Insulin activates parasympathetic hepatic-related neurons of the paraventricular nucleus of the hypothalamus through mTOR signaling

Integration of autonomic and metabolic regulation, including hepatic function, is a critical role played by the brain's hypothalamic region. Specifically, the paraventricular nucleus of the hypothalamus (PVN) regulates autonomic functions related to metabolism, such as hepatic glucose production. Although insulin can act directly on hepatic tissue to inhibit hepatic glucose production, recent evidence implicates that central actions of insulin within PVN also regulate glucose metabolism. However, specific central circuits responsible for insulin signaling with relation to hepatic regulation are poorly understood. As a heterogeneous nucleus essential to controlling parasympathetic motor output with notable expression of insulin receptors, PVN is an appealing target for insulin-dependent modulation of parasympathetic activity. Here, we tested the hypothesis that insulin activates hepatic-related PVN (PVN^hepatic) neurons through a parasympathetic pathway. Using transsynaptic retrograde tracing, labeling within PVN was first identified 24 h after its expression in the dorsal motor nucleus of the vagus (DMV) and 72 h after hepatic injection. Critically, nearly all labeling in medial PVN was abolished after a left vagotomy, indicating that PVN^hepatic neurons in this region are part of a central circuit innervating parasympathetic motor neurons. Insulin also significantly increased the firing frequency of PVN^hepatic neurons in this subregion. Mechanistically, rapamycin pretreatment inhibited insulin-dependent activation of PVN^hepatic neurons. Therefore, central insulin signaling can activate a subset of PVN^hepatic neurons that are part of a unique parasympathetic network in control of hepatic function. Taken together, PVN^hepatic neurons related to parasympathetic output regulation could serve as a key central network in insulin's ability to control hepatic functions.<b>NEW & NOTEWORTHY</b> Increased peripheral insulin concentrations are known to decrease hepatic glucose production through both direct actions on hepatocytes and central autonomic networks. Despite this understanding, how (and in which brain regions) insulin exerts its action is still obscure. Here, we demonstrate that insulin activates parasympathetic hepatic-related PVN neurons (PVN^hepatic) and that this effect relies on mammalian target of rapamycin (mTOR) signaling, suggesting that insulin modulates hepatic function through autonomic pathways involving insulin receptor intracellular signaling cascades.