Hypothalamic AgRP neurons and the regulation of appetite and body weight: A review
Ping Wang;Guo Zhang;Department of Toxicology, School of Public Health, Huazhong University of Science and Technology;
The maintenance of energy balance is essential for the survival of animals. The hypothalamus in the brain plays a central role in this process through the integration of neural, nutritional and hormonal signals. Multiple and distributed neuronal populations in the hypothalamus form complex circuits to regulate appetite and body weight. Located in the arcuate nucleus of hypothalamus, agouti-related peptide(AgRP)-expressing cells are known as the hunger-promoting neurons.Over the past three decades, extensive studies have been performed to understand the role of AgRP neurons in energy balance control. AgRP neurons are both necessary and sufficient to orchestrate feeding behavior. The AgRP neuron activity adapts to and thereby is regulated by the nutritional status in the body. Furthermore, we now know that this alternation is driven by various circulating hormones, such as Leptin and Ghrelin, as well as synaptic inputs from upstream neurons. Neurotransmitters(e.g. glutamate and GABA) play a vital role in the regulation of AgRP neuron activity. The excitatory glutamatergic input is required in fasting-related activation of AgRP neurons, whereas the inhibitory GABAergic inputs is crucial in the rapid reduction of Ag RP neuron activity in response to food-related cues,and thus, to terminate a meal. In addition to these molecules, signaling molecules and pathways in AgRP neurons, such as receptors, ion channels, kinases(e.g. IKK?), endoplasmic reticulum stress(ER stress) and mitochondrial dynamic, are critically involved in the control of its activity. Moreover, AgRP neurons release neuropeptides AgRP and NPY, as well as neurotransmitter GABA to regulate neuronal activity. Both AgRP and NPY potently promote appetite. Although NPY is widely expressed in the central nervous system, it is mainly co-expressed with AgRP in the arcuate nucleus of hypothalamus. The appetite-promoting effect of NPY is mediated by Y1 and Y5 receptors, while AgRP exert its orexigenic effect mainly by antagonizing the central melanocortin system. Surprisingly, ablation of AgRP neurons in neonates has little effect on body weight, whereas these neurons are essential for the maintenance of appetite in adult mice. Moreover, accumulating evidences indicate that GABA released by AgRP neurons is required to retain animals' appetite. At the circuit level, AgRP neurons project to both intra-and extra-hypothalamic regions to regulate energy balance. For example, in arcuate nucleus, AgRP neurons innervate and inhibit POMC neurons via the inhibitory GABAergic synapses. Conversely, POMC neurons release ?-endorphin, a μ-opioid receptor agonist, to inhibit the activity of AgRP neurons. In summary, AgRP neurons play a crucial role in the regulation of appetite and energy balance.Targeting hypothalamic AgRP neurons might be a relevant approach to treat common obesity.