Estrogen Regulates the Trafficking of Leptin Receptors

Abstract

During menopause, when endogenous estrogen levels are depleted, a rise in hypertension is observed in 75% of post-menopausal women, suggesting there is a cardioprotective effect from estrogen. In previous studies, estrogen has been shown to effect hypothalamic paraventricular nuclei by its action to lessen the impact of a glutamate induced increase in blood pressure. These data, along with others, suggest that the cardioprotective effect of estrogen is regionally specific in the central nervous system. However, the mechanism(s) behind estrogen's attenuating effect on blood pressure have not been fully elucidated. We propose that estrogen regulates blood pressure in part, by inhibiting the actions of leptin. Leptin is an adipocyte-derived peptide hormone. Activation of its signaling pathway within the central nervous system can alter blood pressure. Studies with injections of leptin in rodent's dorsomedial hypothalamus showed an increase in blood pressure, while antagonism of leptin receptors correlated with diminished blood pressure. Both results suggest that adjustment of leptin signaling in the dorsomedial hypothalamus is sufficient to alter blood pressure. In this study, we hypothesize that estrogen can block leptin receptor activation and downstream signaling events by increasing the expression of SOCS3 (suppressor of cytokine signaling 3), a negative modulator of leptin signaling. We tested our hypothesis by utilizing an in vitro system (i.e. GT1-7 mouse hypothalamic neuronal cells) and an in vivo system (i.e. female C57B6 mice) that were treated with estradiol (100nM). Our data demonstrated that administering estrogen decreased the expression of leptin receptors in the hypothalamus and we proposed this occurred due to the increase in SOCS3 expression we observed when estradiol was administered. Taken together, these data suggest that estrogen can attenuate leptin's physiological response on blood pressure by increasing an inhibitor (i.e. SOCS3) of leptin's signaling.