Ghrelin Directly Interacts With Neuropeptide-Y-Containing Neurons in the Rat Arcuate Nucleus

Abstract

Ghrelin is a newly discovered peptide that is released from the stomach and from neurons in the hypothalamic arcuate nucleus (ARC) and potently stimulates growth hormone release and food intake. Neuropeptide-Y (NPY) neurons in the ARC play an important role in the stimulation of food intake. The present study aimed to determine whether ghrelin directly activates NPY neurons and, if so, to explore its signaling mechanisms. Whether the neurons that respond to ghrelin could be regulated by orexin and leptin was also examined. G hrelin, an endogenous ligand for the growth hormone secretagogue (GHS) receptor (GHSR), is synthesized abundantly in the stomach and to a much lesser extent in the hypothalamic arcuate nucleus (ARC) (1). Peripheral or intracerebroventricular (ICV) injection of ghrelin releases growth hormone, stimulates food intake, and increases body weight in mice, rats, and humans (1-8). ICV injection of antighrelin IgG suppresses starvation-induced feeding (3). The daily pattern of plasma ghrelin levels in normal humans is characterized by a preprandial rise and postprandial fall (9). These findings have suggested that ghrelin plays a physiological role in the meal initiation.The neuropeptide-Y (NPY)-containing neurons localized in the ARC have been implicated in the stimulation of food intake-injection of NPY into the hypothalamus of rats potently stimulates food intake (10), and NPY secretion in the hypothalamus is increased during fasting (11). Regarding a possible link between ghrelin and the NPY neurons in the ARC, it has been shown that GHSR mRNA is expressed in 94% of the NPY neurons in the ARC by double-labeling in situ hybridization histochemistry (12). Systemic or ICV administration of ghrelin causes the ARC neurons to express Fos and Egr-1 (3,13-15) and ϳ90% of these Fos-positive neurons express NPY mRNA (13). Moreover, ghrelin increases the expression of NPY mRNA (3-5), and ICV administration of a NPY Y1 antagonist suppresses the ghrelin-stimulated food intake (3-5,15). These findings suggest that the NPY neurons in the ARC could be an important effector for the orexigenic action of ghrelin.

Promiscuous Dimerization of the Growth Hormone Secretagogue Receptor (GHS-R1a) Attenuates Ghrelin-mediated Signaling

“…For example, the GHS-R1a receptor has been shown to couple to G␣ i2 in pancreatic islet ␤-cells, mediating the suppression of glucose-induced Ca 2ϩ signaling resulting in attenuated insulin release (74). In addition, in NPY neurons the GHS-R1a-mediated Ca 2ϩ mobilization is achieved through the G s -cAMP-PKA signaling pathway (75). These and other alternate downstream signaling pathways may be able to explain the opposing effects on food intake and should be further investigated.…”

Oxidative Stress in the Hypothalamus: the Importance of Calcium Signaling and Mitochondrial ROS in Body Weight Regulation

“…These findings indicate that Scgn expression might play an important role in appetite by buffering intracellular Ca 2+ in NPY, but not POMC neurons, during negative energy balance. Indeed, ghrelin levels increase during negative energy balance and stimulate feeding behavior by increasing intracellular cytosolic Ca 2+ concentration, CaMKK and AMPK in NPY but not POMC neurons [6, 51, 83]. Thus, there is a direct requirement to buffer Ca 2+ in NPY but not POMC neurons to maintain cellular firing during negative energy balance.…”

Ghrelin triggers the synaptic incorporation of AMPA receptors in the hippocampus

“…GHS-R1a is a G protein-coupled seventransmembrane domain receptor (3), which can signal through guanine nucleotide-binding protein (G protein) subunit alpha 11 (Gq class) to activate phosphatidylinositol-specific phospholipase C, generating 1,4,5-triphosphate (IP 3 ) responsible for Ca 2+ intracellular release from endoplasmic reticulum, and diacylglicerol, which in turn activates protein kinase C (PKC) (11). Ghrelin receptor activation is also coupled to the phosphatidylinositol 3 (PI3)-kinase signaling cascade in different cellular systems through a pertussis toxin-sensitive G protein (G i/o α) (11), and to protein kinase A (PKA) in isolated hypothalamic neurons, modulating N-type Ca 2+ channels (12).…”