Influence of dark phase restricted high fat feeding on myocardial adaptation in mice

Abstract

Prolonged high fat feeding is associated with myocardial contractile dysfunction in rodents. However, epidemiological data do not necessarily support the concept that fat-enriched diets adversely affect cardiac function in humans. When fed in an ad libitum manner, laboratory rodents consume chow throughout the day. In contrast, humans typically consume food only during the awake phase. Discrepancies between rodent and human feeding behaviors led us to hypothesize that the time of day at which dietary lipids are consumed significantly influences myocardial adaptation. In order to better mimic feeding behavior in humans, mice were fed (either a control or high fat diet) only during the 12-hour dark phase (i.e., no food was provided during the light phase). We report that compared to dark phase restricted control diet fed mice, mice fed a high fat diet during the dark phase exhibit: 1) essentially normal body weight gain and energy balance; 2) increased fatty acid oxidation at whole body, as well as skeletal and cardiac muscle (in the presence of insulin and/or at high workloads) levels; 3) induction of fatty acid responsive genes, including genes promoting triglyceride turnover in the heart; 4) no evidence of cardiac hypertrophy; and 5) persistence/improvement of myocardial contractile function, as assessed ex vivo. These data are consistent with the hypothesis that ingestion of dietary fat only during the more active/awake period allows adequate metabolic adaptation, thereby preserving myocardial contractile function. This article is part of a Special Issue entitled "Focus on cardiac metabolism".

Figure 1

Effects of ad libitum versus active phase restricted feeding on body weight (A) and body weight gain (B). Mice were randomly divided into one of four feeding groups: 1) ad libitum control diet fed; 2) ad libitum high fat fed; 3) dark phase restricted control diet (DPCD) fed; and 4) dark phase restricted high fat diet (DPHF) fed. Feeding regimes were enforced for 16 weeks (6 to 22 weeks of age) by a computer-controlled, fully automated CLAMS. Values are expressed as mean ± SEM (n=6). * denotes p<0.05 for ad libitum control versus ad libitum high fat diet (group main effect).

Figure 2

Effects of ad libitum versus active phase restricted feeding on caloric intake (A), energy expenditure (B), and RER (C). Mice were randomly divided into one of four feeding groups: 1) ad libitum control diet fed; 2) ad libitum high fat fed; 3) dark phase restricted control diet (DPCD) fed; and 4) dark phase restricted high fat diet (DPHF) fed. Feeding regimes were enforced by a computer-controlled, fully automated CLAMS. Data are shown in 15 minute intervals across a 24-hour period during week 15 (i), and daily averages determined every other week (ii). Values are expressed as mean ± SEM (n=6).

Figure 2

Effects of ad libitum versus active phase restricted feeding on caloric intake (A), energy expenditure (B), and RER (C). Mice were randomly divided into one of four feeding groups: 1) ad libitum control diet fed; 2) ad libitum high fat fed; 3) dark phase restricted control diet (DPCD) fed; and 4) dark phase restricted high fat diet (DPHF) fed. Feeding regimes were enforced by a computer-controlled, fully automated CLAMS. Data are shown in 15 minute intervals across a 24-hour period during week 15 (i), and daily averages determined every other week (ii). Values are expressed as mean ± SEM (n=6).

Figure 2

Effects of ad libitum versus active phase restricted feeding on caloric intake (A), energy expenditure (B), and RER (C). Mice were randomly divided into one of four feeding groups: 1) ad libitum control diet fed; 2) ad libitum high fat fed; 3) dark phase restricted control diet (DPCD) fed; and 4) dark phase restricted high fat diet (DPHF) fed. Feeding regimes were enforced by a computer-controlled, fully automated CLAMS. Data are shown in 15 minute intervals across a 24-hour period during week 15 (i), and daily averages determined every other week (ii). Values are expressed as mean ± SEM (n=6).

Figure 3

Effects of active phase restricted high fat feeding on soleus muscle (A) and heart (B) substrate utilization. Mice were randomly divided into one of two feeding groups: 1) dark phase restricted control diet (DPCD) fed; and 2) dark phase restricted high fat diet (DPHF) fed. Rates of oleate (i) and glucose (ii) oxidation were determined for soleus muscles and hearts isolated 12 and 16 weeks following initiation of the feeding regimes, respectively. Values are expressed as mean ± SEM (n=6-8). * denotes p<0.05 for control versus high fat diet within a given incubation/perfusion condition. HWL, high workload.

Figure 4

Myocardial transcriptional adaptation to active phase restricted high fat feeding. Mice were randomly divided into one of two feeding groups: 1) dark phase restricted control diet (DPCD) fed; and 2) dark phase restricted high fat diet (DPHF) fed. Hearts were isolated 16 weeks following initiation of the feeding regimes. Quantitative RT-PCR was performed to assess expression of fatty acid responsive genes (pdk4, ucp3; A), fatty acid uptake and β-oxidation genes (cd36, mcad; B), and triglyceride synthesis genes (agpat3, dgat2; C). Values are expressed as mean ± SEM (n=6). * denotes p<0.05 for control versus high fat diet within a given time.

Figure 5

Effects of active phase restricted high fat feeding on indices of myocardial contractile function/dysfunction. Mice were randomly divided into one of two feeding groups: 1) dark phase restricted control diet (DPCD) fed; and 2) dark phase restricted high fat diet (DPHF) fed. Hearts were isolated 16 weeks following initiation of the feeding regimes. Triglyceride content and biventricular weight to tibia length ratio (A), quantitative RT-PCR (anf, bnp; B), and contractile function (cardiac power, rate pressure product; C) were assessed. Values are expressed as mean ± SEM (n=6-8). * denotes p<0.05 for control versus high fat diet within a given incubation/perfusion condition. HWL, high workload.