Endocrine Abstracts (2011) 26 P186

Estrogen signaling in the hypothalamus regulates glucose metabolism in female rats

J Liu1,3, P Bisschop1, L Eggels1, E Foppen1,2, J N Zhou3, E Fliers1 & A Kalsbeek1,2

1Academic Medical Center (AMC), University of Amsterdam (UvA), Amsterdam, The Netherlands; 2Netherlands Institute of Neuroscience, Amsterdam, The Netherlands; 3University of Science and Technology of China, Hefei, People’s Republic of China.

Background: Previous studies reported that direct injection of estrogen (E2) into different hypothalamic nuclei affects food intake, body weight and locomotor activity. We hypothesized that E2 signaling in the hypothalamus regulates glucose metabolism independently of circulating estrogen levels.

Methods: We investigated the effects of hypothalamic estrogen administration on basal glucose production as well as on hepatic and peripheral insulin sensitivity. We selectively modulated estrogen concentrations in the systemic circulation and in the brain using intrahypothalamic reverse microdialysis, stable isotope dilution and selective hepatic sympathetic or parasympathetic denervation in female rats after ovariectomy (OVX).

Results: OVX caused a 17% decrease in plasma glucose as compared to intact animals. E2 administration either in the hypothalamic paraventricular (PVN) or ventromedial (VMH) nucleus restored plasma glucose to levels seen in intact animals (P<0.01), without affecting plasma E2. Administration of propyl-pyrazole-trisphenol (PPT), a selective agonist of estrogen receptor (ER) α, in the PVN or VMH increased plasma glucose concentrations by 10 and 20% respectively, as compared to the vehicle group. Administration of diarylpropionitrile (DPN), a selective ERβ agonist, in the PVN increased plasma glucose concentrations by 25%, while administration in the VMH did not affect plasma glucose. E2 administration in the VMH, but not in the PVN, resulted in hepatic insulin resistance. E2 administration in both the PVN and VMH resulted in peripheral insulin resistance. Sympathetic hepatic denervation blunted the effect of E2 in the VMH on hepatic insulin sensitivity.

Conclusion: Our findings demonstrate that the modulatory role of estrogen in glucose metabolism is partly mediated via the hypothalamus and sympathetic signaling to the liver. Within the hypothalamus the PVN and VHM have differential roles in E2’s effects on glucose metabolism.

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