Robust effect of metabolic syndrome on major metabolic pathways in the myocardium

Abstract

Although the high-fat-diet-induced metabolic syndrome (MetS) is a precursor of human cardiac pathology, the myocardial metabolic state in MetS is far from clear. The discrepancies in metabolite handling between human and small animal models and the difficulties inherent in obtaining human tissue complicate the identification of the myocardium-specific metabolic response in patients. Here we use the large animal model of swine that develops the hallmark criteria of human MetS. Our comparative metabolomics together with transcriptomics and computational nonnegative matrix factorization (NMF) interpretation of the data exposes significant decline in metabolites related to the fatty acid oxidation, glycolysis, and pentose phosphate pathway. Behind the reversal lies decreased expression of enzymes that operate in the pathways. We showed that diminished glycogen deposition is a metabolic signature of MetS in the pig myocardium. The depletion of glycogen arises from disbalance in expression of genes that break down and synthesize glycogen. We show robust acetoacetate accumulation and activated expression of key enzymes in ketone body formation, catabolism and transporters, suggesting a shift in fuel utilization in MetS. A contrasting enrichment in O-GlcNAcylated proteins uncovers hexosamine pathway and O-GlcNAcase (OGA) expression involvement in the myocardial response to MetS. Although the hexosamine biosynthetic pathway (HBP) activity and the availability of the UDP-GlcNAc substrate in the MetS myocardium is low, the level of O-GlcNacylated proteins is high as the O-GlcNacase is significantly diminished. Our data support the perception of transcriptionally driven myocardial alterations in expression of standard fatty acids, glucose metabolism, glycogen, and ketone body related enzymes and subsequent paucity of their metabolite products in MetS. This aberrant energy metabolism in the MetS myocardium provide insight into the pathogenesis of CVD in MetS.

The cardiac molecular setting of metabolic syndrome in pigs reveals disease susceptibility and suggests mechanisms that exacerbate COVID-19 outcomes in patients

“…As we previously reported 7 , in response to twelve weeks long high-fat-high-calorie diet, five months old intact male Yorkshire pigs in our model develop key components of metabolic syndrome: increased weight gain (55 ± 2.5 kg vs 23 ± 2.7 kg), systolic (159 ± 4 mmHg vs 119 ± 3 mmHg) and diastolic (110 ± 5 mmHg vs 69 ± 12 mmHg) blood pressure, fasting plasma glucose (161 ± 15 mg/dL vs 94 ± 12 mg/dL, p < 0.02), triglycerides (1.68 ± 0.5 mmol/L vs 0.65 ± 0.24 mmol/L, p < 0.03), plasma LDL (2.69 ± 0.26 vs 0.47 ± 0.14, p < 0.01), and total cholesterol (5.7 ± 0.6 mmol/L vs 1.09 ± 0.3 mmol/L, p < 0.009I) vs regular normoglycemic diet.…”

“…Pigs have similar cardiac size, heart rate, blood pressure, and coronary anatomy to humans, and the temporal and spatial development of myocardial infarction resembles that of patients 6 . When compared to lean diet control pigs (LD), Yorkshire and Ossabaw pig fed an obesogenic high-fat-high-calory diet quickly develop the hallmark components of MetS, including: hyperglycemia, significant increases in triglycerides, plasma LDL, total cholesterol, significant weight gain, and increased systolic and diastolic blood pressure 7 , 8 . It has been proposed that porcine respiratory coronavirus (PRCV) infection in obese pigs be considered as highly relevant animal model for severe COVID-19 9 .…”

“…In this study, Yorkshire pigs were used as a model for high-fat-high callory diet induced MetS, along with LD control pigs 7 , 8 . Pig myocardium was harvested to generate gene expression profile using whole transcriptome shotgun sequencing (RNA-seq), as well as coupled proteomic and 297 polar metabolites profile using liquid chromatography–tandem mass spectrometry (LC/MS–MS).…”

Nutrition, Bioenergetics, and Metabolic Syndrome

“…The acetyl-CoA resulting from this process can enter the KC and get oxidized, coupled to the production of reducing power [29]. Furthermore, alterations in these metabolic routes have also been widely described in cell and animal models, as well as in patients suffering the most prevalent NCDs such as heart failure, T2D [30], or MetS [31,32]. Mitochondrial dysfunction is characterized by the combination of some of the processes described above and plays a central role in several diseases, such as metabolic syndrome.…”

Effects of Bergamot Polyphenols on Mitochondrial Dysfunction and Sarcoplasmic Reticulum Stress in Diabetic Cardiomyopathy

“…In particular, numerous experimental in vitro and in vivo studies highlighted how a high-fat diet is responsible for heart failure, myocardial hypertrophy, and myocardial lipid accumulation [ 138 ]. A high-fat diet during gestation in several species causes deleterious effects in newborns; in particular, altered gene expression, abnormalities in the functions of antioxidant enzymes, the increased possibility of developing atherogenesis, and damage to the cardiovascular system [ 139 ]. The reduction of fatty acids intake generally has several benefits, such as a reduction in body weight, and cholesterol and triglyceride levels, and an improvement in the functioning of the myocardium [ 140 , 141 ].…”