Maternal high fat diet induces early cardiac hypertrophy and alters cardiac metabolism 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.
References (43)
- et al.
Obesity in pregnancy: prevalence and metabolic consequences
Semin Fetal Neonatal Med
(2010) - et al.
Maternal obesity and congenital heart defects: a population-based study
Am J Clin Nutr
(2010) - et al.
Altered myocardial substrate metabolism and decreased diastolic function in nonischemic human diabetic cardiomyopathy: studies with cardiac positron emission tomography and magnetic resonance imaging
J Am Coll Cardiol
(2009) - et al.
Disruption of the class IIa HDAC corepressor complex increases energy expenditure and lipid oxidation
Cell Rep
(2016) - et al.
Enzymatic activity associated with class II HDACs is dependent on a multiprotein complex containing HDAC3 and SMRT/N-CoR
Mol Cell
(2002) - et al.
Mitochondrial dysfunction has divergent, cell type-dependent effects on insulin action
Molecular Metabolism
(2014) - et al.
Cardiac fatty acid oxidation in heart failure associated with obesity and diabetes
Biochim Biophys Acta
(2016) - et al.
Activation of AMP-activated protein kinase inhibits protein synthesis associated with hypertrophy in the cardiac myocyte
J Biol Chem
(2004) - et al.
Maternal obesity during pregnancy and premature mortality from cardiovascular event in adult offspring: follow-up of 1 323 275 person years
BMJ Br Med J
(2013) - et al.
Risk of childhood overweight or obesity associated with excessive weight gain during pregnancy: a meta-analysis
Arch Gynecol Obstet
(2014)
Childhood cardiometabolic outcomes of maternal obesity during pregnancy: the Generation R Study
Hypertension
Maternal weight gain in different periods of pregnancy and childhood cardio-metabolic outcomes. The Generation R Study
Int J Obes (2005)
A prospective study of maternal prenatal weight and offspring cardiometabolic health in midchildhood
Ann Epidemiol
Gestational weight gain in normal weight women and offspring cardio-metabolic risk factors at 20 years of age
Int J Obes (2005)
Developmental programming of aortic and renal structure in offspring of rats fed fat-rich diets in pregnancy
J Physiol
Understanding the role of maternal diet on kidney development; an opportunity to improve cardiovascular and renal health for future generations
Nutrients
Maternal high-fat diet programs rat offspring hypertension and activates the adipose renin-angiotensin system
Am J Obstet Gynecol
Maternal salt and fat intake causes hypertension and sustained endothelial dysfunction in fetal, weanling and adult male resistance vessels
Sci Rep
Complex energy metabolic changes in heart failure with preserved ejection fraction and heart failure with reduced ejection fraction
Can J Cardiol
Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women
Circulation
Signal-dependent activation of the MEF2 transcription factor by dissociation from histone deacetylases
Proc Natl Acad Sci USA
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