Effects of Steroid Hormones on Insulin Sensitivity and Lipogenesis: An Insight into the Involvement of the Wnt Signaling Pathway

Abstract

The shift in maternal energy metabolism characteristic of pregnancy is thought to be driven by various hormonal changes, especially of ovarian and placental steroids. In this context, the effect of estradiol (E2), progesterone (P4) and testosterone on various aspects of glucose and lipid metabolism in the adipose tissue and skeletal muscle was examined employing an ovariectomized (OVX) rat model. E2 was found to enhance insulin sensitivity in both tissues and inhibit adipose tissue lipogenesis, while P4 increased lipogenic gene expression in OVX rats. Since abnormalities in the Wnt pathway effector TCF7L2 are commonly associated with the occurrence of gestational diabetes mellitus (GDM) in pregnant women, it was hypothesized that the canonical or -catenin-dependant Wnt signaling pathway mediates the metabolic actions of steroids. To test this hypothesis, experiments were carried out with the Wnt inhibitor niclosamide (Nic) in steroid-treated OVX rats. The insulin-sensitizing and anti-lipogenic actions of E2 were found to be mediated by the Wnt pathway, but the effects of P4 on lipogenesis appeared to be independent of it. These findings were further confirmed by studies in pre-adipocytes and adipocytes employing the 3T3-L1 cell line. It was additionally observed that inhibition of Wnt signaling by Nic hastened the adipogenic differentiation process, while E2 inhibited differentiation – an effect that was nullified by Wnt inhibition. Further, the metabolic disturbances accompanying the removal of ovaries by OVX were explored as a model for the menopausal transition in women. Increased body weight gain and food intake were observed in OVX rats in comparison to intact rats. OVX rats also had decreased insulin sensitivity and increased fat accumulation and lipogenesis. The contribution of E2 loss and the subsequent increase in gonadotropin secretion to these changes were examined. The gonadotropin-releasing hormone (GnRH) receptor antagonist cetrorelix (CET) was employed to inhibit the increase in follicle stimulating hormone (FSH) and luteinizing hormone (LH) secretions following OVX. The data suggests that while loss of E2 is the predominant contributor to the deregulation of body weight and food consumption and decreased insulin sensitivity, the gonadotropins appear to play a role in lipogenesis and bone loss following OVX, along with E2. Since abnormal circulating steroid concentrations in various contexts are often linked to metabolic disorders, the findings presented in this study are relevant in understanding the pathophysiology of such conditions and devising methods to manage them.