Neuronal circuits that regulate feeding behavior and metabolism

Abstract

Neurons within the central nervous system receive humoral and central (neurotransmitter or neuropeptide) signals that ultimately regulate ingestive behavior and metabolism. Recent advances in mouse genetics combined with neuroanatomical and electrophysiological techniques have contributed to a better understanding of these central mechanisms. This review integrates recently defined cellular mechanisms and neural circuits relevant to the regulation of feeding behavior, energy expenditure, and glucose homeostasis by metabolic signals.

Keywords: GABA; agouti-related peptide; electrophysiology; glutamate; melanocortin receptor; neuropeptide Y receptor.

Figure 1

Central neuronal circuits that regulate energy and glucose homeostasis. The arcuate nucleus of hypothalamus (Arc) contains two chemically identified neurons: pro-opiomelanocortin (POMC) and neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons. POMC and NPY/AgRP neurons have similar electrical activity profiles: they both have a resting membrane potential of approximately −50 mV and fire action potentials spontaneously (see example traces). POMC neurons release the anorexigenic peptide α-melanocyte stimulating hormone (α-MSH), whereas NPY/AgRP neurons release the orexigenic peptides NPY/AgRP and GABA at their target nuclei in brain and spinal cord. Arcuate POMC and NPY/AgRP neurons express receptors for peripheral (e.g., leptin, insulin, and ghrelin) and central (e.g., melanocortin, NPY, GABA, and serotonin) signals. The electrical activity (resting membrane potential and/or action potential firing frequency) of POMC and NPY/AgRP neurons may be acutely modulated by these signals, which is believed to affect the release of α-MSH and NPY/AgRP/GABA to their target neurons. In the arcuate nucleus there is a local circuit in which POMC neurons receive GABAergic (inhibitory) input from NPY/AgRP neurons. The central melanocortin pathway involves arcuate POMC neurons and melanocortin receptors (MC3R and MC4R) throughout the central nervous system. The melanocortin α-MSH is an agonist and AgRP is an inverse agonist at anorectic MC4R expressed by neurons within central nuclei, including paraventricular nucleus of hypothalamus (PVH), parabrachial nucleus (PBN), dorsal vagal complex (DVC), and intermediolateral column of spinal cord (IML). Notably, MC4R expressed by neurons within PVH mediate the anorexigenic effects independent of energy expenditure and glucose homeostasis. By contrast, MC4R expressed by autonomic preganglionic neurons within DVC and IML regulate energy expenditure and glucose homeostasis with minimal effects on food intake. Traditionally, the orexigenic effects of arcuate NPY/AgRP neurons have been attributed to the release of NPY/AgRP and downstream activation of NPY receptors (NPY1R and NPY5R) and inhibition of melanocortin receptors. However, a central role of GABAergic neurotransmission in the orexigenic circuit has recently been demonstrated in PVH and PBN. Notably, PBN neurons receive glutamatergic (excitatory) input from the nucleus tractus solitarius (NTS) within DVC, which may serve as the satiety signal from the gastrointestinal tract. These signals are believed to antagonize the GABAergic hunger signal from NPY/AgRP neurons. In addition to modulations by melanocortin, NPY, AgRP, and GABA from arcuate POMC and NPY/AgRP neurons, neurons within PVH, PBN, and DVC are directly regulated by central and peripheral signals such as leptin (via LepR), insulin (via InsR), serotonin (via 5-HT_1BR and 5-HT_2CR), and ghrelin (via GHSR).

Figure 2

Intracellular signal pathways of postsynaptic melanocortin and NPY receptors. (A) Anorexigenic effects of α-melanocyte stimulating hormone (α-MSH) released from arcuate pro-opiomelanocortin (POMC) neurons are mediated by melanocortin 4 receptor (MC4R) in the paraventricular nucleus of hypothalamus (PVH). By contrast, autonomic effects (e.g., on thermogenesis, insulin secretion, glucose production, and blood pressure) of α-MSH are mediated by MC4R in autonomic preganglionic neurons within brainstem and spinal cord. In brainstem, MC4R expressed by parasympathetic preganglionic neurons of the dorsal motor nucleus of vagus nerve (DMV) suppress insulin secretion. In spinal cord, MC4R expressed by sympathetic preganglionic neurons of the intermediolateral column (IML) increase energy expenditure and mediate obesity-induced hypertension. The cellular correlates of MC4R effects on parasympathetic and sympathetic nervous systems were recently identified. In sympathetic preganglionic neurons (left), Gs/cAMP-dependent signal pathways open nonselective cation channels (NSCs). By contrast, in parasympathetic preganglionic neurons, MC4R activates Gs protein and adenylyl cyclase (AC) to increase cAMP levels, which in turn activate protein kinase A (PKA) to open K_ATP channels (right). The cellular mechanisms underlying MC4R effects on PVH neurons are still unknown. (B) Orexigenic effects of NPY are mostly mediated by NPY1R and NPY5R within PVH. Thus, targeting of these receptors is considered to be a rational strategy for the development of novel anti-obesity drugs. An understanding of the cellular mechanisms underlying the inhibitory effects of NPY1R and NPY5R should facilitate drug development with minimal side effects. NPY1R and NPY5R activate Gi/o proteins. Typically, α subunits decrease cellular cAMP levels, whereas βγ subunits regulate ion channel activity in a membrane-delimited manner. G-protein-gated inwardly rectifying K⁺ (GIRK) channels are activated and voltage-dependent Ca²⁺ channels (VDCCs) are inhibited by direct binding of βγ subunits.