Kanako Shiba

Neuronal circuits involving ghrelin in the hypothalamus-mediated regulation of feeding

Ghrelin, an n-octanoylated 28-amino acid brain-gut peptide, was first isolated from extracts of porcine stomach. Ghrelin is an endogenous ligand for the growth hormone secretagogue type 1a receptor (GHS-R1a), the functionally active form of GHS-R, and stimulates feeding and growth hormone secretion. Ghrelin is mainly produced in the A/X-like cells of the oxyntic glands of the stomach and is the main orexigenic circulating hormone that acts on the hypothalamus to affect feeding behavior and energy metabolism. Ghrelin-containing neuronal cell bodies are localized in the hypothalamic arcuate nucleus, a center that integrates signals for energy homeostasis. Ghrelin-containing nerve fibers are widely distributed in the brain. Accumulated evidence shows that hypothalamic neuropeptides such as neuropeptide Y (NPY), orexin and proopiomelanocortin (POMC) are involved in the regulation of feeding behavior and energy homeostasis via neuronal circuits in the hypothalamus. Ghrelin also forms part of the feeding-regulating neuronal circuitry in conjunction with other feeding-regulating peptide-containing neurons within the hypothalamus. In view of the fact that one decade has now passed since ghrelin was first discovered, we review advances that have been made in ghrelin research during that time and how this has impacted on our knowledge of feeding regulation in the hypothalamus. We also summarize our current understanding of the neuronal interactions between ghrelin and the different kinds of feeding-regulating peptide-containing neurons in the hypothalamus based on evidence at the ultrastructural level.

Galanin-like peptide and the regulation of feeding behavior and energy metabolism

The hypothalamic neuropeptides modulate physiological activity via G protein‐coupled receptors (GPCRs). Galanin‐like peptide (GALP) is a 60 amino acid neuropeptide that was originally isolated from porcine hypothalamus using a binding assay for galanin receptors, which belong to the GPCR family. GALP is mainly produced in neurons in the hypothalamic arcuate nucleus. GALP‐containing neurons form neuronal networks with several other types of peptide‐containing neurons and then regulate feeding behavior and energy metabolism. In rats, the central injection of GALP produces a dichotomous action that involves transient hyperphasia followed by hypophasia and a reduction in body weight, whereas, in mice, it has only one action that reduces both food intake and body weight. In the present minireview, we discuss current evidence regarding the function of GALP, particularly in relation to feeding and energy metabolism. We also examine the effects of GALP activity on food intake, body weight and locomotor activity after intranasal infusion, a clinically viable mode of delivery. We conclude that GALP may be of therapeutic value for obesity and life‐style‐related diseases in the near future.

Neuropeptide W: a key player in the homeostatic regulation of feeding and energy metabolism?

Neuropeptide W (NPW), recently isolated from porcine hypothalamus, has been identified as the endogenous ligand for both NPBWR1 (GPR7) and NPBWR2 (GPR8), which belong to the orphan G protein–coupled receptor family. NPW is thought to play an important role in the regulation of feeding and drinking behavior, and to be related to the stress response. NPW‐containing neurons are localized in several regions of the brain, including the hypothalamus, hippocampus, limbic system, midbrain, and brain stem. Accumulated evidence suggests that hypothalamic neuropeptides, such as neuropeptide Y (NPY), orexin, melanin‐concentrating hormone (MCH), and proopiomelanocortin (POMC), are involved in the regulation of feeding behavior and energy homeostasis via neuronal circuits in the hypothalamus. NPW also forms part of the feeding‐regulating neuronal circuitry in conjunction with other feeding‐regulating peptide‐containing neurons within the hypothalamus. We summarize our current understanding of the distribution of NPW and of the neuronal interactions between NPW and the different feeding‐regulating peptide‐containing neurons. This review also discusses evidence for the dichotomous actions of NPW on energy balance and the potential mechanisms involved.

Distribution of neuropeptide W in the rat brain

Neuropeptide W (NPW), which was recently isolated from the porcine hypothalamus, has been identified as the endogenous ligand of the orphan G protein-coupled receptors GPR7 (NPBWR1) and GPR8 (NPBWR2). Infusion of NPW increases food intake in the light phase, whereas in the dark phase, it has the opposite effect. In this study, we used RT-PCR analysis to examine the gene expression of NPW mRNA in the rat brain, and performed a detailed analysis of the distribution of NPW-positive neurons by use of immunohistochemistry at both the light and electron microscopic levels. NPW mRNA expression was demonstrated in the hypothalamic paraventricular nucleus (PVN), arcuate nucleus (ARC), ventromedial nucleus (VMH) and lateral hypothalamus (LH). At the light microscopic level, NPW-like immunoreactive (NPW-LI) cell bodies were found in the preoptic area (POA), PVN, ARC, VMH, LH, PMD (dorsal premammillary nucleus), periaqueductal gray (PAG), lateral parabrachial nucleus (LPB), and prepositus nucleus (Pr). NPW-LI axon terminals were shown in the POA, bed nucleus of the stria terminalis (BST), amygdala, PVN, ARC, VMH, LH, and PAG, LPB. In addition, at the electron microscopic level, NPW-LI cell bodies and dendritic processes were often seen to receive inputs from other unknown neurons in the ARC, PVN, VMH and amygdala. Our observations indicate that NPW-LI neurons widely distributed in the rat brain region. These finding suggest that NPW may have important roles in feeding behavior, energy homeostasis, emotional response and regulation of saliva secretion.

Galanin-like peptide: a key player in the homeostatic regulation of feeding and energy metabolism?

The hypothalamus has a critical role in the regulation of feeding behavior, energy metabolism and reproduction. Galanin-like peptide (GALP), a novel 60 amino-acid peptide with a nonamidated C-terminus, was first discovered in porcine hypothalamus. GALP is mainly produced in the hypothalamic arcuate nucleus and is involved in the regulation of feeding behavior and energy metabolism, with GALP-containing neurons forming networks with several feeding-regulating peptide-containing neurons. The effects of GALP on food intake and body weight are complex. In rats, the central effect of GALP is to first stimulate and then reduce food intake, whereas in mice, GALP has an anorectic function. Furthermore, GALP regulates plasma luteinizing hormone levels through activation of gonadotropin-releasing hormone-producing neurons, suggesting that it is also involved in the reproductive system. This review summarizes the research on these topics and discusses current evidence regarding the function of GALP, particularly in relation to feeding and energy metabolism. We also discuss the effects of GALP activity on food intake, body weight and locomotor activity after intranasal infusion, a clinically viable mode of delivery.

Anti-obesity effect of intranasal administration of galanin-like peptide (GALP) in obese mice

Galanin-like peptide (GALP) has an anti-obesity effect in rats and mice. It has been reported that the uptake of GALP by the brain is higher after intranasal administration than with intravenous injection. This study therefore aimed to clarify the effect of intranasal administration of GALP on the feeding behavior of lean and obese mice. Autoradiography revealed the presence of 125I-GALP in the olfactory bulb and the brain microcirculation. The body weights of ob/ob mice gradually increased during vehicle treatment, but remained unchanged in response to repeated intranasal administration of GALP, with both ob/ob and diet-induced obese mice displaying significantly decreased food intake, water intake and locomotor activity when treated with GALP. These results suggest that intranasal administration is an effective route whereby GALP can exert its effect as an anti-obesity drug.