202 AMPK Activation Partially Restores the Anti-Contractile Effect of Perivascular Adipose Tissue in Female Offspring of Obese Rats

Introduction Maternal obesity programmes offspring to develop obesity and associated cardiovascular disease. Perivascular adipose tissue (PVAT) exerts an anti-contractile effect in healthy blood vessels; an effect lost in male offspring of obese dams. However, the mechanism by which maternal obesity programmes PVAT dysfunction in offspring remains unknown. Methods Six week old female Sprague-Dawley rats were fed a control (10% fat) or 45% fat obesogenic diet (HFD) for 12 weeks before mating; during pregnancy and lactation. At weaning, female offspring were provided with the control diet until sacrifice at either 12 (12 wo) or 24 (24 wo) weeks of age. PVAT-denuded mesenteric arteries from pups, with or without exogenous PVAT, were mounted on a wire myograph and concentration-response curves were constructed to thromboxane A 2 receptor agonist U46619 (10 nM-3 µM) ± 10 µM A769662, an activator of AMP-activated protein kinase (AMPK) ± glucosamine (an O-GlcNAcylator). Western blotting was used to asses protein expression in PVAT stimulated with or without glucosamine. Results Body weight, insulin levels and blood pressure were increased in HFD dams and their 12wo and 24 wo offspring compared to age-matched controls. Without PVAT, vessel contractions to U46619 were reduced in 12 wo offspring of HFD dams, effects mimicked in control arteries by pre-incubation with 10 mM glucosamine. PVAT from control, but not from HFD offspring, exerted an anti-contractile effect on the corresponding PVAT-denuded arteries at both ages. Pre-incubation of control PVAT with glucosamine diminished the anti-contractile effect at both ages. PVAT from HFD offspring pre-incubated with glucosamine had no effect on PVAT-denuded vessels but simultaneous AMPK activation within PVAT partially restored anti-contractile capability at both ages. Protein O-GlcNAcylation expression was increased in HFD PVAT and control PVAT incubated with glucosamine, whereas AMPK expression was decreased. Conclusions The enhanced protein O-GlcNAcylation and decreased AMPK expression in HFD PVAT may underlie the reduced anti-contractile effect of PVAT in female offspring of obese dams. Nevertheless, simultaneous AMPK activation within HFD PVAT partially restored the anti-contractile effects of PVAT.