1524-P: Estradiol's Net, Sweet or Not—Estradiol Actions on Amygdalar Perineuronal Nets Regulate Blood Glucose in Male and Female

Central regulation of blood glucose is getting more and more attention. However, amygdala is not traditionally considered as a regulation center for blood glucose. Here we show that perineuronal nets (PNNs) in posterodorsal medial amygdala (MePD) are required to maintain blood glucose levels and are regulated by estradiol. After gonadectomy (GDX), PNN intensity significantly decreased in both male and female mice in the MePD. Interestingly, 17β-estradiol, but not 5α-dihydrotestosterone, restored PNNs in the MePD and decreased glucose in both GDX male mice and female mice. To investigate the function of PNNs in the MePD, we manipulated PNN levels using the tetracycline-controlled Tet-On gene expression system. In TRE-PH20 mice, stereotaxic injection of AAV-hSynI-rtTAV16 to the MePD decreased PNN intensity in the MePD and caused increases in blood glucose and insulin resistance 3 weeks after the surgery, and increases in body weight gain and fat mass gain 9 weeks after the surgery. These mice showed a decrease in energy expenditure in HFD diet. In TRE-HAS2 mice, stereotaxic injection of AAV-hSynI-rtTAV16 to the MePD increased PNN intensity in the MePD and caused decreases in blood glucose, body weight gain and fat mass gain. PNNs enmesh GABAergic neurons in the MePD and destroying PNNs reduces both excitatory and inhibitor post-synaptic currents in GABAergic neurons. Our findings revealed an important role of estradiol in regulating glucose metabolism in not only female mice but also male mice, and identified PNNs in the MePD as novel participants in the central control of glucose homeostasis by estradiol.