Maternal high fat diet induces early cardiac hypertrophy and alters cardiac metabolism in Sprague Dawley rat offspring

https://doi.org/10.1016/j.numecd.2018.02.019Get rights and content

Highlights

  • Increased signalling via the class IIa HDAC:MEF2 axis, which was accompanied by activation of the class IIa HDAC kinase, AMPK.

  • Increased pro-hypertrophic and fatty acid oxidation gene expression downstream of class IIa HDAC:MEF2 axis.

  • Cardiac hypertrophy.

  • Increased cardiac glycolytic rate.

  • Impaired cardiac substrate flexibility.

Abstract

Background and Aim

Maternal high fat diets (mHFD) have been associated with an increased offspring cardiovascular risk. Recently we found that the class IIa HDAC-MEF2 pathway regulates gene programs controlling fatty acid oxidation in striated muscle. This same pathway controls hypertrophic responses in the heart. We hypothesized that mHFD is associated with activation of signal controlling class II a HDAC activity and activation of genes involved in fatty acid oxidation and cardiac hypertrophy in offspring.

Methods and Results

Female Sprague Dawley rats were fed either normal fat diet (12%) or high fat diet (43%) three weeks prior to mating, remaining on diets until study completion. Hearts of postnatal day 1 (PN1) and PN10 pups were collected. Bioenergetics and respiration analyses were performed in neonatal ventricular cardiomyocytes (NVCM). In offspring exposed to mHFD, body weight was increased at PN10 accompanied by increased body fat percentage and blood glucose. Heart weight and heart weight to body weight ratio were increased at PN1 and PN10, and were associated with elevated signalling through the AMPK-class IIa HDAC-MEF2 axis. The expression of the MEF2-regulated hypertrophic markers ANP and BNP were increased as were expression of genes involved in fatty acid oxidation. However this was only accompanied by an increased protein expression of fatty acid oxidation enzymes at PN10. NVCM isolated from these pups exhibited increased glycolysis and an impaired substrate flexibility.

Conclusion

Combined, these results suggest that mHFD induces signalling and transcriptional events indicative of reprogrammed cardiac metabolism and of cardiac hypertrophy in Sprague Dawley rat offspring.

Introduction

Maternal obesity and excessive weight gain during gestation are of increasingly common occurrence, currently affecting ∼30–40% of infants born each year [1]. This adverse maternal environment is associated with an increased cardiovascular disease risk later in life [2], [3], [4], [5], [6], [7], [8]. The underlying mechanisms however remain poorly understood. A number of studies have demonstrated altered cardiovascular structure and function in adult offspring exposed to a mHDF early in life, however, co-morbidities such as hypertension, renovascular disease and aberrant autonomic function in these models has made it difficult to determine whether a primary cardiac phenotype exists, and which signalling pathways may underlie any aetiology [9], [10], [11], [12]. As alterations in cardiac energy metabolism are major contributors to cardiovascular risk we aimed to investigate the impact of a mHFD on signalling and transcriptional responses controlling cardiac energy metabolism and hypertrophy in Sprague Dawley rat offspring. Hypothesising that a mHFD would be associated with activation of signalling controlling class IIa HDAC activity and subsequent downstream activation of genes involved in fatty acid oxidation and cardiac hypertrophy in offspring.

The healthy heart exhibits a high degree metabolic flexibility, adapting its substrate use depending on availability. Typically the adult heart utilizes ∼40% glucose, lactate, ketones and amino acids and ∼60% fatty acids [13]. Impairments in cardiac metabolic flexibility, such as those observed in obesity and type 2 diabetes (T2D) in which the heart has switched to rely predominately on fatty acids, promotes the development of cardiac hypertrophy and dysfunction [13], [14], [15]. Animal studies suggest this is in part due to a subsequent decrease in glucose oxidation, compensatory glycolysis and decreased adenosine triphosphate (ATP) production [13].

We have recently found that the class IIa histone deacetylase – myocyte enhancing factor 2 (HDAC-MEF2) pathway regulates gene programs controlling fatty acid oxidation in striated muscle [16]. This same pathway controls hypertrophic responses in the stressed heart [17]. In a healthy heart class IIa HDACs act to repress transcription of genes involved in hypertrophy and cardiac metabolism through their association with transcription factors in the nucleus such as the myocyte enhancer factor-2 (MEF2). The class IIa HDACs, which include isoforms 4, 5, 7 and 9, are catalytically inactive against acetyl-lysine due to a single amino acid substitution within their active site [18]. They are thought to exert their transcriptional repressive influence through recruitment of a corepressor complex containing HDAC3, which can deacetylate histones and other regulators of gene transcription [19]. The function of this repressive complex is disrupted by phosphorylation of the class IIa HDACs, which results in their nuclear export and the expression of MEF2-depedent genes [20]. Known HDAC kinases include the calcium calmodulin dependent kinase II (CaMKII) [21], 5′ AMP-activated protein kinase (AMPK) [22] and protein kinase D (PKD) [23]. Cardiac CaMKII and PKD have been shown to be activated by neurohormonal signalling and hyperlipidemic conditions [24] and AMPK is activated during times of cardiac metabolic stress to increase energy production, resulting in increased fatty acid oxidation along with increased glucose uptake and glycolysis [25]. Combined, these data from our previous work and past literature support the hypothesis of our current study.

Section snippets

Experimental animals/study design

The study was carried out in accordance with guidelines of the National Health and Medical Research Council (NHMRC) of Australia and was approved by the Deakin University Animal Ethics Committee. Four to ten week old male and female Sprague Dawley rats were obtained from the Animal Resource Centre (Perth, Western Australia). The animals were housed in pairs under constant temperature and humidity control with 12 h light-dark cycles. All males were kept on a normal chow diet three weeks before

Results

Considering the maternal phenotype first, after three weeks on the diet HFD damns consumed a higher average mega joule (MJ) than NFD damns, this remained throughout gestation (Supplementary Fig. 2). However the damns showed no differences in % changes in body weight or changes in blood glucose throughout the study (Supplementary Fig. 2). Comparing male offspring born from NFD and HFD damns, body weight (g) was unchanged at PN1 (6.33 ± 0.16 g vs 6.37 ± 0.28 g) but was higher at PN10

Discussion

While maternal obesity and excessive weight gain during gestation have been associated with increased risk of cardiovascular disease risk later in life, the underlying mechanisms remain unclear. In the current study we have provided insight into early metabolic adaptations that occur in the heart in response to a mHFD in Sprague Dawley rat offspring. The major findings from the study were that mHFD induced early offspring cardiac hypertrophy, elevated cardiac AMPK-class IIa HDAC-MEF2

Funding

JAA: NHRMC and Deakin University (DVC-R). SB: Deakin University Faculty Research Development Grant.

Author contributions

Study concept and design; KADJ, SB, RJWB, JAA and SLM. Performed experiments; KADJ, SB, DLDA and RJWB. Data analysis; KADJ, SB, JKC, GDL and SLM. Wrote the manuscript; KADJ, SB and SLM. Critical analysis of manuscript; KADJ, SB, JKC, GDL, JAA and SLM. All authors approved the final manuscript.

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