Neuronal control of peripheral insulin sensitivity and glucose metabolism

Abstract

The central nervous system (CNS) has an important role in the regulation of peripheral insulin sensitivity and glucose homeostasis. Research in this dynamically developing field has progressed rapidly due to techniques allowing targeted transgenesis and neurocircuitry mapping, which have defined the primary responsive neurons, associated molecular mechanisms and downstream neurocircuitries and processes involved. Here we review the brain regions, neurons and molecular mechanisms by which the CNS controls peripheral glucose metabolism, particularly via regulation of liver, brown adipose tissue and pancreatic function, and highlight the potential implications of these regulatory pathways in type 2 diabetes and obesity.

Figure 1. Glucoregulatory roles of the pancreatic-derived hormones insulin and glucagon.

The pancreatic islets of Langherhans, containing alpha cells and beta cells, secrete glucagon and insulin respectively. Insulin and glucagon exert antagonistic effects on peripheral organs to control blood glucose levels. Insulin exerts its glucose lowering effects by stimulating glucose uptake in skeletal muscle, through inhibiting hepatic glucose production and by blunting lipolysis. By contrast, glucagon raises circulating glucose levels by increasing gluconeogenesis and lipolysis.

Figure 2. Key brain nuclei and areas involved in CNS control of glucose homeostasis.

Schematic representing a sagittal section of a mouse brain in which critical brain regions controlling glucose homeostasis and peripheral insulin sensitivity as well as brown fact activity are depicted. Three main regions are highlighted: the bed nucleus of the stria terminalis (BNST), the hypothalamus and the medulla. The hypothalamus contains the preoptic area, the paraventricular nucleus (PVH), the lateral hypothalamic area (LHA), the ventromedial nucleus of the hypothalamus (VMH, where SF-1-expressing neurons reside), the dorsomedial nucleus of the hypothalamus (DMH) and the arcuate nucleus of the hypothalamus (ARH) where AgRP/NPY and POMC neurons are located. In the caudal part the brain, the medulla contains key areas such as the dorsal vagal complex (DVC) and the raphe pallidus nucleus (RPA). 3V, third ventricle; 4V, fourth ventricle; fx, fornix; LV, lateral ventricle; me, median eminence.

Figure 3. Pathways involved in the control of glucose homeostasis.

The central nervous system contains high density of receptors for the white adipose tissue (WAT)-derived hormone leptin as well as receptors for the pancreatic hormone insulin. Leptin and insulin act on specific brain regions that will in turn modulate glucose utilization and production in peripheral tissue via the autonomic nervous system. Notably, the vagus nerve links brain insulin action and the liver in the control of hepatic gluconeogenesis. At the pancreatic level, the autonomic nervous system is involved in pancreatic hormone secretion. The brown adipose tissue (BAT) receives sympathetic innervation which activity directly control BAT glucose uptake. NA, noradrenaline.