Maternal and offspring high-fat diet leads to platelet hyperactivation in male mice offspring

Maternal over-nutrition increases the risk of diabetes and cardiovascular events in offspring. While prominent effects on cardiovascular health are observed, the impact on platelet physiology has not been studied. Here, we examined whether maternal high-fat diet (HF) ingestion affects the platelet function in lean and obese offspring. C57BL6/N mice dams were given a HF or control (C) diet for 8 weeks before and during pregnancy. Male and female offspring received C or HF diets for 26 weeks. Experimental groups were: C/C, dam and offspring fed standard laboratory diet; C/HF dam fed standard laboratory diet and offspring fed HF diet; HF/C and HF/HF. Phenotypic and metabolic tests were performed and blood collected for platelet studies. Compared to C/C, offspring HF groups were obese, with fat accumulation, hyperglycaemia and insulin resistance. Female offspring did not present platelet hyperactivity, hence we focused on male offspring. Platelets from HF/HF mice were larger, hyperactive and presented oxidative stress when compared to C/C. Maternal and offspring HF diet results in platelet hyperactivation in male mouse offspring, suggesting a novel ‘double-hit’ effect

Investigating the transcriptional and histological profile of pericardial adipose tissue

Introduction: The nutritional environment encountered in utero and during adulthood influences the development of adipose tissue (AT). Brown-like cells residing in AT that often promote a beneficial metabolic profile, may become dysfunctional in metabolic disease. Alterations in AT may increase the risk of developing Cardiovascular Disease and Type 2 Diabetes. Aim: There is still a lack of knowledge regarding the role of AT associated with the heart, such as pericardial adipose tissue (PAT), in normal and dysregulated metabolism. This thesis aims to provide an insight into the therapeutic potential and adipogenic, inflammatory and thermogenic capacity of PAT, in mice. Method: The transcriptional and histological profile of PAT, compared to other adipose depots, was assessed in male C57BL/6 mice. Firstly, PAT was harvested from mice fed either a chow or high-fat (HF)-diet, for 7 or 26 weeks. Secondly, PAT was sampled from offspring mice fed a post-weaning diet of either a chow or HF-diet for 26 weeks, from dams fed a chow or HF�diet prior to and during pregnancy and lactation. Finally, PAT was collected from chow and HF-fed mice treated orally with and without Compound 14 (Cpd14) for 10 days and after a 26- day recovery period. Results: Firstly, there were differences in brown and white adipocyte markers of PAT, depending on the nutritional environment encountered. Secondly, both the maternal and offspring diet influenced the thermogenic potential of PAT. Finally, Cpd14 potentially upregulated the thermogenic capacity of PAT to induce weight loss in obese mice. Conclusion: Collectively, PAT in mice has a unique transcriptional and histological profile, altered by dietary exposure in utero and during adulthood, and upon therapeutic stimulation. The underlying mechanisms involved are still unknown, however there is compelling evidence that PAT as a beige depot is an attractive therapeutic target

Leptin-dependent differential remodelling of visceral and pericardial adipose tissue following chronic exercise and psychosocial stress

Obesity is driven by an imbalance between caloric intake and energy expenditure, causing excessive storage of triglycerides in adipose tissue at different sites around the body. Increased visceral adipose tissue (VAT) is associated with diabetes, whilst pericardial adipose tissue (PAT) is associated with cardiac pathology. Adipose tissue can expand either through cellular hypertrophy or hyperplasia, with the former correlating with decreased metabolic health in obesity. The aim of this study was to determine how VAT and PAT remodel in response to obesity, stress, and exercise. Here we have used the male obese Zucker rats, which carries two recessive fa alleles that result in the development of hyperphagia with reduced energy expenditure, resulting in morbid obesity and leptin resistance. At 9 weeks of age, a group of lean (Fa/Fa or Fa/fa) Zucker rats (LZR) and obese (fa/fa) Zucker rats (OZR) were treated with unpredictable chronic mild stress or exercise for 8 weeks. To determine the phenotype for PAT and VAT, tissue cellularity and gene expression were analysed. Finally, leptin signalling was investigated further using cultured 3T3-derived adipocytes. Tissue cellularity was determined following haematoxylin and eosin (H&E) staining, whilst qPCR was used to examine gene expression. PAT adipocytes were significantly smaller than those from VAT and had a more beige-like appearance in both LZR and OZR. In the OZR group, VAT adipocyte cell size increased significantly compared with LZR, whilst PAT showed no difference. Exercise and stress resulted in a significant reduction in VAT cellularity in OZR, whilst PAT showed no change. This suggests that PAT cellularity does not remodel significantly compared with VAT. This data indicates that the extracellular matrix of PAT is able to remodel more readily than in VAT. In the LZR group, exercise increased insulin receptor substrate 1 (IRS1) in PAT but was decreased in the OZR group. In VAT, exercise decreased IRS1 in LZR, whilst increasing it in OZR. This suggests that in obesity, VAT is more responsive to exercise and subsequently becomes less insulin resistant compared with PAT. Stress increased PPAR-γ expression in the VAT but decreased it in the PAT in the OZR group. This suggests that in obesity, stress increases adipogenesis more significantly in the VAT compared with PAT. To understand the role of leptin signalling in adipose tissue remodelling mechanistically, JAK2 autophosphorylation was inhibited using 5μM 1,2,3,4,5,6-Hexabromocyclohexane (Hex) in cultured 3T3-derived adipocytes. Palmitate treatment was used to induce cellular hypertrophy. Hex blocked adipocyte hypertrophy in response to palmitate treatment but not the increase in lipid droplet size. These data suggest that leptin signalling is necessary for adipocyte cell remodelling and its absence induces whitening. Taken together, our data suggest that leptin signalling is necessary for adipocyte remodelling in response to obesity, exercise and psychosocial stress