments. Higher levels of induction of the PPAR-regulated gene pdk4 were observed during the dark phase in both heart and soleus muscle (Fig. 5). Although high-fat feeding, fasting, and uncontrolled STZ-induced diabetes each affects multiple neurohumoral influences imposed on cardiac and skeletal muscle, a major commonality between these interventions is elevation of circulating NEFA. Thus, taken together, these observations expose marked diurnal variations in the responsiveness of cardiac and skeletal muscle to fatty acids, with increased responsiveness during the dark phase.
Whether responsiveness of the PPAR system within cardiac and skeletal muscle exhibits a similar diurnal variation was next addressed by acutely (4 h) challenging this system with a specific agonist (WY-14643). The agonist rapidly induced the expression of pdk4 in both heart and soleus muscle (Fig. 6). Regardless of the muscle type investigated, higher levels of induction were always observed during the dark phase (ZT18/21; Fig. 6). Similar results were obtained for the PPAR-regulated genes mcd and ucp3. From these observations, we conclude that cardiac and skeletal muscle exhibit marked diurnal variations in responsiveness of the PPAR system, with highest responsiveness during the dark phase. The latter likely mediates the observed diurnal variations in cardiac and skeletal muscle fatty acid responsiveness.
To gain insight into the potential mechanism(s) responsible for the diurnal variations in cardiac and skeletal muscle responsiveness to fatty acids, we characterized diurnal variations in various components of the PPAR system within these two tissues. We report here that a coordinated upregulation of positive components of this system (ppar, rxr, pgc1, p300) was observed during the dark phase, with a concomitant downregulation of the negative component rev-erba. Of these, diurnal variations in rev-erba were most striking. Indeed, rev-erba expression peaks at ZT9 in both cardiac and skeletal muscle, a time at which we consistently observe the lowest level of induction of PPAR-regulated genes in these muscle types (Figs. 3–7). REV-ERBA represses the transcriptional activity of the PPAR/RXR heterodimer by binding to the FARE of target promoters (13). REV-ERBA has recently been shown to be an integral component of the circadian clock (an intracellular molecular mechanism that enables the cell to anticipate diurnal variations in its environment) (6, 16). As with many other circadian clock components, the transcript encoding for rev-erba is translated immediately, such that rhythms in rev-erba mRNA and REV-ERBA protein are identical (16). We have characterized fully the circadian clock within both rat heart (25) and soleus muscle (Stavinoha MA and Young ME, unpublished observations). Taken together, these observations lead us to propose that REV-ERBA may serve as a novel link between the circadian clock and fatty acid metabolism in cardiac and skeletal muscle. In doing so, REV-ERBA would allow these muscle types to anticipate increased fatty acid availability during the dark phase. Clearly, such diurnal variations in plasma NEFA levels do not occur in the ad libitum-fed laboratory rat (Fig. 2A). This has led us to hypothesize that diurnal variations in fatty acid responsiveness may be in anticipation of prolongation of fasting, when the animal in the wild is initially unsuccessful in its forage for food (19, 24). This hypothesis is akin to the Thrifty Gene Hypothesis, which states that it is a selective advantage to anticipate periods of prolonged fasting/starvation (5). Indeed, the data in Fig. 4 illustrate the rapid and dramatic nature of pdk4 induction at the light-to-dark transition in the fasted rat. This would transiently enable efficient utilization of fatty acids at the initiation of the active phase, when availability of this substrate is increased (as the forage for food continues).
Diurnal variations in metabolic gene expression.
Both the heart and soleus muscles are highly vascularized, insulin-sensitive tissues that rely heavily on oxidative metabolism for their energetic demands. Their evidenced metabolic similarities are echoed by similarities in diurnal variations in fatty acid responsiveness. In marked contrast, diurnal variations in pdk4 expression between these muscles (isolated from the ad libitum-fed rat) were antiphase with respect to one another. Similar opposing diurnal variations are also observed for the PPAR-regulated genes mcd and ucp3 (Fig. 6) (17). Studies are currently underway to identify the molecular mechanisms directing the opposing rhythms in these seemingly similar muscle types. Initial studies suggest that PPAR-independent transcriptional mechanisms are involved (Stavinoha MA and Young ME, unpublished observations).
Experimental implications.
The results presented within this study have far-reaching implications, both at the benchside and at the bedside. In the former case, our observations highlight the importance of time-of-day considerations in the design of experimental protocols. Failure to do so may result in erroneous conclusions. For example, isolation of hearts from HFD-fed rats between ZT6 and ZT9 (i.e., 1:00 PM to 4:00 PM) would incorrectly suggest that high-fat feeding has little or no effect on either circulating NEFA levels or PPAR-regulated gene expression in cardiac and skeletal muscle (Fig. 3). This is likely the situation in the recent study by Hoeks et al. (11), who reported that although high-fat feeding results in increased UCP3 protein expression in cardiac and skeletal muscle, circulating NEFA levels and PPAR-regulated gene expression are not significantly increased (11). The investigators conclude that the induction of UCP3 is through PPAR-independent mechanisms. As these studies were likely performed during the light phase, increased circulating NEFA levels and increased muscle PPAR-regulated gene expression would be inadvertently missed, leading to erroneous conclusions.
Clearly it is not feasible for every scientific investigation to be performed over a 24-h period. Instead, preliminary studies should be carried out to determine the most appropriate time of day at which future studies are continued. In the case of investigations related to the PPAR system in cardiac and skeletal muscle, ZT18 is consistently the optimal time for nonerroneous conclusions to be drawn. This is experimentally feasible by housing rodents in a reverse light-dark cycle (i.e., lights on at 7:00 PM) and isolating tissues at 1:00 PM. Using this insight, we have identified mitochondrial thioesterase 1 as a PPAR-regulated gene in cardiac and skeletal muscle (17). Such temporal considerations will undoubtedly aid in reducing discrepancies between studies performed in different laboratories as well as discrepancies between animal and human studies (e.g., by investigating both organisms in their awake/active phase).
Study limitations.
The present study has shown that cardiac and skeletal muscle exhibit marked diurnal variations in responsiveness to fatty acids at the level of gene expression. In contrast, we have not investigated whether the observed changes in gene expression are associated with concomitant changes in protein expression. The present study also has not established a causal relationship between diurnal variations in fatty acid responsiveness and expression levels of investigated components of the PPAR system. Alternative influences, such as diurnal variations in posttranslational modification of PPAR (e.g., phosphorylation), may mediate changes in fatty acid responsiveness over the course of the day. Additionally, we have not defined the mechanism(s) responsible for cardiac and skeletal muscle diurnal variations in metabolic gene expression (pdk4, mcd, and ucp3) in the ad libitum-fed rat. These are areas of future research initiated in our laboratories.
In conclusion, circulating fatty acids exhibit a diurnal variation, with the greatest level during the light phase. In contrast, cardiac and skeletal muscle exhibit diurnal variations in their responsiveness to fatty acids, with greatest responsiveness during the dark phase. This is likely mediated by diurnal variations in the responsiveness of the PPAR system in these muscles. The apparent dissociation between diurnal variations in fatty acid availability and responsiveness of the PPAR system within cardiac and skeletal muscle may be a selective advantage, allowing anticipation of prolongation of fasting when the animal in the wild is initially unsuccessful in its forage for food.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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M. P. Chandler, E. E. Morgan, T. A. McElfresh, T. A. Kung, J. H. Rennison, B. D. Hoit, and M. E. Young Heart failure progression is accelerated following myocardial infarction in type 2 diabetic rats Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1609 - H1616. [Abstract] [Full Text] [PDF]
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