NPY mediates the rapid feeding and glucose metabolism regulatory functions of AgRP neurons

Abstract

Activation of Agouti-Related Peptide (AgRP)-expressing neurons promotes feeding and insulin resistance. Here, we examine the contribution of neuropeptide Y (NPY)-dependent signaling to the diverse physiological consequences of activating AgRP neurons. NPYdeficient mice fail to rapidly increase food intake during the first hour of either chemo-or optogenetic activation of AgRP neurons, while the delayed increase in feeding is comparable between control and NPY-deficient mice. Acutely stimulating AgRP neurons fails to induce systemic insulin resistance in NPY-deficient mice, while increased locomotor activity upon AgRP neuron stimulation in the absence of food remains unaffected in these animals. Selective re-expression of NPY in AgRP neurons attenuates the reduced feeding response and reverses the protection from insulin resistance upon optogenetic activation of AgRP neurons in NPY-deficient mice. Collectively, these experiments reveal a pivotal role of NPYdependent signaling in mediating the rapid feeding inducing effect and the acute glucose regulatory function governed by AgRP neurons.

MCH Neurons Regulate Permeability of the Median Eminence Barrier

“…Although most energy regulatory neurocircuits, such as melanocortin neurons in the ARC, exert their metabolism regulatory function through neuropeptide and neurotransmitter-dependent signaling in their widespread neurocircuitry in a conventional way by synaptic transmission ( Betley et al., 2015 , Engström Ruud et al., 2020 , Fenselau et al., 2017 , Steculorum et al., 2016 ), MCH neurons have previously been shown to exert at least part of their metabolism regulatory function through additional mechanisms. First, they densely innervate the ependymal cells of the ventricle to regulate cilia beating and CSF circulation ( Conductier et al., 2013 ).…”

Neuropeptide Y Is an Immunomodulatory Factor: Direct and Indirect

“…Researches have revealed that NPY plays a vital role in the regulation of blood glucose homeostasis in diabetic models ( 119 ). The ability of AgRP neurons to induce insulin resistance depends on the expression of NPY ( 120 ), and the application of NPY in the CNS has been shown to efficiently reduce sympathetic activation of BAT and improve systemic insulin sensitivity ( 8 , 107 ). Therefore, the NPY-dependent regulation of systemic insulin sensitivity is consistent with reducing energy expenditure in mice under fasting conditions, possibly by regulating the sympathetic activation of BAT.…”

Effects of metabolic state on the regulation of melanocortin circuits

“…These two neuronal populations form neural circuits with various hypothalamic target sites such as the lateral (LHA), and paraventricular (PVH) nucleus as well as with extrahypothalamic nuclei including the bed nucleus of the stria terminalis (BNST), amygdala (AMY), lateral parabrachial nucleus (LPB), periaqueductal grey (PAG), the nucleus of the solitary tract (NTS) and the intermediolateral cell column of the spinal cord (IML) ( Fig. 1 ) [ 8 , 15 , 19 , 30 , 65 , 66 , 93 , 123 , 124 , 128 , 170 , 173 , 182 , 192 ].These neuronal circuit connections are crucial for the proper regulation of feeding behavior, energy homeostasis, and glucose metabolism [ 9 , 19 , 67 , 84 , 115 , 129 , 178 , 187 , 195 ].…”

“…Interestingly, the ARH POMC neuron induced reduction of food intake and body weight requires melanocortin receptor signaling [ 9 ] while the AgRP neuron induced hyperphagia is independent of melanocortins [ 9 , 45 , 130 ]. As AgRP is an inverse agonist of melanocortin receptors, these studies highlight the role of NPY and GABA, independent of melanocortin signaling, for the acute ability of AgRP neurons to regulate feeding [ 45 , 58 , 67 , 199 – 202 ].…”