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Agouti Gene

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Richard P. Woychik – One of the best experts on this subject based on the ideXlab platform.

  • Liver-specific expression of the Agouti Gene in transgenic mice promotes liver carcinoGenesis in the absence of obesity and diabetes
    Molecular cancer, 2004
    Co-Authors: Alexander Kuklin, R. L. Mynatt, Richard P. Woychik, Mitchell L. Klebig, William O. Wilkison, Laura L. Kiefer, Edward J Michaud
    Abstract:

    Background The Agouti protein is a paracrine factor that is normally present in the skin of many species of mammals. Agouti regulates the switch between black and yellow hair pigmentation by signalling through the melanocortin 1 receptor (Mc1r) on melanocytes. Lethal yellow (Ay) and viable yellow (Avy) are dominant regulatory mutations in the mouse Agouti Gene that cause the wild-type protein to be produced at abnormally high levels throughout the body. Mice harboring these mutations exhibit a pleiotropic syndrome characterized by yellow coat color, obesity, hyperglycemia, hyperinsulinemia, and increased susceptibility to hyperplasia and carcinoGenesis in numerous tissues, including the liver. The goal of this research was to determine if ectopic expression of the Agouti Gene in the liver alone is sufficient to recapitulate any aspect of this syndrome. For this purpose, we Generated lines of transgenic mice expressing high levels of Agouti in the liver under the regulatory control of the albumin promoter. Expression levels of the Agouti transGene in the liver were quantified by Northern blot analysis. Functional Agouti protein in the liver of transgenic mice was assayed by its ability to inhibit binding of the α-melanocyte stimulating hormone (αMSH) to the Mc1r. Body weight, plasma insulin and blood glucose levels were analyzed in control and transgenic mice. Control and transgenic male mice were given a single intraperitoneal injection (10 mg/kg) of the hepatocellular carcinogen, diethylnitrosamine (DEN), at 15 days of age. Mice were euthanized at 36 or 40 weeks after DEN injection and the number of tumors per liver and total liver weights were recorded.

  • The Role of the Agouti Gene in the Yellow Obese Syndrome
    Journal of Nutrition, 1997
    Co-Authors: R. J. Miltenberger, R. L. Mynatt, John E. Wilkinson, Richard P. Woychik
    Abstract:

    The yellow obese syndrome in mice encompasses many pleiotropic effects including yellow fur, maturity-onset obesity, hyperinsulinemia, insulin resistance, hyperglycemia, increased skeletal length and lean body mass, and increased susceptibility to neoplasia. The molecular basis of this syndrome is beginning to be unraveled and may have implications for human obesity and diabetes. Normally, the Agouti Gene is expressed during the hair-growth cycle in the neonatal skin where it functions as a paracrine regulator of pigmentation. The secreted Agouti protein antagonizes the binding of the alpha-melanocyte-stimulating hormone to its receptor (melanocortin 1 receptor) on the surface of hair bulb melanocytes, causing alterations in intracellular cAMP levels. Widespread, ectopic expression of the mouse Agouti Gene is central to the yellow obese phenotype, as demonstrated by the molecular cloning of several dominant Agouti mutations and the ubiquitous expression of the wild-type Agouti Gene in transgenic mice. Recent experiments have revealed that the hypothalamus and adipose tissue are biologically active target sites for Agouti in the yellow obese mutant lines.

  • Combined effects of insulin treatment and adipose tissue-specific Agouti expression on the development of obesity
    Proceedings of the National Academy of Sciences of the United States of America, 1997
    Co-Authors: R. L. Mynatt, Michael B. Zemel, R. J. Miltenberger, Mitchell L. Klebig, John E. Wilkinson, William O. Wilkison, Richard P. Woychik
    Abstract:

