Glucose is undoubtedly the primary energy fuel for practically all tissues in mammals. Because both hypo- and hyperglycemia have adverse consequences, understanding the mechanisms involved in maintaining glucose levels within a narrow range has been a long-standing scientific quest. The direct effects of glucose on the endocrine pancreas, which coordinately adjusts the secretion of glucagon and insulin, is without doubt essential for adapting changes in blood glucose concentrations [1]. However, numerous studies, some dating back to the 19th century [2], have demonstrated that also the brain plays a crucial role in adjusting glucose levels by dynamically integrating multiple signals monitoring energy availability, and coordinating in turn glucose entry and removal from circulation [3]. Importantly, growing evidence indicates that physiologically important changes in pancreatic hormone secretion as well as peripheral tissue glucose entry can be centrally initiated even in the absence of changes in blood glucose levels [4], [5], [6].

Vagal efferents - the efferent arm of the vagus nerve - are a major neural pathway for the brain to control peripheral target tissues related to glucose metabolism [7], [8], [9], [10]. In addition, vagal afferents - the afferent arm of the vagus nerve - transmit nutrient-related signals from peripheral tissues to the brain, and thereby contribute to adaptive glucoregulatory responses, e.g. following food consumption [11], [12]. Thus, the vagus nerve constitutes a bidirectional communication pathway crucial for mediating glycemic control (Fig. 1). Of relevance to this role, impaired vagal transmission or dysregulation of neurocircuits that are up- or downstream of the vagus nerve have been associated with prevalent glucose metabolism disorders such as type 2 diabetes mellitus [13], [14], [15], [16], [17].

Extensive histological and lesion studies have revealed the central projection and tissue innervation patterns of vagal efferents and afferents, and linked vagal transmission to glycemic control [18], [19], [20], [21]. This body of work provided important insights into how vagal endings innervate key abdominal organs, and how the vagus nerve can contribute to the relay of glucoregulatory cues from and to the brain. In addition, technological advances in neuroscience and mouse genetics have extensively increased our understanding of brain control of glucose metabolism [4], [22], [23], [24]. This prior work has identified discrete neurocircuits that integrate multiple sensory signals related to nutrient availability and predicted changes thereof. This has been pioneered in the hypothalamus and is comprehensively reviewed elsewhere [3], [6]. These earlier findings will provide the organizational anchors for this review. In addition, the revolution of sequencing and imaging approaches has enabled an in-depth cellular analysis of vagal efferents and vagal afferents, and it is now clear that molecularly-defined vagal subtypes respond to different stimuli, and that their peripheral endings have distinct innervation patterns in thoracic and abdominal organs [11], [12], [25], [26], [27], [28], [29], [30]. On the other hand, the elucidation of the populations that participate in the regulation of glucose levels and their circuit organization has just begun. In this review, we will highlight a selection of recent work on the role of distinct vagal populations, and synthesize these findings into a general framework of how vagal pathways contribute to the systemic regulation of glucose metabolism.