Original Article

International Journal of Obesity (2010) 34, 1589–1598; doi:10.1038/ijo.2010.63; published online 30 March 2010

Time-of-day-dependent dietary fat consumption influences multiple cardiometabolic syndrome parameters in mice

M S Bray1,2, J-Y Tsai2, C Villegas-Montoya2, B B Boland2, Z Blasier2, O Egbejimi2, M Kueht2 and M E Young2,3

  1. 1Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
  2. 2Department of Pediatrics, USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA
  3. 3Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

Correspondence: Dr ME Young, Division of Cardiovascular Diseases, Department of Medicine, University of Alabama at Birmingham, 703 19th Street S., ZRB 308, Birmingham, AL 35294, USA. E-mail: meyoung@uab.edu

Received 8 December 2009; Revised 26 January 2010; Accepted 19 February 2010; Published online 30 March 2010.

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Abstract

Background:

 

Excess caloric intake is strongly associated with the development of increased adiposity, glucose intolerance, insulin resistance, dyslipidemia, and hyperleptinemia (that is the cardiometabolic syndrome). Research efforts have focused attention primarily on the quality (that is nutritional content) and/or quantity of ingested calories as potential causes for diet-induced pathology. Despite growing acceptance that biological rhythms profoundly influence energy homeostasis, little is known regarding how the timing of nutrient ingestion influences development of common metabolic diseases.

Objective:

 

To test the hypothesis that the time of day at which dietary fat is consumed significantly influences multiple cardiometabolic syndrome parameters.

Results:

 

We report that mice fed either low- or high-fat diets in a contiguous manner during the 12h awake/active period adjust both food intake and energy expenditure appropriately, such that metabolic parameters are maintained within a normal physiologic range. In contrast, fluctuation in dietary composition during the active period (as occurs in human beings) markedly influences whole body metabolic homeostasis. Mice fed a high-fat meal at the beginning of the active period retain metabolic flexibility in response to dietary challenges later in the active period (as revealed by indirect calorimetry). Conversely, consumption of high-fat meal at the end of the active phase leads to increased weight gain, adiposity, glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia (that is cardiometabolic syndrome) in mice. The latter perturbations in energy/metabolic homeostasis are independent of daily total or fat-derived calories.

Conclusions:

 

The time of day at which carbohydrate versus fat is consumed markedly influences multiple cardiometabolic syndrome parameters.

Keywords:

adiposity; chronobiology; feeding; glucose tolerance; metabolism

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Introduction

Concurrent with the dramatic rise in obesity and related co-morbidities that has taken place in the last 25 years, a number of striking changes have also occurred in our environment during this time. In addition to an increase in the abundance of energy-dense, low-quality, highly palatable food and a decrease in physical activity duration, time spent awake has also increased dramatically. We now live in a 24-h environment in which patterns of sleeping, eating, and physical activity may be substantially out of synchrony with the daily cycles of light and dark. Several studies have shown that both shift work and sleep deprivation are associated with increased risk for obesity, type 2 diabetes, and cardiovascular disease.1, 2, 3 Only a limited number of human studies have examined the influences that the timing of feeding has on features of the cardiometabolic syndrome.4, 5 Similarly, very few animal studies have been performed to address this highly relevant question. Recently, Arble et al.6 reported that limiting high-fat intake to the 12-h light phase (which represents the inactive/sleep phase for rodents) results in significantly greater weight gain in mice compared with animals restricted to high-fat feeding during the 12-h dark phase (the active/awake phase for rodents). Although this observation is important, limiting food availability to the time in which these nocturnal animals are normally sleeping is also associated with disturbed biological rhythms at multiple levels, ranging from behavior (for example sleep) to molecular (for example circadian clocks).7

The purpose of this study was to examine how manipulations in the timing of feeding during the normal waking phase would influence physiologic measures related to the cardiometabolic syndrome. Here, we show that when mice are fed contiguously (either high- or low-fat diets) during their normal waking period, they are able to respond to the caloric density of the food and adjust both food intake and energy expenditure to maintain normal growth and adiposity. In contrast, mice fed a variable diet that includes time-of-day-restricted ‘meals’ of both low- and high-fat food show significant differences in their phenotypic response to the changes in food quality. We report that high-fat feeding at the transition from sleeping to waking seems to be critically important in enabling metabolic flexibility and adaptation to high-carbohydrate meals presented at later time points. Conversely, high-carbohydrate feeding at the beginning of the waking period dramatically impairs the metabolic plasticity required for responding appropriately to high-fat meals presented at the end of the waking period. Calorically, dense high-fat food ingestion at the end of the waking period is associated with excessive body weight gain, adiposity, impaired glucose tolerance, hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia (that is cardiometabolic syndrome), despite no differences in daily total or fat-derived calories. These findings are directly relevant to human beings, in which mixed meals and high-caloric density at the end of the waking period have become the norm.

