Insulin evokes release of endozepines from astrocytes of the NTS to modulate glucose metabolism in male rats

The central nervous system (CNS) plays a key role in regulating metabolic functions, but conditions like obesity and diabetes can disrupt this balance. Within the CNS, the nucleus of the solitary tract (NTS) in the dorsal vagal complex (DVC) senses insulin and regulates feeding behaviour and hepatic glucose production. However, we still know little about which cells in the NTS are sensitive to insulin. We show that in male rats insulin receptors in astrocytes are crucial for the NTS's ability to regulate glucose production in the liver. We demonstrate that insulin evokes the release of endozepines from primary astrocytes and direct infusion of endozepines into the NTS mimics the effects of insulin. Inhibition of the benzodiazepine binding site of GABA_A receptors prevents action of both insulin and endozepines. The effect of endozepines within the NTS is mimicked by GABA_A antagonists and prevented by an agonist, suggesting that insulin prompts astrocytes to release endozepines, which then attenuate GABA_A receptor activity, ultimately reducing glucose production in the liver. We also show that high-fat-diet-induced insulin resistance in the NTS can be circumvented by endozepine administration. Our study is the first to show that insulin-dependent release of endozepines from NTS-astrocytes is fundamental to control blood glucose levels.