Midlife Estradiol Treatment Decreases the Activity of Liver-Related PVN Neurons in Ovariectomized Obese Mice

Estrogen plays a critical role in the regulation of a variety of physiological functions, including metabolism, and its involvement in the regulation of insulin sensitivity and glucose homeostasis has major clinical relevance. Consequently, postmenopausal women have an increased risk of developing metabolic disorders. In our previous study, we found that treatment with 17-β estradiol (E2) prevented the development of metabolic impairment observed in ovariectomized mice kept on low fat diet (LFD) and it improved the metabolism of mice kept on high-fat diet (HFD) by decreasing fat mass and improving glucose homeostasis. In obese and diabetic conditions, increased activity of the sympathetic nervous system is known to play a significant role in the development and/or progression of diseases associated with impaired glucose homeostasis. Here, we tested the hypothesis that systemic E2 treatment decreases firing activity of liver-related neurons in the paraventricular nucleus of the hypothalamus (PVN) in HFD fed mice. Approximately nine-month-old, female C57BL/6J mice were fed with a phytoestrogen free high-fat diet (HFD, BioServ #F3282) or a control diet (LFD, BioServ #F4031) for 10 to 14 weeks before ovariectomy (OVX). Following OVX, mice received a silastic tube implant containing either E2 or vehicle (VEH, cholesterol) and stayed on their respective diets for an additional 8-10 weeks. Liver-related PVN neurons were identified with a retrograde, transsynaptic viral tracer and patch-clamp recordings were conducted to determine the activity of neurons in VEH and E2 treated mice kept on LFD and HFD. Data were analyzed with two-way ANOVAs followed by uncorrected Fisher’s LSD pairwise comparisons. In HFD-VEH mice the activity of liver-related PVN neurons was increased compared to LFD-VEH mice (3.83±1.10 Hz, n=7 vs. 0.87±0.31 Hz, n=17; p=<0.0001). Intriguingly, in HFD-E2 mice the action potential frequency was significantly lower compared to HFD-VEH mice (1.29±0.36 Hz, n=8 vs 3.83±1.10 Hz, n=7; p=0.0021). In addition, in HFD-E2 mice the amplitude of excitatory postsynaptic currents was larger compared to LFD-E2 mice (16.44±1.75 pA, n=14 vs. 13.29±0.80 pA, n=30; p=0.0352), whereas there was no difference between the VEH treated groups. Our electrophysiological data demonstrated that pre-existing obesity leads to overactivity of liver-related PVN neurons in middle aged ovariectomized mice and chronic, systemic E2 treatment decreases the firing activity. Our findings suggest that midlife E2 treatment has beneficial effects on the activity of liver-related PVN neurons that may contribute to the improved metabolic status observed in estradiol treated obese mice. Source of funding: P01AG071746 (Project 4 – Zsombok) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.