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Neuromedin U (NMU) is a structurally highly conserved neuropeptide and has been paired with the G-protein-coupled receptors (GPCRs) NMUR1 and NMUR2, which were formerly classified in the orphan receptor family. Activation of the G protein Gq/11 subunit causes a pertussis toxin (PTX)-insensitive activation of both phospholipase C and mitogen-activated protein kinase (MAP), and activation of the Go subunit causes a PTX-sensitive inhibition of adenyl cyclase. Additionally, NMU selectively inhibits L-type high-voltage-gated Ca2+ channels in mouse hippocampus, as well as low-voltage-activated T-type Ca2+ channels in mouse dorsal root ganglia (DRG). NMU peptide and its receptors are predominantly expressed in the gastrointestinal tract and specific structures within the brain, reflecting its major role in the regulation of energy homeostasis. A novel neuropeptide, neuromedin S (NMS), is structurally related to NMU. They share a C-terminal core structure and both have been implicated in the regulation of food intake, as well as the circadian rhythms. The acute anorectic and weight-reducing effects of NMU and NMS are mediated by NMUR2. This suggests that NMUR2-selective agonists may be useful for the treatment of obesity.

The maintenance of energy homeostasis is achieved with 'detectors' that receive signals from the external and internal environment and with multidirectional 'communication routes' including neuronal networks and body fluids, such as blood and cerebrospinal fluid. Changes in the energy demands of organisms are caused by current physiological status and environmental conditions, including season and food availability. Little is known about the interactions between the metabolic indicators involved in the maintenance of energy homeostasis, e.g., leptin, orexins and ghrelin. Sheep and other seasonal animals are highly adaptable to their environments because of the plasticity of their neural and endocrine systems. Sheep exhibit leptin resistance and are thus an extremely interesting model for research on the relationship between hormonal indicators of energy metabolism. The paper is focused mainly on the anatomical and functional communication between leptin, ghrelin and orexins, which play principal roles in the adaptation of energetic demands to environmental fluctuations. [ABSTRACT FROM AUTHOR]