# Impact of estradiol on the central regulation of glucose homeostasis and subsequent implications for hippocampal function.

> **NIH NIH P01** · TULANE UNIVERSITY OF LOUISIANA · 2024 · $541,486

## Abstract

Project 4 Summary
Midlife obesity and diabetes mellitus (DM) are risk factors for all dementias including Alzheimer’s disease (AD),
vascular cognitive impairment, and vascular dementia. Loss of estrogens due to menopause results in decreased
energy expenditure and impaired glucose homeostasis, leading to increased prevalence of Type 2 DM.
Hypothalamic estrogen receptor signaling plays a role in the central regulation of energy homeostasis via
modulation of both liver glucose production and tissue glucose uptake. Systemic glucose homeostasis is largely
regulated by central autonomic circuits, and the risk of developing Type 2 DM is high if autonomic dysfunction is
present. Autonomic dysfunction, including suppression of parasympathetic tone accompanied by sympathetic
predominance and disruption of hypothalamic circuits involved in autonomic control of metabolism, has been
observed in patients with several forms of cognitive impairment including AD. It is therefore crucial to determine
cellular mechanisms that impair autonomic regulation of the liver and glucose homeostasis, and thus contribute
to cognitive dysfunction. In addition, while obesity, insulin resistance and DM are known to impair hippocampal
synaptic plasticity and cognitive function, there is a lack of comprehensive studies investigating the effects of
midlife estradiol treatment on hypothalamic neurons involved in the central regulation of glucose homeostasis
and on hippocampal function in the context of obesity. Our preliminary observations have revealed that estradiol
treatment improves glucose levels in ovariectomized (OVX) animals. In addition, liver-related neurons in the
paraventricular nucleus (PVN) of high-fat diet (HFD) treated mice are more active and HFD interferes with insulin-
dependent suppression of excitatory neurotransmission in pre-sympathetic PVN neurons. Furthermore, estradiol
enhances long-term potentiation (LTP) in hippocampal neurons of middle-aged OVX animals. These findings led
to the central hypothesis that midlife estradiol treatment in OVX mice provides beneficial effects required to
maintain proper function of the brain-liver pathway, hippocampal LTP, a cellular correlate for learning and
memory, and hippocampus-dependent cognitive function, but these beneficial effects are attenuated in mice on
HFD due to insulin resistance. The proposed studies will determine the effect of midlife estradiol treatment on 1)
the cellular properties of preautonomic PVN neurons, 2) synaptic plasticity and cellular properties in the
hippocampus, and 3) glucose homeostasis and cognition in control and HFD mice. These studies may lead to
new strategies to improve glucose homeostasis during cognitive impairment as well as to a better understanding
of the effect of midlife estradiol treatment on hypothalamic and hippocampal function.

## Key facts

- **NIH application ID:** 10772120
- **Project number:** 5P01AG071746-03
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Andrea Zsombok
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $541,486
- **Award type:** 5
- **Project period:** 2022-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772120

## Citation

> US National Institutes of Health, RePORTER application 10772120, Impact of estradiol on the central regulation of glucose homeostasis and subsequent implications for hippocampal function. (5P01AG071746-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10772120. Licensed CC0.

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