Agouti and Agouti-related Protein: Analogies and Contrasts

Abstract

The discovery a decade ago of the murine agouti gene was intended to bring scientists a step closer to understanding the complexities of mammalian pigmentation. The first obesity gene was also uncovered in the process. What followed was an explosion of major discoveries in murine as well as human obesity and diabetes research. Recently, a new gene, the agouti-related protein (AGRP), 1 was discovered and found to share a striking similarity in structure and function with agouti, although their patterns of distribution are completely different. Identification of a hypothalamic melanocortin receptor, MC4-R, together with AGRP as central components of feeding behavior and metabolism has helped build a picture, albeit incomplete, of the neuronal pathways involved in energy homeostasis. This review will compare and contrast Agouti and AGRP structure and function and gene regulation and their interaction with melanocortin receptors (MC1-R and MC4-R) and suppressors (mahogany/mahoganoid). Agouti and Extension, a Brief Historyagouti and extension were first described several decades ago (1, 2) as the genetic loci that control the relative amount and distribution of eumelanin (brown/black) and phaeomelanin (red/yellow) pigments in the mammalian coat. extension encodes a member (MC1-R) (3) of the melanocortin receptors, a family of G s -coupled receptors, of which five isoforms are presently known (reviewed in Ref. 4). MC1-R is the melanocyte-stimulating hormone receptor expressed in melanocytes and has a physiological role in pigmentation (5). MC4-R is expressed mainly in the brain (6, 7) and has been implicated in the regulation of feeding behavior and metabolism (8). MC3-R is found primarily in the hypothalamic and limbic systems (9); however, no definitive function has been assigned to MC3-R as yet. Melanocortins such as ␣-melanocyte-stimulating hormone (␣-MSH) and adrenocorticotropic hormone (ACTH) are the natural ligands for this family of receptors (␣-MSH for MC1-, MC3-, MC4-, and MC5-R and ACTH for MC2-R). Melanocortins are cleaved from a larger polypeptidic precursor termed pro-opiomelanocortin that is produced in the pituitary gland, hypothalamus, brainstem, and peripheral sites such as skin.Agouti is a paracrine-signaling factor that is secreted by dermal papillae cells, adjacent to melanocytes, and acts within the hair follicle microenvironment to block melanocortin action at the MC1-R (10, 11). Binding of ␣-MSH to the receptor triggers elevation of cAMP levels and activation of tyrosinase, the rate-limiting enzyme of melanogenesis, and results in eumelanin production. In the presence of Agouti the opposite is true; eumelanin synthesis is shut down and the default pathway that has phaeomelanin as the final product is activated. There are now more than 20 dominant, recessive, and pseudoagouti alleles that have been identified in rodent, fox, and cattle, with interesting functional variations from species to species. In rodents agouti is expressed in skin only. In humans, however, agouti has a wider pattern of di...

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