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Materials and methods

Animals

Male wild-type mice (on the FVB/N background) were housed at the Children's Nutrition Research Facility of the Children's Nutrition Research Center at Baylor College of Medicine (Houston, TX, USA) under temperature-, humidity-, and light-controlled conditions. A strict 12-h light/12-h dark cycle regime was enforced (lights on at 2200 hours; zeitgeber time [ZT] 0). Mice received food and water ad libitum, unless otherwise specified. Mice were housed in standard micro-isolator cages, before initiation of feeding protocols (during which time mice were housed on wire-bottom cages to prevent consumption of bedding and feces). All animal experiments were approved by the Institutional Animal Care and Use Committee of Baylor College of Medicine.

Rodent diets and feeding studies

A high-fat diet (45% calories from fat, Research Diets, New Brunswick, NJ, USA; catalogue number D12451) and a control diet for the high-fat feeding studies (10% calories from fat, Research Diets; catalogue number D12450B) were used for this study. Diets were matched for protein content, and fat and carbohydrate were derived from the same source for each diet. Mice were randomly assigned to one of four different experiments (see Figure 1). The first and second studies included extended (12h) periods of contiguous access to a specific diet. In the first study (Figure 1a), mice were fed either 12h high-fat diet during the light phase (starting at ZT 0), followed by 12h control diet during the dark phase (starting at ZT 12), or 12h of control diet during the light phase, followed by 12h high-fat diet during the dark phase. In the second, third, and forth studies, food access was restricted to the 12h dark period, which represents the normal waking period for these nocturnal animals. In the second study (Figure 1b), mice were fed either a high-fat or a control diet for the entire 12h dark phase. The third and forth studies were designed to simulate ‘meals’ of different compositions presented at distinct times during the awake/active phase. The awake/active phase was divided into three distinct 4h time periods (TPs; which could be considered as periods of breakfast, lunch, and dinner for TP1, TP2, and TP3, respectively). In the third study (Figure 1c), mice were either given 4h of high-fat diet at the beginning of the dark phase (that is sleep/wake transition, TP1), followed by 8h of control diet (TP2 and TP3), or mice were given 8h of control diet at the beginning of the dark phase (that is TP1and TP2), followed by 4h of high-fat diet during the last 4h of the dark phase (that is TP3). In the fourth experiment (Figure 1d), 4h meals at the beginning and end of the waking period were separated by 4h of food restriction. Mice were either given a high-fat ‘meal’ during the first 4h of the dark phase (that is sleep/wake transition, TP1), followed by no food for 4h (that is TP2) and a control ‘meal’ during the last 4h of the waking period (that is TP3), or mice were given a control ‘meal’ on waking (that is first 4h of the dark phase, TP1), followed by no food for 4h (that is TP2) and a high-fat ‘meal’ during the last 4h of the dark phase (that is TP3). All feeding regimes were enforced for 12 weeks.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Feeding regimes used in this study. This diagram illustrates the feeding regimes utilized for Study 1 (a), Study 2 (b), Study 3 (c), and Study 4 (d). Mice were feed either a high fat or control diet in a time-of-day-dependent manner, for a duration of 12 weeks.

Full figure and legend (135K)

Non-invasive mouse monitoring

Food intake was monitored daily during feeding protocols, using self-contained feeders designed to eliminate spillage (Research Products International Corp., Mt. Prospect, IL, USA). Body weight was monitored in mice during feeding protocols at 1-week intervals. Twenty-four-hour patterns of food intake, energy expenditure (indirect calorimetry), and physical activity were measured using a Comprehensive Laboratory Animal Monitoring System (Columbus Instruments Inc., Columbus, OH, USA). Comprehensive Laboratory Animal Monitoring System-derived data are presented at 4-h intervals; data at 30-min intervals are located within Supplementary Figures, with the exception of Figure 6.

Body composition

Body composition was determined in mice using the Lunar PIXImus Densitometer (GE Medical Systems, Madison, WI, USA). Mice were sedated with ketamine/xylaxine (80 and 16mgkg–1, respectively).

