Maternal High-fat Diet During Pregnancy Programs Platelet Hyperactivation in Male Mouse Offspring

Abstract

Background: Maternal over-nutrition increases the risk of diabetes and cardiovascular events in offspring. While prominent effects on cardiovascular health are observed, the impact of this on platelet physiology has not been studied. Here, we sought to determine whether maternal high-fat diet (HF) ingestion can affect the platelet function in offspring.Methods: C57BL6/N mice dams were given a HF or control (C) diet for 8 weeks prior to and during pregnancy. Male offspring also received either C or HF diets for 26 weeks. Experimental groups were: C/C, dam and offspring fed chow; C/HF dam fed chow and offspring fed high-fat diet; HF/C and HF/HF. Various phenotypic (including body weight and % of body fat) and metabolic (glycaemia, triglyceridemia) tests were performed and blood collected for platelet studies. Results: Compared to C/C, HF/HF animals were obese, with fat accumulation, hyperglycaemia, insulin resistance and low respiratory exchange rate. HF/HF, but not C/HF mice also showed hypertriglyceredaemia and higher mean platelet volume. These platelets were hyperreactive, displaying higher fibrinogen binding after stimulation with different agonists. They also showed increased platelet adhesion and spreading on collagen. Maternal obesity led to an overall effect of increased platelet reactivity in offspring. Both maternal and offspring HF groups presented decreased levels of collagen receptor GPVI with increased oxidative stress. Western blotting experiments in stimulated platelets showed increased phosphorylation of PKC substrates, total tyrosine and AKT at Ser473, whilst response to nitric oxide donor PAPA-NONOate was unchanged compared to C/C.Conclusions: Maternal HF diet ingestion programmes platelet hyperactivation in male mouse offspring, whilst HF in both dams and offspring resulted in a 'double-hit' effect of increased serum triglyceride levels, large platelets and increased reactivity. This involved enhanced Tyr phosphorylation, ROS production and decreased GPVI expression. Since platelet function can be programmed by early developmental periods, it is possible to use this window of intervention to reduce the risk of thrombotic events.