Dataset Information

Multi-omics of a pre-clinical model of diabetic cardiomyopathy reveals increased fatty acid supply impacts mitochondrial metabolic selectivity

ABSTRACT: The incidence of type 2 diabetes (T2D) is increasing globally, with long-term implications for human health and longevity. Heart disease is the leading cause of death in T2D patients, who display an elevated risk of an acute cardiovascular event and worse outcomes following such an insult. The underlying mechanisms that predispose the diabetic heart to this poor prognosis remain to be defined. This study developed a pre-clinical model (Rattus norvegicus) that complemented caloric excess from a high-fat diet (HFD) and pancreatic β-cell dysfunction from streptozotocin (STZ) to produce hyperglycaemia, peripheral insulin resistance, hyperlipidaemia and elevated fat mass to mimic the clinical features of T2D. Ex vivo cardiac function was assessed using Langendorff perfusion with systolic and diastolic contractile depression observed in T2D hearts. Cohorts representing untreated, individual HFD- or STZ-treatments and the combined HFD+STZ approach were used to generate ventricular samples (n=9 per cohort) for sequential and integrated analysis of the proteome, lipidome and metabolome by liquid chromatography-tandem mass spectrometry. This study found that in T2D hearts, HFD treatment primed the metabolome, while STZ treatment was the major driver for changes in the proteome. Both treatments equally impacted the lipidome. Our data suggest that increases in β-oxidation and early TCA cycle intermediates promoted rerouting via 2-oxaloacetate to glutamate, γ aminobutyric acid and glutathione. Furthermore, we suggest that the T2D heart activates networks to redistribute excess acetyl-CoA towards ketogenesis and incomplete β-oxidation through the formation of short-chain acylcarnitine species. Multi-omics provided a global and comprehensive molecular view of the diabetic heart, which distributes substrates and products from excess β-oxidation, reduces metabolic flexibility and impairs capacity to restore high energy reservoirs needed to respond to and prevent subsequent acute cardiovascular events.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Heart

DISEASE(S): Type 2 Diabetes Mellitus

SUBMITTER: Melanie White

LAB HEAD: Melanie White

PROVIDER: PXD029587 | Pride | 2022-11-01

REPOSITORIES: Pride

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			Action	DRS
	20210702_QEHFX3_MYW_5BLv1_8Plex_Proteome_HILICFr1.raw	Raw
	20210702_QEHFX3_MYW_5BLv1_8Plex_Proteome_HILICFr2.raw	Raw
	20210702_QEHFX3_MYW_5BLv1_8Plex_Proteome_HILICFr3.raw	Raw
	20210702_QEHFX3_MYW_5BLv1_8Plex_Proteome_HILICFr4.raw	Raw
	20210702_QEHFX3_MYW_5BLv1_8Plex_Proteome_HILICFr5.raw	Raw

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Multi-omics of a pre-clinical model of diabetic cardiomyopathy reveals increased fatty acid supply impacts mitochondrial metabolic selectivity.

Li Desmond K DK Smith Lauren E LE Rookyard Alexander W AW Lingam Shivanjali J SJ Koay Yen C YC McEwen Holly P HP Twigg Stephen M SM Don Anthony S AS O'Sullivan John F JF Cordwell Stuart J SJ White Melanie Y MY

Journal of molecular and cellular cardiology 20211124

The incidence of type 2 diabetes (T2D) is increasing globally, with long-term implications for human health and longevity. Heart disease is the leading cause of death in T2D patients, who display an elevated risk of an acute cardiovascular event and worse outcomes following such an insult. The underlying mechanisms that predispose the diabetic heart to this poor prognosis remain to be defined. This study developed a pre-clinical model (Rattus norvegicus) that complemented caloric excess from a h ...[more]

PMID: 34826416

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Project description:The global prevalence of type 2 diabetes (T2D) is increasing, and it is contributing to the susceptibility to diabetes and its related epidemic in offspring. Although the impacts of paternal T2D on metabolism of offspring have been well established, the exact molecular and mechanistic basis that mediates these impacts remains largely unclear. Here we show that paternal T2D increases the susceptibility to diabetes in offspring through the gametic epigenetic alterations. Paternal T2D led to glucose intolerance and insulin resistance in offspring. Relative to controls, offspring of T2D fathers exhibited altered gene expression patterns in the pancreatic islets, with downregulation of several genes involved in glucose metabolism and insulin signaling pathway. Epigenomic profiling of offspring pancreatic islets revealed numerous changes in cytosine methylation depending on paternal T2D, including reproducible changes in methylation over several insulin signaling genes. Paternal T2D altered overall methylome patterns in sperm, with a large portion of differentially methylated genes overlapped with that of pancreatic islets in offspring. Our study revealed, for the first time, that T2D can be inherited transgenerationally through the mammalian germline by an epigenetic manner. For all comparisons shown, male F0 founders were weaned from mothers at 3 weeks of age, and sibling males were put into cages with high-fat diet (33% energy as fat) or control diet until 12 weeks of age, at which point mice fed with HFD were injected intraperitoneally with a low dose of STZ and kept on the same diet for 4 weeks. Fasting blood glucose was examined each week post-STZ for 4 weeks, and only glucose level at 7~11 mM was considered as type 2 diabetes. Females were always raised on standard diet. At 16 weeks, male F0 founders were mated with females. After 1 or 2 days, males were removed, and pregnant females were left alone until their litters were 3 weeks of age. Note that we always used virgin females to avoid confounding effects brought about by the females. At 3 weeks of age a portion of the offspring were sacrificed and islets were generated, each from an independent father.Samples from six control and six paternal type 2 diabetes offspring were chosen for microarray analysis.