Glucose tolerance test

For glucose tolerance tests, 12-h fasting glucose levels were measured in triplicate for each mouse (that is, technical replicates), followed by administration of 10% D-glucose at a dose of 1gkg–1 (i.p.). Plasma glucose was measured 15, 30, 60, and 120min after glucose injection. During the glucose tolerance tests, glucose measurements were performed using a Freestyle Lite glucometer (Abbott Laboratories, Abbott Park, IL, USA). This test was performed at ZT12 (that is the light-to-dark transition), such that the 12-h fast was enforced during the sleep phase.

Humoral factor measurements

Non-fasted (that is fed state) plasma glucose, insulin, triglyceride, and leptin concentrations were measured using commercially available kits (Thermo Scientific, Waltham, MA, USA; Wako Diagnostics, Richmond, VA, USA; Crystal Chem Inc., Downers Grove, IL, USA).

Statistical analysis

All results are expressed as the mean±s.e.m. Statistical analysis was performed using two-way or repeated-measure ANOVA. Stata version IC10.0 (Stata Corp., San Antonio, TX, USA) was used to perform two-way ANOVA to investigate the main effects of diet and time. Repeated-measure ANOVA was used to determine the effects of different diets over a 24-h period. A full model including second-order interactions was conducted for each experiment. Significant differences were determined using type III sums of squares. The null hypothesis of no model effects was rejected at P<0.05. Bonferroni post hoc analyses were performed for pair-wise comparisons.

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Results

Contiguous high-fat feeding throughout the waking phase does not result in cardiometabolic syndrome development

We and others have shown that ad libitum high-fat feeding (that is 45% calories from fat) for 12 weeks results in significantly increased body weight gain and adiposity in wild-type FVB/N mice, along with predicted alterations in whole body energy expenditure and metabolism, as well as decreased glucose tolerance (Supplementary Figures 1 and 2).8, 9, 10 We subsequently investigated whether consumption of the high-fat diet during the light versus the dark phase would influence these parameters, whereas taking care not to overtly disrupt circadian behavior. Mice were randomly assigned to one of two groups, as illustrated in Figure 1a. Mice in the light phase high-fat (LPHF) group were provided the high-fat diet during the light phase, followed by the control diet during the dark phase. Mice in the dark phase high-fat (DPHF) group were provided the control diet during the light phase, followed by the high-fat diet during the dark phase. Food was available ad libitum during both phases. Although daily total caloric intake did not differ between the two groups, DPHF mice consumed more fat-derived calories compared with LPHF mice (Figure 2a). A large proportion of the dietary fat consumed occurred at the initiation of dark phase and light phase for DPHF and LPHF mice, respectively (Figure 2a; Supplementary Figure 3). No significant differences were observed for body weight or body composition between LPHF and DPHF mice after 12 weeks of the feeding regime (Figures 2b and c). In addition, no significant differences were observed for glucose tolerance between mice in these two feeding groups (Figure 2d). Indirect calorimetry exposed higher oxygen consumption and energy expenditure in DPHF mice, compared with LPHF mice (Figure 2e; Supplementary Figure 3). This did not seem to be due to differences in physical activity (Figure 2e; Supplementary Figure 3). These data suggest that, during extended periods of a contiguous diet, animals are able to adequately adjust whole body homeostasis, allowing for excess dietary lipid ingestion.

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Mice were divided into two distinct feeding groups, as depicted in Figure 1a. The effects of these feeding regimes on caloric intake (a), body weight (b), percent body fat (c), glucose tolerance (d), as well as energy expenditure, respiratory quotient, and physical activity (e) were determined. Data are shown as mean +/− s.e.m. for 5–8-independent observations. * denotes P<0.05 main diet effect and $ denotes P<0.05 diet effect at a specific ZT.

