Neuropeptides Controlling Energy Balance: Orexins and Neuromedins

Abstract

In this section we review the feeding and energy expenditure effects of orexin (also known as hypocretin) and neuromedin. Orexins are multifunctional neuropeptides that affect energy balance by participating in regulation of appetite, arousal, and spontaneous physical activity. Central orexin signaling for all functions originates in the lateral hypothalamus–perifornical area, and is likely functionally differentiated based on site of action and on interacting neural influences. The effect of orexin on feeding is likely related to arousal in some ways, but is nonetheless a separate neural process that depends on interactions with other feeding related neuropeptides. In a pattern distinct from other neuropeptides, orexin stimulates both feeding and energy expenditure. Orexin increases in energy expenditure are mainly by increasing spontaneous physical activity, and this energy expenditure effect is more potent than the effect on feeding. Global orexin manipulations, such as in transgenic models, produce energy balance changes consistent with a dominant energy expenditure effect of orexin. Neuromedins are gut-brain peptides that reduce appetite. There are gut sources of neuromedin, but likely the key appetite related neuromedin producing neurons are in hypothalamus and parallel other key anorectic neuropeptide expression in the arcuate to paraventricular hypothalamic projection. As with other hypothalamic feeding related peptides, hindbrain sites are likely also important sources and targets of neuromedin anorectic action. Neuromedin increases physical activity in addition to reducing appetite, thus producing a consistent negative energy balance effect. Together with the various other neuro-peptides, -transmitters, -modulators and –hormones, neuromedin and orexin act in the appetite network to produce changes in food intake and energy expenditure, which ultimately influences the regulation of body weight.

Role of the locus coeruleus in enhanced orexin A-induced spontaneous physical activity in obesity-resistant rats

“…Total fat and fat-free mass were measured using a quantitative magnetic resonance body composition analyzer (EchoMRI-900, Houston, TX) (29,47). Animals were weighed and placed in a small cylindrical Plexiglas chamber.…”

Orexin A decreases lipid peroxidation and apoptosis in a novel hypothalamic cell model

“…The orexins (hypocretins) are hypothalamic neuropeptides (orexin A and orexin B; also known as hypocretin-1 and -2) that act on two related G-coupled protein receptors (OxR1 and OxR2) to influence diverse physiological processes such as control of food intake, sleep-wake behavior, arousal, energy balance, and energy expenditure [12, 19, 32, 37]. The most immediate cellular response to orexin receptor activation in both overexpression and in vivo models is increased intracellular Ca 2+ influx, by either protein kinase C-dependent activation or by voltage-gated Ca 2+ receptors [2, 3].…”

“…SPA effects on OR and weight gain depend in part upon OxA signaling in the rostral lateral hypothalamus (rLH) [44]. OxA promotes SPA when injected into rLH, and rats with higher OxA responsiveness have higher gene expression levels for OxA receptors [32, 42, 44]. At present the intracellular signaling mechanisms through which OxA might mediate short- or long-term changes in SPA and OR are unknown.…”

<i>p</i>-Synephrine: A Novel Agonist for Neuromedin U2 Receptor

“…nisms and physiological roles of NMU system in the brain. 16) NMU2R played an essential role in the regulation of food intake and energy homeostasis, [17][18][19] and had been proposed to be an important CNS target of metabolic diseases such as eating disorders, obesity, and type 2 diabetes. 19,20) However, the existing NMU analogs, antibodies, and small interfering RNAs had limited clinical value due to their poor pharmacokinetic properties.…”