Vagal Insulin Signaling Regulates Sympathovagal Balance to Determine Peripheral Metabolic and Inflammatory State

The vagus nerve (VN) is a major component of the parasympathetic nervous system that regulates vital functions, including glucose and energy homeostasis. However, the specific molecular signaling pathways within vagal neurons that regulate metabolism are unclear. Here, we show that enhanced PI3K signaling within the vagal neurons through the deletion of its endogenous negative regulator, phosphatase and tensin homolog (Pten), enhanced VN function along with decreased inflammation within the vagal neurons. This was associated with an anti-inflammatory state in peripheral metabolic tissues such as the adipose, liver and skeletal muscle, with protection against high fat diet (HFD) induced glucose intolerance and insulin resistance. This was driven at least in part by macrophages, such that their depletion led to abolishment of metabolic protection. Single nuclear RNA sequencing analysis of the neuronal clusters within the nodose ganglia of the VN revealed that Pten-deficiency lead to upregulation of genes involved in myelination and neuronal growth, in keeping with large myelinated nerve fibers conducive for improved VN function. Intriguingly, upregulation of genes involved in adrenergic signaling was present in these neurons which correlated with enhanced beiging and lipolysis, increased sympathetic nerve density and increased norepinephrine levels in the adipose tissue. Finally, to assess specific role of insulin signaling given multiple upstream stimuli that can activate PI3K signaling, we generated mice with Insulin receptor deficiency specifically in the vagal neurons. These mice exhibited reduced vagal function and exacerbated HFD-induced metabolic abnormalities and inflammation which was rescued with concomitant Pten deletion. Together, we show that insulin signaling within the vagal neurons plays an essential role in optimizing sympathovagal balance in determining peripheral inflammatory and metabolic homeostasis which can be harnessed as novel therapeutic strategy to combat diabetes and obesity.