Full figure and legend (263K)

To investigate further whether high-fat feeding during the waking phase influences cardiometabolic syndrome parameters, mice were randomly assigned into one of two groups, as shown in Figure 1b. Here, mice were allowed to consume either a control diet or a high-fat diet only during the dark phase (normal waking period); during the light phase (the sleep/inactive phase for the rodent), mice were not allowed access to food (that is period of food withdrawal). Mice fed the high-fat diet consumed more fat-derived calories compared with mice fed the control diet (Figure 3a). Again, the majority of calories were consumed at the beginning of the dark phase (Figure 3a; Supplementary Figure 4). Despite these differences in fat-derived calories, no differences were observed in body weight or glucose tolerance between the two feeding groups (although a slight, but significant increase in body fat composition was observed in the high-fat feeding group; Figures 3b–d). Indirect calorimetry showed no significant differences in oxygen consumption or energy expenditure in high-fat-fed mice versus control mice (Figure 3e; Supplementary Figure 4). No difference in physical activity was observed (Figure 3e; Supplementary Figure 4). However, respiratory exchange ratio (RER) was significantly lower in high-fat-fed mice, consistent with increased fatty-acid oxidation (Figure 3e; Supplementary Figure 4). These data are again consistent with the hypothesis that mice fed a contiguous diet for extended periods during the waking phase are able to compensate and adjust energy expenditure to match the quality and quantity of calories consumed.

Figure 3.
Figure 3 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Mice were divided into two distinct feeding groups, as depicted in Figure 1b. The effects of these feeding regimes on caloric intake (a), body weight (b), percent body fat (c), glucose tolerance (d), as well as energy expenditure, respiratory quotient, and physical activity (e) were determined. Data are shown as mean +/− s.e.m. for 5–25-independent observations. * denotes P<0.05 main diet effect and $ denotes P<0.05 diet effect at a specific ZT.

Full figure and legend (266K)

Dietary composition at the beginning versus the end of the active phase ‘programs’ metabolism

The above-described feeding studies suggest that extended periods of a contiguous diet during the waking phase results in concomitant alterations in whole body energy metabolism, thereby preventing cardiometabolic syndrome development. In both feeding regimes investigated thus far, introduction of the high-fat diet at the beginning of the waking phase resulted in an immediate consumption of the diet at that time. We, therefore, hypothesized that consumption of a high-fat diet at the beginning of the waking phase may have an important function in energy homeostasis. To test this hypothesis, mice were randomly assigned to one of two distinct feeding groups, as depicted in Figure 1c. For both groups, mice were allowed access to food only during the waking (dark) phase, and feeding was divided into three distinct TPs, as described in Materials and methods section. Early high-fat-fed mice consumed more fat-derived calories compared with late high-fat-fed mice (Figure 4a). In contrast, late high-fat-fed mice consumed significantly more total calories, particularly during TP2 and TP3 (Figure 4a; Supplementary Figure 5). Increased caloric intake in late high-fat-fed mice was associated with significantly higher body weights, as well as decreased glucose tolerance, compared with early high-fat-fed mice (Figures 4b and d). Consistent with insulin resistance in late high-fat-fed mice, hyperinsulinemia and hypertriglyceridemia were observed (P<0.05, main diet effect; Figure 4e). Indirect calorimetry studies showed greater energy expenditure in late high-fat-fed mice (Figure 4f; Supplementary Figure 5). Interestingly, RER values remained low in early high-fat-fed mice throughout the dark phase, despite consumption of a control (low-fat) diet for 8h during the active/awake period (Figure 4f; Supplementary Figure 5). Similarly, RER values remained elevated in the late high-fat-fed mice throughout the dark phase, despite consumption of a high-fat diet for the last 4h during this waking period, suggesting that the waking meal programs metabolism for the remainder of the active/waking period.

Figure 4.
Figure 4 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Mice were divided into two distinct feeding groups, as depicted in Figure 1c. The effects of these feeding regimes on caloric intake (a), body weight (b), percent body fat (c), glucose tolerance (d), humoral factors (e), as well as energy expenditure, respiratory quotient, and physical activity (f) were determined. Data are shown as mean +/− s.e.m. for 6–24-independent observations. * denotes P<0.05 main diet effect, $ denotes P<0.05 diet effect at a specific ZT and # denotes P<0.05 time effect within a specific feeding group.

