PubMed · 16251053
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Shi-liang Shen, Gregory S Barsh, Zhong-bi Wu. 2005. [Attractin].. https://pubmed.ncbi.nlm.nih.gov/16251053/
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A number of different neuropeptides exert powerful concerted controls on feeding behavior and energy balance, most of them being produced in hypothalamic neuronal networks under stimulation by anabolic and catabolic peripheral hormones such as ghrelin and leptin, respectively. These peptide-expressing neurons interconnect extensively to integrate the multiple opposing signals that mediate changes in energy expenditure. In the present review I have summarized our current knowledge about two key peptidic systems involved in regulating appetite and energy homeostasis, the melanocortin system (alpha-MSH, agouti and Agouti-related peptides, MC receptors and mahogany protein) and the melanin-concentrating hormone system (proMCH-derived peptides and MCH receptors) that contribute to satiety and feeding-initiation, respectively, with concurrent effects on energy expenditure. I have focused particularly on recent data concerning transgenic mice and the ongoing development of MC/MCH receptor antagonists/agonists that may represent promising drugs to treat human eating disorders on both sides of the energy balance (anorexia, obesity).
The melanocortin system consists of five seven-transmembrane spanning G-protein coupled (GPCRs) receptors (MC1R-MC5R), the endogenous agonists a-, B- and melanocyte stimulating hormone (MSH), adrenocorticotropic hormone (ACTH), and the endogenous antagonists Agouti and Agouti-related protein (AGRP). Melanocortin agonists are involved in the regulation of feeding behavior and weight omeostasis in mammals. Structure-activity relationships (SAR) have been performed on the endogenous melanocortin receptor agonists and antagonists that have identified ligand amino acid residues implicated as important for receptor binding and stimulation. Knowledge of putative ligand-receptor interactions may help to design molecules as therapeutic agents for the treatment of physiological diseases.
Studies of mammalian pigmentation have identified many genes involved in the development, migration, and function of melanocytes. Molecular and biochemical mechanisms that switch melanocytes between the production of eumelanin or pheomelanin involve the opposing action of two signaling molecules, alpha-Melanocyte Stimulating Hormone (alphaMSH) and Agouti Signal Protein (ASP). AlphaMSH affects various aspects of melanocyte behavior, stimulating melanocyte dendricity, attachment to extracellular matrix proteins, but also up-regulating the expression of eumelanogenic genes. In response to ASP, melanocytes switch from producing eumelanin to pheomelanin concomitant with the down-regulation of melanogenic genes transcription. Since activation of signaling pathways leads to mRNA expression, microarray technology can provide a quantitative assessment of the consequences of this activation. Significant up/down regulation of all known melanogenic genes by alphaMSH/ASP in cultured melanocytes has been previously reported. We have now used the cDNA microarray technique to screen alphaMSH-treated melanocytes to identify genes that are transcriptionally enhanced by this factor. We report the melanocytic expression and alphaMSH up-regulation of 11 genes spanning 7 functional categories such as apoptosis, body weight control, intracellular transport, signal transduction, oncogenic transformation, transcription factors and genes coding for keratin associated proteins.