    The Agouti Gene product is a secreted protein that acts in a paracrine manner to regulate coat color in mammals. Several dominant mutations at the Agouti locus in mice cause the ectopic, ubiquitous expression of Agouti, resulting in a condition similar to adult-onset obesity and non-insulin-dependent diabetes mellitus. The human Agouti protein is 85% homologous to mouse Agouti; however, unlike the mouse Agouti Gene, human Agouti is normally expressed in adipose tissue. To address whether expression of Agouti in human adipose tissue is physiologically relevant, transgenic mice were Generated that express Agouti in adipose tissue. Similar to most humans, these mice do not become obese or diabetic. However, we found that daily insulin injections significantly increased weight gain in the transgenic lines expressing Agouti in adipose tissue, but not in nontransgenic mice. These results suggest that insulin triggers the onset of obesity and that Agouti expression in adipose tissue potentiates this effect. Accordingly, the investigation of Agouti’s role in obesity and non-insulin-dependent diabetes mellitus in mice holds significant promise for understanding the pathophysiology of human obesity.

Gregory S. Barsh – One of the best experts on this subject based on the ideXlab platform.

  • Characterization of the dog Agouti Gene and a nonAgoutimutation in German Shepherd Dogs
    Mammalian Genome, 2004
    Co-Authors: Julie A. Kerns, J. Newton, Tom G. Berryere, Edward M. Rubin, Jan-fang Cheng, Sheila M. Schmutz, Gregory S. Barsh
    Abstract:

    The interaction between two Genes, Agouti and Melanocortin-1 receptor ( Mc1r ), produces diverse pigment patterns in mammals by regulating the type, amount, and distribution pattern of the two pigment types found in mammalian hair: eumelanin (brown/black) and pheomelanin (yellow/red). In domestic dogs ( Canis familiaris ), there is a tremendous variation in coat color patterns between and within breeds; however, previous studies suggest that the molecular Genetics of pigment-type switching in dogs may differ from that of other mammals. Here we report the identification and characterization of the Agouti Gene from domestic dogs, predicted to encode a 131-amino-acid secreted protein 98% identical to the fox homolog, and which maps to chromosome CFA24 in a region of conserved linkage. Comparative analysis of the Doberman Pinscher Agouti cDNA, the fox cDNA, and 180 kb of Doberman Pinscher genomic DNA suggests that, as with laboratory mice, different pigment-type-switching patterns in the canine family are controlled by alternative usage of different promoters and untranslated first exons. A small survey of Labrador Retrievers, Greyhounds, Australian Shepherds, and German Shepherd Dogs did not uncover any polymorphisms, but we identified a single nucleotide variant in black German Shepherd Dogs predicted to cause an Arg-to-Cys substitution at codon 96, which is likely to account for recessive inheritance of a uniform black coat.

  • characterization of the dog Agouti Gene and a nonAgouti mutation in german shepherd dogs
    Mammalian Genome, 2004
    Co-Authors: Julie A. Kerns, Tom G. Berryere, Edward M. Rubin, Jan-fang Cheng, Sheila M. Schmutz, J M Newton, Gregory S. Barsh
    Abstract:

    The interaction between two Genes, Agouti and Melanocortin-1 receptor (Mc1r), produces diverse pigment patterns in mammals by regulating the type, amount, and distribution pattern of the two pigment types found in mammalian hair: eumelanin (brown/black) and pheomelanin (yellow/red). In domestic dogs (Canis familiaris), there is a tremendous variation in coat color patterns between and within breeds; however, previous studies suggest that the molecular Genetics of pigment-type switching in dogs may differ from that of other mammals. Here we report the identification and characterization of the Agouti Gene from domestic dogs, predicted to encode a 131-amino-acid secreted protein 98% identical to the fox homolog, and which maps to chromosome CFA24 in a region of conserved linkage. Comparative analysis of the Doberman Pinscher Agouti cDNA, the fox cDNA, and 180 kb of Doberman Pinscher genomic DNA suggests that, as with laboratory mice, different pigment-type-switching patterns in the canine family are controlled by alternative usage of different promoters and untranslated first exons. A small survey of Labrador Retrievers, Greyhounds, Australian Shepherds, and German Shepherd Dogs did not uncover any polymorphisms, but we identified a single nucleotide variant in black German Shepherd Dogs predicted to cause an Arg-to-Cys substitution at codon 96, which is likely to account for recessive inheritance of a uniform black coat.

