Vascular dysfunction and impaired insulin signaling in high-fat diet fed ovariectomized mice

Abstract The metabolic syndrome, characterized by conditions such as obesity and insulin resistance, is more prevalent in postmenopausal women than in premenopausal women, and increases the risk of cardiovascular disease and type 2 diabetes. The main objective of the present study was to investigate the combined effects of ovariectomy (OVX) and high-fat diet (HFD) on metabolic parameters, vascular function and glucose homeostasis in mice. After OVX or sham operation (Sham), mice were fed with either a normal diet (ND) or a HFD. Mice were divided into ND + Sham, ND + OVX, HFD + Sham, and HFD + OVX groups. After 4 weeks, HFD + OVX mice developed marked increases in body weight and plasma insulin levels, but not blood glucose levels. The area under the glucose tolerance curve (Δ AUC glucose ) following an oral glucose tolerance test and the homeostasis model assessment of insulin resistance (HOMA-IR) revealed that HFD + OVX mice had higher values than any other group. Concomitantly with these metabolic disturbances, decreased tail skin blood flow and augmented tail skin flushing, a marker of hot flashes, were observed in HFD + OVX mice. These vascular modulations likely result from vasomotor dysfunction. Furthermore, we investigated whether OVX and HFD affect the insulin signaling pathway in mice. Insulin-induced Akt phosphorylation in the livers of HFD + OVX mice was significantly downregulated compared with ND + Sham and HFD + Sham mice. Thus, the HFD + OVX mice used in the present study constitute an experimental animal model of postmenopausal metabolic syndrome. Herein, we provide experimental evidence that vascular dysfunction and impaired insulin signaling may contribute to the pathogenesis of postmenopausal metabolic syndrome.