Wired on sugar: the role of the CNS in the regulation of glucose homeostasis

Abstract

Obesity and type 2 diabetes mellitus (T2DM)--disorders of energy homeostasis and glucose homeostasis, respectively--are tightly linked and the incidences of both conditions are increasing in parallel. The CNS integrates information regarding peripheral nutrient and hormonal changes and processes this information to regulate energy homeostasis. Recent findings indicate that some of the neural circuits and mechanisms underlying energy balance are also essential for the regulation of glucose homeostasis. We propose that disruption of these overlapping pathways links the metabolic disturbances associated with obesity and T2DM. A better understanding of these converging mechanisms may lead to therapeutic strategies that target both T2DM and obesity.

Figure 1. Leptin and insulin actions in the ARC

The arcuate nucleus (ARC) of the hypothalamus contains two main sets of neurons that either express the neuropeptide pro-opiomelanocortin (POMC) or co-express agouti-related protein (AGRP) and neuropeptide Y (NPY). Both sets of neurons express leptin receptors (OBRs) and insulin receptors (IRs). Leptin acts on POMC neurons, and the effect of these actions on glucose production is partially mediated by melanocortin receptor 4 (MC4R) neurons in extra-arcuate sites (for example, the paraventricular nucleus). Insulin acts on NPY–AGRP neurons and at least partially on POMC neurons to regulate hepatic glucose production; this effect is independent of MC4Rs. Leptin and insulin actions on POMC neurons have additive effects on the regulation of hepatic glucose production, possibly because they act on different POMC populations within the ARC (not shown). In addition, insulin actions on neuronal populations of currently unknown phenotype result in the activation of ATP-sensitive potassium (K_ATP) channels, mammalian target of rapapmycin (mTOR) and peroxisome proliferator-activated receptor-γ (PPARγ) to regulate hepatic glucose production. Leptin acts on PPARγ to regulate food intake, but it is unknown whether this pathway also regulates glucose homeostasis. Thus, leptin and insulin signalling in the ARC use both divergent and overlapping circuits and mechanisms.

Figure 2. Fuel sensing in CNS neurons

a | Various molecular machineries sense the bioavailability of glucose, amino acids and lipids, as well as ATP stores. Metabolism of glucose and amino acids (leucine) via glycolytic and tricarboxylic acid (TCA) cycle pathways results in increased ATP levels. In the hypothalamus, this in turn results in inhibition of AMP-activated protein kinase (AMPK), activation of mammalian target of rapamycin (mTOR) and activation of neuronal ATP-sensitive potassium (K_ATP) channels. Each of these isolated events has been associated with the regulation of hepatic glucose production (HGP). Bioavailable lipids act as a ligand for hypothalamic peroxisome proliferator-activated receptor-γ (PPARγ), the activation of which reduces HGP, possibly by modulating levels of reactive oxygen species (ROS) in hypothalamic neurons. In general, as nutrients become bioavailable, overall HGP decreases. b | Although these pathways are clearly important for regulating glucose homeostasis, only some are also involved in the regulation of energy homeostasis. For example, hypothalamic mTOR and PPARγ activation regulate both processes (albeit in opposite directions), whereas K_ATP channels seem to play no part in energy homeostasis. ARC, arcuate nucleus; BW, body weight.

Figure 3. Overlapping CNS circuitries regulate energy balance and glucose homeostasis

Most receptor populations and neuropeptides discussed in this Review overlap in the way they control energy balance and glucose homeostasis. The hypothalamic arcuate nucleus (ARC) melanocortin system, consisting of pro-opiomelanocortin (POMC) and neuropeptide Y (NPY)–agouti-related protein (AGRP) neurons, has a key role in regulating both energy and glucose homeostasis. On POMC neurons, activation of 5-hydroxytryptamine 2C (5-HT_2C) receptors (via 5-HT released from the midbrain), leptin receptors (OBRs) or insulin receptors (IRs) regulates both energy and glucose homeostasis. In NPY–AGRP neurons, OBRs are important in the regulation of energy but not glucose homeostasis, whereas IRs only regulate glucose homeostasis. Downstream of these ARC neurons are melanocortin receptor 4 (MC4R)-expressing neurons within the paraventricular nucleus (PVN), which are also important for both energy and glucose homeostasis. Within the ARC fuel-sensing systems, both mammalian target of rapamycin (mTOR) and ATP-activated protein kinase (AMPK) seem to be important for regulating both energy and glucose homeostasis, whereas ATP-sensitive potassium (K_ATP) channel activation is only important in regulating glucose homeostasis. Other regulatory systems that control both energy and glucose homeostasis but that are independent of the ARC involve IRs and OBRs on steroidogenic factor 1 (SF1) neurons within the ventromedial hypothalamus (VMH), as well as MC4Rs located on the sympathetic neurons (in the nucleus of the solitary tract (NTS) in the dorsal motor nucleus of the vagus (DMV) in the hindbrain. Lastly, the gut hormones cholecystokinin (CKK) and glucagon-like peptide 1 (GLP1) act centrally by innervating NMDA receptors (NMDARs) on vagal afferents to the hindbrain. GLP1R, GLP1 receptor; SNS, sympathetic nervous system.