  • Differential spontaneous transformation in vitro of newly established mouse fibroblast lines carrying or lacking the viable yellow mutation (Avy) of the mouse Agouti locus.
    Molecular carcinogenesis, 1996
    Co-Authors: Wen-luang Wendy Hsiao, Gregory S. Barsh, Michael Martin Ollmann, George L. Wolff, Beverly M. North, Hung Fan
    Abstract:

    The pleiotropic effects of the viable yellow mutation (Avy), an allele of the mouse Agouti coat-color locus, include increased susceptibility to spontaneous and chemically induced tumors that affect a wide variety of tissues. As a first step toward understanding the molecular basis of this phenomenon, we established permanent fibroblast-like cell lines from newborn Avy/a and control congenic a/a mice and compared their growth characteristics in vitro. From the VY/WffC3Hf/Nctr and YS/WffCH3f/Nctr-Avy inbre strains, each of which carries the Avy allele on a congenic background, 38 clonal Avy/a and 16 clonal a/a lines were established. Regardless of inbred strain, all Avy/a cell lines exhibited a significant degree of spontaneous transformation, as assessed by focus formation in monolayer culture, whereas none of the a/a cell lines formed foci in prolonged cultures. To test whether changes in dosage of the Avy- or a-bearing chromosomes were related to these events, we analyzed each cell line with a closely linked molecular probe from the Emv-15 locus, which in the VY strain detects a restriction fragment length variant (RFLV) informative for the Avy- and a-bearing chromosomes. Most of the transformed foci maintained heterozygosity for RFLVs detected by the probe, but two of the transformants lost the a-associated RFLV, and at least one of the transformants exhibited amplification of the Avy-associated RFLV. When the transformants were analyzed with 5′ sequences derived from the recently cloned Agouti Gene, three of eight transformants lost the a-associated RFLV, and two of the transformants showed amplification of the Avy-associated RFLV. Reverse trantranscriptasepolymerase chain reaction assays indicated that Agouti RNA was detected in Avy/a, not a/a cell lines. Surprisingly, some of the Avy/a transformants lacked Agouti RNA. These results suggest that deregulated expression of the Avy allele is required for the initiation but not for the maintenance of transformation of the Avy/a cell cultures. These cell lines may provide an in vitro culture system for studying the effect of the Agouti Gene on tumorigenicity as well as to potentially study other pleiotropic phenotypes.

Edward J Michaud – One of the best experts on this subject based on the ideXlab platform.

  • Liver-specific expression of the Agouti Gene in transgenic mice promotes liver carcinoGenesis in the absence of obesity and diabetes
    Molecular cancer, 2004
    Co-Authors: Alexander Kuklin, R. L. Mynatt, Richard P. Woychik, Mitchell L. Klebig, William O. Wilkison, Laura L. Kiefer, Edward J Michaud
    Abstract:

    Background The Agouti protein is a paracrine factor that is normally present in the skin of many species of mammals. Agouti regulates the switch between black and yellow hair pigmentation by signalling through the melanocortin 1 receptor (Mc1r) on melanocytes. Lethal yellow (Ay) and viable yellow (Avy) are dominant regulatory mutations in the mouse Agouti Gene that cause the wild-type protein to be produced at abnormally high levels throughout the body. Mice harboring these mutations exhibit a pleiotropic syndrome characterized by yellow coat color, obesity, hyperglycemia, hyperinsulinemia, and increased susceptibility to hyperplasia and carcinoGenesis in numerous tissues, including the liver. The goal of this research was to determine if ectopic expression of the Agouti Gene in the liver alone is sufficient to recapitulate any aspect of this syndrome. For this purpose, we Generated lines of transgenic mice expressing high levels of Agouti in the liver under the regulatory control of the albumin promoter. Expression levels of the Agouti transGene in the liver were quantified by Northern blot analysis. Functional Agouti protein in the liver of transgenic mice was assayed by its ability to inhibit binding of the α-melanocyte stimulating hormone (αMSH) to the Mc1r. Body weight, plasma insulin and blood glucose levels were analyzed in control and transgenic mice. Control and transgenic male mice were given a single intraperitoneal injection (10 mg/kg) of the hepatocellular carcinogen, diethylnitrosamine (DEN), at 15 days of age. Mice were euthanized at 36 or 40 weeks after DEN injection and the number of tumors per liver and total liver weights were recorded.

