Melanocortin receptor accessory proteins in adrenal gland physiology and beyond.

The melanocortin receptor (MCR) family consists of five G-protein-coupled receptors (MC1R-MC5R) with diverse physiological roles. MC1R controls pigmentation, MC2R is a critical component of the hypothalamic-pituitary-adrenal axis, MC3R and MC4R have a vital role in energy homeostasis and MC5R is involved in exocrine function. The melanocortin receptor accessory protein (MRAP) and its paralogue MRAP2 are small single-pass transmembrane proteins that have been shown to regulate MCR expression and function. In the adrenal gland, MRAP is an essential accessory factor for the functional expression of the MC2R/ACTH receptor. The importance of MRAP in adrenal gland physiology is demonstrated by the clinical condition familial glucocorticoid deficiency, where inactivating MRAP mutations account for ∼20% of cases. MRAP is highly expressed in both the zona fasciculata and the undifferentiated zone. Expression in the undifferentiated zone suggests that MRAP could also be important in adrenal cell differentiation and/or maintenance. In contrast, the role of adrenal MRAP2, which is highly expressed in the foetal gland, is unclear. The expression of MRAPs outside the adrenal gland is suggestive of a wider physiological purpose, beyond MC2R-mediated adrenal steroidogenesis. In vitro, MRAPs have been shown to reduce surface expression and signalling of all the other MCRs (MC1,3,4,5R). MRAP2 is predominantly expressed in the hypothalamus, a site that also expresses a high level of MC3R and MC4R. This raises the intriguing possibility of a CNS role for the MRAPs.

Cerebellin1 is a novel orexigenic peptide.

AIM: Cerebellin1 (Cbln1) is highly expressed in the hypothalamus, a region of the brain involved in appetite regulation. However, the effects of Cbn1 on food intake are not known. The present study aimed to investigate the effect of Cbln1 on appetite regulation in rats. METHODS: We determined the effect of (i) intracerebroventricular (ICV) injection of Cbln1 on food intake, behaviour and plasma pituitary hormone levels in male Wistar rats; (ii) Cbln1 on the release of hypothalamic neuropeptides known to modulate food intake from hypothalamic explants and (iii) fasting on hypothalamic Cbln1 mRNA expression. RESULTS: (i) ICV administration of Cbln1 significantly increased food intake in rats and caused no adverse behaviours. ICV administration of Cbln1 significantly reduced plasma thyroid stimulating hormone (TSH) levels 10 min postinjection in rats. (ii) Cbln1 significantly increased the release of neuropeptide Y (NPY) from hypothalamic explants. (iii) Cbln1 mRNA expression levels were increased in the ventromedial nucleus of the hypothalamus in fasted rats. CONCLUSIONS: These data suggest that Cbln1 is a novel orexigenic peptide, which may mediate its effects via hypothalamic NPY.