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Agouti-signaling protein

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-Agouti is a gene responsible for the distribution of melanin pigment in mammals<ref>{{cite journal |last1=Silvers |first1=W. K. |last2=Russell |first2=E. S. |title=An experimental approach to action of genes at the agouti locus in the mouse |journal=Journal of Experimental Zoology |date=1955 |volume=130 |pages=199-220}}</ref>. The wild type agouti allele (A) presents a grey phenotype, however, many allele variants have been identified through genetic analyses, which result in a wide range of phenotypes distinct from the typical grey coat<ref name="Bultman">{{cite journal |last1=Bultman |first1=S. J. |last2=Michaud |first2=E. J. |last3=Woychik |first3=R. P. |title=Molecular Characterization of the Mouse Agouti Locus. |journal=Cell |date=1992 |volume=71 |pages=1195-1204}}</ref>. The most widely studied allele variants are the lethal yellow mutation (Ay) and ‘’viable yellow’’ mutation (Avy), caused by ectopic expression of agouti<ref name="Bultman"/>. These are synonymous with the ‘yellow obese syndrome’ which is characterized by early onset obesity, hyperinsulinemia and tumorigenesis<ref name="Bultman"/><ref name="Wolff">{{cite journal |last1=Wolff |first1=G. L. |last2=Roberts |first2=D. W. |last3=Mountjoy |first3=K. G. |title=Physiological consequences of ectopic agouti gene expression: the yellow obese mouse syndrome. |journal=Physiological genomics |date=1999 |volume=1 |issue=3 |pages=151-163}}</ref>.
- [[File:Proposed mechanism for the relationship between ectopic agouti expression and the development of ‘yellow obese mouse syndrome’.jpg|thumb|]]
-===Pigment development===
-The murine agouti gene locus is found on chromosome 2 and encodes a 131 amino acid protein. This protein signals the distribution of melanin pigments in the epithelial melanocytes located at the base of hair follicles<ref name="Mayer">{{cite journal |last1=Mayer |first1=T. C. |last2=Fishbane |first2=J. L. |title=). Mesoderm-Ectoderm Interaction In the Production of the Agouti Pigmentation Pattern in Mice |journal=Genetics |date=1972 |volume=71 |pages=297-303}}</ref>. The type of pigment secreted is determined by mesoderm and ectoderm genotypes at the agouti locus. Expression is more sensitive on ventral hair than dorsal hair<ref name="Melmed">{{cite book |last1=Melmed |first1=S. (Ed) |title=The Pituitary |date=2010 |publisher=Academic Press |location=Cambridge: MA |edition=3rd}}</ref>. The mechanism of agouti expression differs to most genes that affect coat color, as the protein is not directly secreted in the melanocyte, instead, it is secreted as a paracrine factor from the dermal papillae cells to inhibit release of melanocortin<ref name="Miltenberger">{{cite journal |last1=Miltenberger |first1=R. J. |last2=Mynatt |first2=R. L. |last3=Wilkinson |first3=J. E. |last4=Woychik |first4=R. P. |title=The role of the agouti gene in the Yellow Obese Syndrome. |journal=Journal of Nutrition |date=1997 |volume=127 |issue=9 |pages=1902-1907}}</ref>. Melanocortin acts on follicular melanocytes to increase production of eumelanin, a melanin pigment responsible for brown and black hair. However, when agouti is expressed, production of phaeomelanin dominates, another type of melanin pigment that produces yellow or red colored hair<ref name="Lu">{{cite journal |last1=Lu |first1=D. |last2=Willard |first2=D. |last3=Patel |first3=I. R. |last4=Kadwell |first4=S. |last5=Overton |first5=L. |last6=Kost |first6=T. |last7=Luther |first7=M. |last8=Wenbiao |first8=C. |last9=Woychik |first9=R. P. |last10=Wilkison |first10=W. O. |last11=Cone |first11=R. R. |title=Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor |journal=Nature |date=1994 |volume=371 |pages=799-802}}</ref>. The dominance hierarchy of pigment expression explains the evolutionary persistence of the yellow phenotype of agouti, as pheomelanin expression always dominates over eumelanin expression<ref name="Mayer"></ref>.
-===Mutations===
-The lethal yellow mutation (Ay) was the first embryonic mutation to be characterized in mice, as homozygous ‘’lethal yellow’’ mice (Ay/ Ay) die early in development, due to an error in trophectoderm differentiation<ref name="Mayer"></ref>. However, lethal yellow homozygotes are rare today, as ‘’lethal yellow’’ and ‘’viable yellow’’ heterozygotes (Ay/a and Avy/a) persist more commonly. These phenotypes are caused by ectopic expression of the agouti gene and are associated with the ‘yellow obese syndrome’, characterized by early onset obesity, hyperinsulinemia and tumorigenesis<ref name="Mayer">{{cite journal |last1=Mayer |first1=T. C. |last2=Fishbane |first2=J. L. |title=). Mesoderm-Ectoderm Interaction In the Production of the Agouti Pigmentation Pattern in Mice |journal=Genetics |date=1972 |volume=71 |pages=297-303}}</ref>.
