Arcuate Nucleus-Dependent Regulation of Metabolism-Pathways to Obesity and Diabetes Mellitus

Abstract

The central nervous system (CNS) receives information from afferent neurons, circulating hormones, and absorbed nutrients and integrates this information to orchestrate the actions of the neuroendocrine and autonomic nervous systems in maintaining systemic metabolic homeostasis. Particularly the arcuate nucleus of the hypothalamus (ARC) is of pivotal importance for primary sensing of adiposity signals, such as leptin and insulin, and circulating nutrients, such as glucose. Importantly, energy state-sensing neurons in the ARC not only regulate feeding but at the same time control multiple physiological functions, such as glucose homeostasis, blood pressure, and innate immune responses. These findings have defined them as master regulators, which adapt integrative physiology to the energy state of the organism. The disruption of this fine-tuned control leads to an imbalance between energy intake and expenditure as well as deregulation of peripheral metabolism. Improving our understanding of the cellular, molecular, and functional basis of this regulatory principle in the CNS could set the stage for developing novel therapeutic strategies for the treatment of obesity and metabolic syndrome. In this review, we summarize novel insights with a particular emphasis on ARC neurocircuitries regulating food intake and glucose homeostasis and sensing factors that inform the brain of the organismal energy status.

Keywords: arcuate nucleus; energy homeostasis; feeding; hypothalamus; obesity; type 2 diabetes mellitus.

Graphical Abstract

Figure 1.

Photostimulation of agouti-related peptide (AgRP) neuron axon projections increases food intake. Schematic illustration of a sagittal brain section showing AgRP projection fields that increase food intake on photostimulation. Photostimulation of inhibitory AgRP projections to the anterior bed nucleus of the stria terminals (BNST), lateral hypothalamus (LHA), and the paraventricular nucleus of the hypothalamus (PVH) evokes a profound feeding response. Activation of AgRP → paraventricular thalamic nucleus (PVT) projections induced a moderate level of feeding. However, photostimulation of AgRP projections to the amygdala and the hindbrain did not increase feeding (35). Projection trajectories are schematic. The illustration of the sagittal brain section was created with BioRender.com.

Figure 2.

Signal dependent regulation of melanocortin neurons. Agouti-related peptide (AgRP) neurons transiently adapt their firing properties to sensory food perception as the presentation of food cues produced a rapid inactivation of AGRP neurons (59). Sensory food perception activates pro-opiomelanocortin (POMC) neurons and this activation is sufficient to prime metabolic liver adaption to the postprandial state (63). Furthermore, these neurons receive gut-innervation dependent signals from chemoreceptors and mechanoreceptors on an intermediate time scale and are subject to long-term regulation through homeostatic hormonal regulation. Furthermore, POMC neurons regulate a wide array of different physiological functions, including feeding behavior and energy expenditure, hepatic glucose production, regulation of blood glucose levels, and blood pressure. Similarly, AgRP neurons are involved in feeding behavior and energy expenditure, substrate use, regulation of glucose metabolism, and inflammatory pain.

Figure 3.

Regulation of arcuate nucleus neurons by circulating hormonal cues. Neurons in the arcuate nucleus of the hypothalamus (ARC) receive hormonal cues and integrate this information to produce adequate metabolic responses. Circles indicate neuronal subpopulations. Ghrelin increases the firing activity of Agouti-related peptide (AgRP)/neuropeptide Y (NPY) neurons through growth hormone secretagogue receptor signaling and inhibits firing activity of pro-opiomelanocortin (POMC) neurons through ghrelin-induced increases in the frequency of GABAergic inhibitory postsynaptic currents of POMC neurons (93). The adipokine leptin potently inhibits AgRP neuronal activity and activates POMC neurons gradually on a timescale of hours. Insulin either activates or inhibits feeding via POMC inhibition or activation, dependent on the regulation of insulin receptor signaling by the phosphatase TCPTP (T-cell protein tyrosine phosphatase) (76).

Figure 4.

Neuronal regulation of feeding. Activation of agouti-related peptide (AgRP) neurons potently promotes feeding, whereas activation of pro-opiomelanocortin (POMC) neurons decrease feeding over longer time scales. AgRP and POMC neurons send projections to the paraventricular nucleus of the hypothalamus (PVH) neurons that express melanocortin 4 receptor (MC4R), which is highly abundant in the PVH (109, 134). A fast-acting satiety mechanism is conveyed by glutamate-releasing oxytocin-receptor expressing (Vglut2/OxtR) neurons in the arcuate nucleus of the hypothalamus (ARC). Excitatory Vglut2/OxtR projections synaptically converge with GABAergic AgRP projections on PVH^MC4R neurons and rapidly cause satiety (135). PVH^MC4R neurons are a critical satiety-promoting neuronal population and act as a second-order node in the regulation of feeding. In the PVH, MC4R-expressing neurons release glutamate and excite downstream neuronal targets in the lateral parabrachial nucleus (LPBN), establishing the LPBN as possible a third-order node in feeding regulation (20).