Characterization of the sea bass melanocortin 5 receptor: a putative role in hepatic lipid metabolism

Abstract

SUMMARYThe melanocortin 5 receptor (MC5R) plays a key role in the regulation of exocrine secretion in mammalian species. This receptor has also been characterized in some fish species but its function is unknown. We report the molecular and pharmacological characterization, as well as the tissue expression pattern, of sea bass MC5R. Cloning of five active alleles showing different levels of sensitivity to endogenous melanocortin and one non-functional allele demonstrate the allelic complexity of the MC5R locus. The sea bass receptor was activated by all the melanocortins tested, with ACTH and desacetyl-MSH and -MSH showing the lowest efficiency. The acetylation of the MSH isoforms seems to be critical for the effectiveness of the agonist. Agouti-related protein had no effect on basal or agonist-stimulated activation of the receptor. SbMC5R was mainly expressed in the brain but lower expression levels were found in several peripheral tissues, including liver. Progressive fasting did not induce up-or downregulation of hypothalamic MC5R expression, suggesting that central MC5R is not involved in the regulation of food intake in the sea bass. MTII, a sbMC5R agonist, stimulated hepatic lipolysis in vitro, measured as free fatty acid release into the culture medium after melanocortin agonist exposure of liver fragments, suggesting that MC5R is involved in the regulation of hepatic lipid metabolism. Taken together, the data suggest that different allelic combinations may confer differential sensitivity to endogenous melanocortin in tissues where MC5R is expressed and, by extension, in hepatic lipid metabolism.

Multifunctional Roles of Melanocyte-Stimulating Hormone and Melanin-Concentrating Hormone in Fish: Evolution from Classical Body Color Change

“…Similar potentiating pigmentation-related functions have also been observed in frogs and rats (Kawauchi et al 1984;Eberle 1988;Cangemi et al 1995). Pharmacological studies on sea bass MC5R have revealed a higher efficacy of α-MSH than of Des-Ac-α-MSH to stimulate cellular activities (Sanchez et al 2009). These results together with the high sequence identity observed between flounder MC5R and sea bass MC5R suggest that this receptor may exhibit similar binding affinities for α-MSHrp in the two species.…”

Fish melanocortin system

“…We have demonstrated that melanocortin MC 5 receptor is highly expressed within the ventral skin but not in the dorsal skin of the sea bass (Sánchez et al, 2009b). Similarly, goldfish melanocortin MC 5 receptor is also expressed in the skin despite the lack of differentiation between dorsal and ventral areas (Cerdá-Reverter et al, 2003b).…”

“…Experiments in goldfish (Cerdá-Reverter and Peter 2003) and zebrafish (Song et al, 2003) demonstrated that hypothalamic AGRP expression is dramatically increased during fasting at the same time intervals in which POMC expression remains constant. Our pharmacological experiments in goldfish and sea bass melanocortin receptors have demonstrated that zebrafish AGRP (83-127) is a potent competitive antagonist at sea bass melanocortin MC 4 receptor (Sánchez et al, 2009a) but not at sea bass melanocortin MC 5 receptor (Sánchez et al, 2009b). The C-terminal fragment of the zebrafish AGRP can also work as an inverse agonist, inhibiting both basal and forskolin-induced melanocortin MC 4 receptor activity (Sánchez et al, 2009a;Sánchez et al, 2010).…”

“…The C-terminal fragment of the zebrafish AGRP can also work as an inverse agonist, inhibiting both basal and forskolin-induced melanocortin MC 4 receptor activity (Sánchez et al, 2009a;Sánchez et al, 2010). (Sánchez et al, 2009b), suggesting that the central melanocortin effects on food intake are mediated via melanocortin MC 4 receptor. In situ hybridization studies in goldfish (Cerdá-Reverter et al, 2003b) and sea bass (Sánchez et al, 2009a) have demonstrated that this receptor is profusely expressed within the CNS.…”

“…This suggests that the melanocortin system plays a dual role in the control of the energy balance by activating peripheral lipolytic activity, thus enhancing energy expenditure, and through the central inhibition of food intake. Experiments in sea bass have demonstrated that MSH can stimulate hepatic lypolisis via sea bass melanocortin MC 5 receptor (Sánchez et al, 2009b) …”