-The ‘’lethal yellow’’ (Ay) mutation is due to a deletion upstream to the start site of agouti transcription. The deletion causes the genomic sequence of agouti to be lost, except for the promoter and the first non-encoding exon of ‘’Raly’’, a ubiquitously expressed gene in mammals<ref name="Melmed"/> This leads the coding exons of agouti to be placed under the control of the ‘’Raly’’ promoter, initiating ubiquitous expression of agouti, increasing production of pheomelanin over eumelanin and resulting in the development of a yellow phenotype<ref name="Tollefsbol">{{cite book |last1=Tollefsbol |first1=T. (Ed.) |title=Epigenetics in Human Disease |date=2012 |publisher=Academic Press |location=Cambridge: MA |edition=6}}</ref>. The ‘’viable yellow’’ (Avy) mutation is due to a change in the mRNA length of agouti, as the expressed gene becomes longer than the normal gene length of agouti. This is caused by the insertion of a single intracisternal A particle (IAP) retrotransposon upstream to the start site of agouti transcription<ref name="Dolinoy">{{cite journal |last1=Dolinoy |first1=D. C. |title=The agouti mouse model: an epigenetic biosensor for nutritional and environmental alterations on the fetal epigenome |journal=Nutrition Reviews |date=2008 |volume=66 |issue=1 |pages=7-11}}</ref>. In the proximal end of the gene, an unknown promoter then causes agouti to be constitutionally activated, and individuals to present with phenotypes consistent with the ‘’lethal yellow’’ mutation. Although the mechanism underlying the activation of the promotor controlling the ‘’viable yellow’’ mutation is unknown, the strength of coat color has been correlated with the degree of gene methylation, which is determined by maternal diet and environmental exposure<ref name="Dolinoy" />. Nonetheless, as agouti itself acts as an inhibitor of melanocortin receptors responsible for eumelanin production, the yellow phenotype is exacerbated in both ‘’lethal yellow’’ and ‘’viable yellow’’ mutations.
-‘’Viable yellow’’ (Avy/a) and ‘’lethal yellow’’ (Ay/a) heterozygotes have shortened life spans and increased risks for developing early onset obesity, type II diabetes mellitus and various tumors<ref name="Miltenberger" /><ref name="Spiegelman">{{cite journal |last1=Spiegelman |first1=B. M. |last2=Flier |first2=J. S. |title=Adipogenesis and obesity: rounding up the big picture |journal=Cell |date=1996 |volume=87 |pages=377-389}}</ref>. The mechanisms underlying the increased risks of developing obesity are due to the dysregulation of appetite, as agouti agonizes the agouti-related protein (AGRP), responsible for the stimulation of appetite via hypothalamic NPY/AGRP orexigenic neurons<ref name="Dolinoy" />. Agouti also promotes obesity by antagonizing melanocyte-stimulating hormone (MSH) at the melanocortin receptor (MC4R), as MC4R is responsible for regulating food intake by inhibiting appetite signals<ref name="Adan">{{cite journal |last1=Adan |first1=R. A. H. |last2=Tiesjema |first2=B. |last3=Hillebrand |first3=J. J. G. |last4=la Fleur |first4=S. E. |last5=Kas |first5=M. J. H. |last6=De Krom |first6=M. |title=The MC4 Receptor and Control of Appetite |journal=British Journal of Pharmacology |date=2006 |volume=149 |issue=7 |pages=815-827}}</ref>. The increase in appetite is coupled to alterations in nutrient metabolism due to the paracrine actions of agouti on adipose tissue, increasing levels of hepatic lipogenesis, decreasing levels of lipolysis and increasing adipocyte hypertrophy<ref name="Johnson">{{cite journal |last1=Johnson |first1=P. R. |last2=Hirsch |first2=J. |title=Cellularity of adipose depots in six strains of genetically obese mice. |journal=Obesity Research |date=1972 |volume=7 |issue=5 |pages=506-514}}</ref>. This leads to increased body mass and increased difficulties for weight loss as metabolic pathways are dysregulated. Hyperinsulinemia is caused by mutations to agouti, as the agouti protein functions in a calcium dependent manner to increase insulin secretion in pancreatic beta cells, increasing risks of insulin resistance . Increased tumor formation is due to the increased mitotic rates of agouti, which are localized to epithelial and mesenchymal tissues<ref name="Tollefsbol"/>.
-===Methylation and diet intervention===
-Correct functioning of agouti requires DNA methylation. The methylation mechanism for the ‘’viable yellow’’ mutation occurs in six guanine-cytosine (GC) rich sequences in the 5’ long terminal repeat of the IAP element<ref name="Spiegelman" />. When this area is unmethylated, ectopic expression of agouti occurs, and yellow phenotypes present. However, when the region is methylated, agouti is expressed normally, and grey phenotypes develop. The epigenetic state of the IAP element varies through different methylation densities, as individuals show a wide range of phenotypes based on their degree of DNA methylation<ref name="Spiegelman" />. Increased methylation is correlated with increased expression of the normal agouti gene. Low levels of methylation can also induce gene imprinting. This results in offspring showing consistent phenotypes to their parents, as ectopic expression of agouti is inherited through non-genomic mechanisms<ref name="Dolinoy" /><ref name="Constância">{{cite journal |last1=Constância |first1=M. |last2=Pickard |first2=B. |last3=Kelsey |first3=G. |last4=Reik |first4=W. |title=Imprinting Mechanisms |journal=Genome Research |date=1998 |volume=8 |pages=881-900}}</ref>.