Full figure and legend (348K)

The results described above suggested that the composition of the diet consumed during the beginning versus the end of the dark (active) phase potentially has an important function in dictating metabolism throughout the active period. However, differences in total and fat-derived calories, independent of the time of day, were observed between the feeding groups (Figure 4a). In an attempt to ensure that the only variable between the two feeding groups was the time of day at which dietary fat was consumed (as opposed to total or fat-derived calories), in the absence of enforced paired feeding, two additional feeding groups were next used, as illustrated in Figure 1d. Again, early high-fat-fed mice were allowed access to the high-fat diet during the first 4h of the awake/dark phase (that is TP1) and were provided the control diet during the last 4h of the awake/dark phase (that is TP3), with food access withdrawn during both the middle 4h of the awake/dark phase (that is TP2), as well as during the sleep/light phase. A similar feeding strategy was used for late high-fat-fed mice, with the exception that control diet was provided during TP1 and high-fat diet was provided during TP3. Mice within the two feeding groups consumed identical total and fat-derived calories; the only variable was the time of day at which the dietary fat was consumed (Figure 5a; Supplementary Figure 6). Despite identical daily total caloric consumption, early high-fat-fed mice exhibited significantly lower body weights and body fat composition, as well as increased glucose tolerance, relative to late high-fat-fed mice (Figures 5b–d). Along with insulin resistance and excess adiposity in late high-fat-fed mice, hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia were also observed (P<0.05 main diet effect; Figure 5e). Indirect calorimetry revealed anticipated time-of-day-dependent changes in RER for the early high-fat-fed mice, with low-RER values during TP1, that decrease further during the TP2 4-h fast and that approach a value close to 1 during carbohydrate consumption in TP3 (Figure 5f). Remarkably, metabolic plasticity is completely lost in the late high-fat-fed mice, as RER values remain close to a value of 1 throughout the entire awake/dark phase, despite a period of fasting, followed by high-fat diet consumption (Figure 5f); these diet-induced differences in metabolic plasticity are readily apparent on inspection of the 30-min interval data (Figure 6).

Figure 5.
Figure 5 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Mice were divided into two distinct feeding groups, as depicted in Figure 1d. The effects of these feeding regimes on caloric intake (a), body weight (b), percent body fat (c), glucose tolerance (d), humoral factors (e), as well as energy expenditure, respiratory quotient, and physical activity (f) were determined. Data are shown as mean +/− s.e.m. for 5–25-independent observations. * denotes P<0.05 main diet effect, $ denotes P<0.05 diet effect at a specific ZT, and # denotes P<0.05 time effect within a specific feeding group.

Full figure and legend (347K)

Figure 6.
Figure 6 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Mice were divided into two distinct feeding groups, as depicted in Figure 1d. The effects of these feeding regimes on respiratory quotient were determined at 30-min intervals. Data are shown as mean +/− s.e.m. for five-independent observations. * denotes P<0.05 main diet effect.

Full figure and legend (81K)

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Discussion

The purpose of this study was to determine whether the time of day at which a calorically dense high-fat diet is consumed influences multiple cardiometabolic syndrome parameters in mice. At the same time, care was taken not to overtly disrupt normal biological rhythms (as observed when feeding is restricted to the inactive/sleep phase). We report that mice adequately adapt to high-fat diets when presented in a contiguous manner throughout the active/waking period. However, when fed meals of different caloric quantity and quality at distinct periods during the waking phase, whole body metabolic maladaptation can ensue. For example, consumption of a high-carbohydrate diet during the beginning of the active phase impairs metabolic plasticity. Furthermore, consumption of a calorically dense, high-fat diet at the end of the active phase leads to accelerated weight gain, increased adiposity, glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia (that is the cardiometabolic syndrome). The latter is independent of daily total or fat-derived calories. As such, the time of day at which high-fat diets are consumed profoundly influences multiple cardiometabolic syndrome parameters.

Evidence exists in support of a relationship between time-of-day-dependent food consumption and body weight in human beings. Individuals who do not eat breakfast tend to have an increased BMI, relative to those individuals that do eat breakfast.11 It has been suggested that greater total daily caloric intake in individuals that skip breakfast likely contributes toward increased BMI. Along the same lines, consumption of a carbohydrate-enriched breakfast has been associated with reduced caloric intake later in the day.12, 13 Conversely, night-eating syndrome is associated with a higher BMI.14 Shift workers also have increased BMI, as well as increased risk for diabetes mellitus and cardiovascular disease.2, 3 Despite a clear time of day dependence for these reported observations, total caloric intake is typically considered the primary cause of elevated BMI in human beings.

