Nikayla Patel

Background: The placenta stands at the maternal–fetal interface and is a key organ regulating the intrauterine environment. In pregnancies exposed to obesity, placental function, signaling, and nutrient handling are adversely altered. Pre-conception weight loss is a potential intervention to alter an obesogenic milieu of pregnancy, which we investigated in a mouse model of maternal obesity using diet or administration of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide. Methods: Pre-pregnancy weight loss in C57BL/6 high-fat diet (HFD)-fed dams was induced in the pre-pregnancy period by switching diet from HFD to chow diet or administering liraglutide (0.3 mg/kg/day subcutaneously for 4 weeks) whilst continuing HFD. In addition, a group of HFD-fed dams were switched to chow diet post-conception. The metabolomic profile and gene expression within the placenta was compared at day 18–20 of gestation. Results: ¹H NMR spectroscopy metabolomic analysis of placenta of HFD mice showed an altered amino acid metabolomic profile, with lower aspartate, glutamate, and glutamine levels compared to the placenta of chow-fed mice (p < 0.05). Meanwhile, gene expression analysis identified both oxidative stress and inflammation in the placentas of HFD-fed dams. Whilst dietary modification alone was sufficient to reduce markers of oxidative stress and inflammation, liraglutide treatment modulated pathological changes, including placental metabolic stress but not inflammation. Conclusions: These findings highlight the importance of dietary or pharmacological interventions in the pre- or immediate post-conception period, with pre-conception offering a critical window to reduce aberrant placental changes induced by obesity.

The naked mole-rat Heterocephalus glaber is a eusocial mammal exhibiting extreme longevity (37-year lifespan), extraordinary resistance to hypoxia and absence of cardiovascular disease. To identify the mechanisms behind these exceptional traits, metabolomics and RNAseq of cardiac tissue from naked mole-rats was compared to other African mole-rat genera (Cape, Cape dune, Common, Natal, Mahali, Highveld and Damaraland mole-rats) and evolutionarily divergent mammals (Hottentot golden mole and C57/BL6 mouse). We identify metabolic and genetic adaptations unique to naked mole-rats including elevated glycogen, thus enabling glycolytic ATP generation during cardiac ischemia. Elevated normoxic expression of HIF-1α is observed while downstream hypoxia responsive-genes are down-regulated, suggesting adaptation to low oxygen environments. Naked mole-rat hearts show reduced succinate levels during ischemia compared to C57/BL6 mouse and negligible tissue damage following ischemia-reperfusion injury. These evolutionary traits reflect adaptation to a unique hypoxic and eusocial lifestyle that collectively may contribute to their longevity and health span.

Chronic kidney disease (CKD) affects millions of people globally and, for most patients, the risk of developing cardiovascular disease is higher than that of progression to kidney failure. Moreover, mortality owing to cardiovascular complications in patients with CKD is markedly higher than in matched individuals from the general population. This mortality was traditionally thought to be driven by coronary heart disease but >75% of patients with CKD have left ventricular hypertrophy, which contributes to mortality, particularly sudden cardiac death. The aetiology of cardiac complications in CKD is multifactorial. In addition to haemodynamic overload, uraemic toxin accumulation and altered ion homeostasis, which are known to underlie left ventricular hypertrophy in CKD and drive cardiac dysfunction, we examine the role of myocardial metabolic remodelling in CKD. Uraemic cardiomyopathy is characterized by myriad cardiac metabolic maladaptations, including altered mitochondrial function, changes in myocardial substrate utilization, altered metabolic transporter function and expression, and impaired insulin response and phosphoinositide-3 kinase–AKT signalling, which collectively lead to impaired cardiac energetics. Interestingly, none of the standard treatments used to treat CKD target the metabolism of the uraemic heart directly. An improved understanding of the cardiac metabolic perturbations that occur in CKD might allow the development of novel treatments for uraemic cardiomyopathy.