-DNA methylation is determined in utero, by maternal nutrition and environmental exposures<ref name="Spiegelman" />. Methyl is synthesized de novo or attained through the diet, through folic acid, methionine, betaine and choline as components of these nutrients feed into a consistent metabolic pathway for methyl synthesis<ref name="Cooney">{{cite journal |last1=Cooney |first1=C. A. |last2=Dave |first2=A. A. |last3=Wolff |first3=D. L. |title=Maternal Methyl Supplements In Mice Affect Epigenetic Variation and DNA Methylation of Offspring. |journal=Journal of Nutrition |date=2002 |volume=132 |issue=8 |pages=2398-2400}}</ref>. Adequate zinc and vitamin B12 are also required for methyl synthesis as these act as cofactors for transferring methyl groups<ref name="Wilson">{{cite journal |last1=Wilson |first1=B. D. |last2=Ollman |first2=M. M. |last3=Kang |first3=L. |last4=Stoffel |first4=M. |last5=Bell |first5=G. I. |last6=Barsh |first6=G. S. |title=Structure and Function of ASP, the human homolog of the mouse agouti gene. |journal=Human Molecular Genetics |date=1995 |volume=4 |issue=2 |pages=223-230}}</ref>.
-When inadequate methyl is present during early embryonic development, DNA methylation cannot occur, which increases levels of ectopic expression and results in the presentation of the ‘’lethal yellow’’ and ‘’viable yellow’’ phenotypes which persist into adulthood. This leads to the development of the ‘yellow obese syndrome’, which impairs normal development and greatly increases risks for disease development later in life. Therefore, ensuring maternal diets are high in methyl equivalents is a key preventative measure for reducing ectopic expression of agouti in offspring. Diet intervention through methyl supplementation has decreased levels of imprinting at the agouti locus, as with increased consumption of methyl equivalents, the IAP element becomes completely methylated and ectopic expression of agouti is reduced<ref name="Lopez-Calderero">{{cite journal |last1=Lopez-Calderero |first1=I. |last2=Sanchez Chavez |first2=E. |last3=Garcia-Carbonero |first3=R. |title=The insulin-like growth fator pathway as a target for cancer therapy. |journal=Clinical and Translational Oncology |date=2010 |volume=12 |pages=326-338}}</ref>. This lowers the proportion of heterozygotes in offspring which present with a yellow phenotype, and increase offspring that better resemble wild type agouti mice, as they have a grey coat<ref name="Dolinoy" />.
-===The human homologue of agouti, the agouti signaling protein (ASP)===
-Agouti signaling protein (ASP) is the human homologue of murine agouti. It is encoded by the human agouti gene on chromosome 20 and is a 132 amino acid protein. It is expressed more broadly than murine agouti, as it is found in adipose tissue, pancreas, testis and ovary<ref name="Wilson" />. ASP has 85% similarity to the murine form of agouti<ref name="Kwon">{{cite journal |last1=Kwon |first1=H. Y. |last2=Bultman |first2=S. J. |last3=Loffler |first3=C. |last4=Chen |first4=W. J. |last5=Furdon |first5=P. J. |last6=Powell |first6=J. G. |last7=Usala |first7=A. L. |last8=Wilkison |first8=W. |last9=Hansmann |first9=I. |last10=Woychik |first10=R. P. |title=Molecular structure and chromosomal mapping of the human homolog of the agouti gene |journal=Proceedings of the National Academy of Sciences of the United States |date=1994 |volume=91 |issue=21 |pages=9760-9764}}</ref>. As ectopic expression of agouti leads to the development of ‘yellow obese syndrome’ in mice, this is expected in humans<ref name="Kwon" />. The ‘yellow obese syndrome’ increases the development of chronic diseases, including obesity, type II diabetes mellitus and tumorigenesis.
-ASP shows similar pharmacological activation to murine agouti, as it inhibits melanocortin receptors through competitive antagonism. Inhibition of melanocortin by ASP can also be through non-competitive methods, broadening its range of effects<ref name="Tollefsbol"</ref>. ASP does not have the same function as murine agouti. ASP effects the quality of hair pigmentation whereas murine agouti controls the distribution of pigments for the determination of coat color<ref name="Dolinoy" />. ASP also has neuroendocrine functions consistent with murine agouti, as it agonizes AGRP via AGRP neurons in the hypothalamus and antagonizes MSH at MC4Rs decreasing satiety signals. Therefore, as appetite signals increase and satiety signals decrease, body mass increases and individuals are more susceptible to become obese. The mechanism underlying hyperinsulinemia in humans is also consistent with murine agouti, as insulin secretion is heightened through calcium sensitive signaling in pancreatic beta cells. The mechanism for ASP induced tumorigenesis remains unknown in humans.