Recent animal studies suggest that an intrinsic, cell autonomous, molecular mechanism, known as the circadian clock, dramatically influences both appetite and energy expenditure over the course of the day.15, 16 Circadian clocks are defined as a self-sustained, transcriptionally based series of positive and negative feedback loops, with a periodicity of approximately 24h.17 These clocks have been identified within virtually every mammalian cell, including critical organs/centers influencing metabolic homeostasis.18 Genetic disruption of this clock mechanism markedly influences multiple cardiometabolic syndrome parameters. For example, mutation of the transcription factor circadian locomotor output cycles kaput (CLOCK) is associated with disrupted feeding/fasting rhythms (hyperphagia during the inactive/sleep phase), increased weight gain, and hypertriglyceridemia (when mice are on a C57BL/6J background).19 Conversely, genetic loss of the gene encoding for brain and muscle Arnt-like protein-1 (the heterodimerization partner for CLOCK) is associated with leanness.20 Indeed, brain and muscle Arnt-like protein-1 has been reported to have a critical function in adipogenesis.21 More recently, we have shown that cell autonomous clocks directly regulate triglyceride metabolism, promoting increased triglyceride synthesis at the end of the active/awake phase.8

Given that time-of-day-dependent food intake is associated with BMI in human beings and that animal models of disrupted circadian behavior (that is CLOCK mutant and brain and muscle Arnt-like protein-1 null mice) exhibit marked alterations in adiposity, we investigated whether the time of day at which a caloric-dense high-fat diet is consumed influences various cardiometabolic syndrome parameters in mice. Consistent with such a concept, Arble et al.6 recently reported that restricting high-fat diet consumption to the inactive/sleep phase is associated with increased weight gain in mice. However, restricting food intake to this inappropriate time of the day has been shown to desynchronize peripheral clocks from the central, master clock, and to profoundly influence behavioral, physiological, and molecular rhythms.7 In attempts to avoid such a dyssynchony, and instead mimic more closely normal human behavior, the present studies presented diets either throughout the entire 24-h period, or only during the waking period. These feeding regimes (Figure 1) had no overt periodicity effects on biological rhythms, such as physical activity or energy expenditure (Figures 2e, 3e, 4f, and 5f). In addition, given our recent findings that circadian clock-mediated triglyceride synthesis is greatest at the end of the active phase,8 we anticipated that consumption of a high-fat diet at this time would promote adiposity.

This study reports that feeding mice a high-fat diet throughout the waking phase does not significantly influence body weight, adiposity, or glucose tolerance (Figures 2 and 3). This is despite increased daily fat consumption (Figures 2a and 3a). The lack of weight gain seems to be due to a compensatory increase in energy expenditure and/or a balancing of total caloric intake (Figures 2 and 3). In contrast, when mice are fed carbohydrate- or fat-rich meals at distinct windows of time during the active/awake, cardiometabolic syndrome parameters are dramatically influenced. Feeding mice a calorically dense high-fat diet at the end of the active period is associated with increased weight gain, adiposity, glucose intolerance, hyperinsulinemia, hypertriglyceridemia, and hyperleptinemia (Figures 4 and 5). This is independent of daily total or fat-derived calories (Figure 5a). In addition, consumption of a high-carbohydrate meal at the beginning of the active/awake phase results in a profound metabolic inflexibility, again independent of daily total or fat-derived calories (Figures 5f and 6).

The implications of the present research are important for human dietary recommendations. Human beings seldom eat a uniform diet throughout the day, thus requiring the ability to respond to alterations in diet quality. Currently, a typical human diet consists of a high-carbohydrate morning meal, followed by higher fat and/or more calorie-dense meals later in the day. Our studies provide evidence that the capacity to adjust to the dietary composition of a given meal or bout of feeding is an important component in energy balance and that such capacity seems to depend on the meal ingested on waking. Consumption of a high-fat waking meal is associated with increased ability to respond appropriately to carbohydrate meals ingested later in the waking period, whereas a high-carbohydrate morning meal seems to ‘fix’ metabolism toward carbohydrate usage and impairs the ability to adjust metabolism toward fat usage later in the waking period. In addition, consumption of a calorically dense high-fat meal at the end of the active period promotes cardiometabolic syndrome development in mice. The findings of this study suggest that dietary recommendations for weight reduction and/or maintenance should include information about the timing of dietary intake, as well as the quality and quantity of intake.

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Conflict of interest

The authors declare no conflict of interest.

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Acknowledgements

This work was supported by Kraft Foods Inc., the USDA/ARS (6250–51000–046 and 6250–51000–044), and the National Heart, Lung, and Blood Institute (HL-074259). Ju-Yun Tsai was supported by the DeBakey Heart Fund at Baylor College of Medicine.

Supplementary Information accompanies the paper on International Journal of Obesity website

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