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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 |doi=10.1002/jez.1401300203}}</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 |doi=10.1016/S0092-8674(05)80067-4}}</ref> The most widely studied allele variants are the ''lethal yellow'' mutation (A<sup>y</sup>) and the ''viable yellow'' mutation (A<sup>vy</sup>) which are caused by ectopic expression of ''agouti''.<ref name="Bultman"/> These mutations 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 |doi=10.1152/physiolgenomics.1999.1.3.151|pmid=11015573}}</ref>
-[[File:Proposed mechanism for the relationship between ectopic agouti expression and the development of ‘yellow obese mouse syndrome’.jpg|thumb|'''Proposed mechanism for the relationship between ectopic ''agouti'' expression and the development of ''yellow obese syndrome''''']]
-===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 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|pmid=4558326|pmc=PMC1212784|url=https://www.genetics.org/content/genetics/71/2/297.full.pdf}}</ref> 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> ''Agouti'' is not directly secreted in the melanocyte as it works as a [[paracrine]] factor on 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 |doi=10.1093/jn/127.9.1902S |pmid=9278579}}</ref> Melanocortin acts on follicular melanocytes to increase production of [[eumelanin]], a melanin pigment responsible for brown and black hair. When ''agouti'' is expressed, production of [[phaeomelanin]] dominates, a 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 |doi=10.1038/371799a0}}</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 (A<sup>y</sup>) was the first embryonic mutation to be characterized in mice, as homozygous ''lethal yellow'' mice (A<sup>y</sup>/ A<sup>y</sup>) die early in development, due to an error in trophectoderm differentiation.<ref name="Mayer"></ref> ''Lethal yellow'' homozygotes are rare today, as ''lethal yellow'' and ''viable yellow'' heterozygotes (A<sup>y</sup>/a and A<sup>vy</sup>/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"/>
-The ''lethal yellow'' (A<sup>y</sup>) mutation is due to an upstream deletion at the start site of ''agouti'' transcription. This deletion causes the genomic sequence of ''agouti'' to be lost, except the promoter and the first non-encoding exon of ''Raly'', a ubiquitously expressed gene in mammals.<ref name="Melmed"/> The coding exons of ''agouti'' are 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'' (A<sup>vy</sup>) 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 |doi=10.1111/j.1753-4887.2008.00056.x |pmc=PMC2822875 |pmid=18673496}}</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 for 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" /> As ''agouti'' itself inhibits melanocortin receptors responsible for eumelanin production, the yellow phenotype is exacerbated in both ''lethal yellow'' and ''viable yellow'' mutations as ''agouti'' gene expression is increased.
-''Viable yellow'' (A<sup>vy</sup>/a) and ''lethal yellow'' (A<sup>y</sup>/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 |doi=10.1016/S0092-8674(00)81359-8 |pmid=8898192}}</ref> The increased risk of developing obesity is 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 |doi=10.1038/sj.bjp.0706929 |pmc=PMC2014686 |pmid=17043670}}</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 |pmid=5059196 |url=http://www.jlr.org/content/13/1/2.full.pdf}}</ref> This increases body mass and leads to difficulties with weight loss as metabolic pathways become 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]].<ref name="Moussa">{{cite journal |last1=Moussa |first1=N. M. |last2=Claycombe |first2=K. J. |title=The Yellow Mouse Obesity Syndrome and Mechanisms of Agouti-Induced Obesity. |journal=Obesity Research |date=1999 |volume=13 |pages=2-11 |doi=10.1002/j.1550-8528.1999.tb00440.x}}</ref> 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. Methylation occurs in six guanine-cytosine (GC) rich sequences in the 5’ long terminal repeat of the IAP element in the ''viable yellow'' mutation.<ref name="Spiegelman" /> When this area is unmethylated, ectopic expression of ''agouti'' occurs, and yellow phenotypes present. When the region is methylated, ''agouti'' is expressed normally, and grey phenotypes develop. The epigenetic state of the IAP element is determined by the level of methylation, 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 induce [[gene imprinting]] which results in offspring displaying 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 |doi=10.1101/gr.8.9.881}}</ref>
-DNA methylation is determined ''in utero'' by maternal nutrition and environmental exposure.<ref name="Spiegelman" /> Methyl is synthesized ''de novo'' but attained through the diet by folic acid, methionine, betaine and choline, as 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 |doi=10.1093/jn/132.8.2393S |pmid=12163699}}</ref> Adequate [[zinc]] and [[vitamin B12]] are required for methyl synthesis as they 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 |doi=10.1093/hmg/4.2.223 |pmid=7757071}}</ref>
-When inadequate methyl is available during early embryonic development, DNA methylation cannot occur, which increases ectopic expression of ''agouti'' 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 increases susceptibility to the development of chronic disease. 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 reduces imprinting at the ''agouti'' locus, as increased methyl consumption causes the IAP element to become completely methylated and ectopic expression of ''agouti'' to be 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 |doi=10.1007/s12094-010-0514-8 |pmid=20466617}}</ref> This lowers the proportion of offspring that present with the yellow phenotype and increases the number offspring that resemble ''agouti'' wild type mice with grey coats.<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, testes and ovaries.<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 |doi=10.1073/pnas.91.21.9760 |pmc=PMC44896 |pmid=7937887}}</ref> As ectopic expression of murine ''agouti'' leads to the development of the ''yellow obese syndrome'', this is expected to be consistent in humans.<ref name="Kwon" /> The ''yellow obese syndrome'' increases the development of many chronic diseases, including obesity, type II diabetes mellitus and tumorigenesis.<ref name="Bultman" />
-ASP has similar pharmacological activation to murine ''agouti'', as melanocortin receptors are inhibited through competitive antagonism.<ref>{{cite book |last1=Takeuchi |first1=S. |title=Handbook of Hormones |date=2015 |publisher=Academic Press |location=Cambridge: MA |pages=66-67}}</ref> Inhibition of melanocortin by ASP can also be through non-competitive methods, broadening its range of effects.<ref name="Tollefsbol"/> The function of ASP differs to murine ''agouti''. ASP effects the quality of hair pigmentation whereas murine ''agouti'' controls the distribution of pigments that determine coat color.<ref name="Dolinoy"/> ASP has neuroendocrine functions consistent with murine ''agouti'', as it agonizes AGRP via AGRP neurons in the hypothalamus and antagonizes MSH at MC4Rs which reduce satiety signals. As appetite signals increase and satiety signals decrease, body mass is likely to increase and individuals are more susceptible to becoming obese. The mechanism underlying hyperinsulinemia in humans is 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.