Midlife estradiol treatment reduces the firing rate of liver-related PVN neurons in ovariectomized high-fat diet-fed mice.

Estrogen plays a critical role in the regulation of physiological functions, including metabolism, and its involvement in the regulation of insulin sensitivity and glucose homeostasis has major clinical relevance. Despite the importance of the brain-liver pathway in the regulation of glucose metabolism and that postmenopausal women have an increased risk of developing metabolic disorders, the effect of hormone therapy on hypothalamic neurons involved in the regulation of liver metabolism is not known. Here, we tested the hypothesis that in middle-aged, high-fat diet (HFD)-fed female mice, the excitability of liver-related neurons in the paraventricular nucleus (PVN) of the hypothalamus is increased, whereas estradiol treatment attenuates this increase. Mice fed with phytoestrogen-free control (low-fat diet) or HFD were ovariectomized, received a silastic capsule implant containing either estradiol or vehicle, and stayed on their respective diets. Estradiol treatment resulted in less fat mass and lower body weight. Liver-related neurons were identified with a retrograde, transsynaptic viral tracer, and patch-clamp recordings were conducted from identified neurons in the PVN. Our data show that the excitability of liver-related PVN neurons was increased in ovariectomized HFD mice compared with LFD-fed mice. In estradiol-treated HFD mice, the firing of liver-related PVN neurons was significantly reduced compared with vehicle-treated HFD mice, whereas in LFD mice, estradiol treatment did not alter the activity of liver-related PVN neurons. Our findings suggest that midlife estradiol treatment has beneficial effects on liver-related PVN neurons and thus may contribute to the improved metabolic status observed in estradiol-treated HFD mice.NEW & NOTEWORTHY Menopause increases the risk of metabolic disorders, and despite the importance of the brain-liver pathway in the regulation of glucose homeostasis, the effect of estradiol treatment on liver-related neurons is not known. Our data show that in middle-aged, high-fat diet-fed, ovariectomized female mice, the excitability of liver-related neurons in the paraventricular nucleus is increased, whereas estradiol treatment attenuates this increase. These data suggest that midlife estradiol treatment is beneficial for the brain-liver pathway.