Trends in Neurosciences
ReviewFeeding and body-weight regulation by hypothalamic neuropeptides—mediation of the actions of leptin
Section snippets
Negative feedback loop of body adiposity
The products of the ob and db genes make up a hormone–receptor pair that constitutes one system through which the status of energy stores is signaled to the brain12, 13, 14, 15, 16, 17, 18. Total inability to produce leptin in adipose tissue (as seen in ob/ob mice) or to respond to it in the hypothalamus (seen in db/db mice and fa/fa rats) results in profound, early onset obesity with persistently excessive food intake, decreased energy expenditure, increased serum corticosterone levels, severe
Neuropeptide Y as an important orexigenic molecule in the hypothalamus
Neuropeptide Y is a 36-amino-acid peptide that has emerged in the past 15 years as a possible key neurotransmitter candidate for the regulation of energy homeostasis1, 8, 9, 24, 25, 26, 27, 28. It is synthesized throughout the brain but is particularly abundant in the hypothalamus. Within the hypothalamus, NPY is synthesized largely in neurons whose cell bodies lie in the arcuate nucleus and send projections into surrounding hypothalamic structures. These structures include the paraventricular
Leptin antagonizes the effects of NPY
Leptin inhibits NPY-mediated neuronal activity in the hypothalamus35, 36, 37, 38; it also reduces levels of NPY mRNA in the arcuate nucleus and NPY levels in the arcuate, paraventricular and dorsomedial nuclei. Co-expression of leptin-receptor mRNA and NPY mRNA has been demonstrated in neurons of the arcuate nucleus39, 40. Leptin inhibits synaptic transmission in the NPY-containing arcuate neurons41 and the activity of glucose-responsive neurons of the ventromedial and arcuate nuclei via
Hypothalamic–melanocortin system
Evidence points to an important role of the hypothalamic-melanocortin (MC) system in the regulation of food intake and body weight2, 6, 11, 50, 51, 52, 53 (Table 1 and Box 1). The MC system involves peptides that are processed from the polypeptide precursor, pro-opiomelanocortin (POMC), which is produced by neurons within the hypothalamic arcuate nucleus. Several of the peptide products of the POMC gene such as α-melanocyte-stimulating hormone (α-MSH), have been implicated in the regulation of
Corticotropin-releasing factor
Corticotropin-releasing factor (CRF), a 41 amino-acid peptide, is produced in the paraventricular nucleus and other brain regions1, 3. Whereas the actions of NPY result in increases in energy intake and storage, the effects of CRF on energy balance are catabolic in nature and oppose those of NPY (29, 48, 49). In addition to its role as controller of the hypothalamic–pituitary–adrenal (HPA) axis, CRF inhibits food intake, increases energy expenditure and produces sustained weight loss.
Other potential leptin targets
Melanin-concentrating hormone (MCH), a cyclic 19 amino-acid neuropeptide, was identified initially in the intermediate lobe of the teleost fish pituitary from which it is released into circulation and causes aggregation of malanophores67. In mammals, cell bodies containing immunoreactive MCH are found exclusively in the zona incerta and the lateral hypothalamus. It is reported to stimulate food intake after central administration68 and expression of the gene encoding MCH is upregulated in ob/ob
Neuropeptidergic cascade downstream of leptin signaling
The complicated nature of neuropeptide-mediated regulation of appetite and energy homeostasis is illustrated well by the normal phenotype of NPY knockout mice. Other such examples are the knockout mice of CRF (Ref. 80) or the GLP-1 receptor81, which also do not exhibit gross disturbances in food intake and body weight. Redundancy and plasticity of the regulatory machinery appear to be important in energy homeostasis, which is characteristic of regulated biological systems. For example, although
Concluding remarks
It is thought that the general organization of the feeding–regulatory system is a cascade, with the emphasis on driving feeding1. The development of the cascade hypothesis was in an attempt to form a useful framework to help the understanding of the complex nature of the neuropeptide interactions that are involved in feeding and body-weight regulation. Inherent in the hypothesis is that there are a number of different pathways that might act as fail-safe mechanisms. It is likely that these
Acknowledgements
The author is indebted to Prof. Masato Kasuga and Prof. Shigeaki Baba, Kobe University, for many stimulating discussions. The author's research was supported by grants from the Ministry of Education, Science, Sports and Culture of Japan.
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