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

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) controls glucose metabolism and feeding behaviour. In rodents, the NTS senses insulin and communicates with the liver to regulate glucose production. Even short-term exposure to a high-fat diet (HFD) can lead to insulin resistance and impair NTS function. However, we still know little about which cells in the NTS are sensitive to insulin. Our study aimed to identify these insulin-sensitive cells and understand how they affect glucose metabolism. We found that insulin receptors in astrocytes are crucial for the NTSs ability to regulate glucose production in the liver. Insulin evokes the release of endozepines from astrocytes, and injecting endozepines into the NTS reduces glucose production. The effect of endozepines within the NTS is mimicked by GABAA antagonists and prevented by an agonist, suggesting that insulin prompts astrocytes to release endozepines, which then attenuate GABAA receptor activity, ultimately reducing glucose production in the liver. Our study is the first to show that insulin-dependent release of endozepines from NTS- astrocytes is fundamental to control blood glucose levels, providing valuable insights into the mechanisms underlying insulin function within this specific region of the CNS.