  • upregulation of adipocyte metabolism by Agouti protein possible paracrine actions in yellow mouse obesity
    American Journal of Physiology-endocrinology and Metabolism, 1996
    Co-Authors: Brynn H Jones, Michael B. Zemel, Richard P. Woychik, William O. Wilkison, Edward J Michaud, Jung Han Kim, N. Moustaid
    Abstract:

    Mutations leading to ectopic expression of the murine Agouti Gene (a) result in progressive obesity. To further characterize this model, we analyzed adipose and hepatic mRNA levels for fatty acid s…

  • Upregulation of adipocyte metabolism by Agouti protein: possible paracrine actions in yellow mouse obesity
    American Journal of Physiology-Endocrinology and Metabolism, 1996
    Co-Authors: Brynn H Jones, Michael B. Zemel, Richard P. Woychik, William O. Wilkison, Edward J Michaud, Jung Han Kim, N. Moustaid
    Abstract:

    Mutations leading to ectopic expression of the murine Agouti Gene (a) result in progressive obesity. To further characterize this model, we analyzed adipose and hepatic mRNA levels for fatty acid synthase (FAS) and stearoyl-CoA desaturase (SCD), two key enzymes in de novo fatty acid synthesis and desaturation, respectively. FAS and SCD mRNA in both tissues of obese (Avy) mice were dramatically increased relative to lean (ala) controls. Excessive expression of these Genes in this model could be due to direct effects of the Agouti Gene product; to test this possibility we treated 3T3-L1 adipocytes in vitro with recombinant Agouti protein. Agouti treatment increased FAS and SCD mRNA levels by 1.5- and 4-fold, respectively. In addition, FAS activity and triglyceride content were 3-fold higher in Agoutitreated 3T3-L1 cells relative to controls; these effects were attenuated by simultaneous treatment with a calcium channel blocker (nitrendipine). These data demonstrate that the Agouti protein can directly increase lipoGenesis in adipocytes and suggest that these effects are mediated through an intracellular calcium-dependent mechanism.

William O. Wilkison – One of the best experts on this subject based on the ideXlab platform.

  • Liver-specific expression of the Agouti Gene in transgenic mice promotes liver carcinoGenesis in the absence of obesity and diabetes
    Molecular cancer, 2004
    Co-Authors: Alexander Kuklin, R. L. Mynatt, Richard P. Woychik, Mitchell L. Klebig, William O. Wilkison, Laura L. Kiefer, Edward J Michaud
    Abstract:

    Background The Agouti protein is a paracrine factor that is normally present in the skin of many species of mammals. Agouti regulates the switch between black and yellow hair pigmentation by signalling through the melanocortin 1 receptor (Mc1r) on melanocytes. Lethal yellow (Ay) and viable yellow (Avy) are dominant regulatory mutations in the mouse Agouti Gene that cause the wild-type protein to be produced at abnormally high levels throughout the body. Mice harboring these mutations exhibit a pleiotropic syndrome characterized by yellow coat color, obesity, hyperglycemia, hyperinsulinemia, and increased susceptibility to hyperplasia and carcinoGenesis in numerous tissues, including the liver. The goal of this research was to determine if ectopic expression of the Agouti Gene in the liver alone is sufficient to recapitulate any aspect of this syndrome. For this purpose, we Generated lines of transgenic mice expressing high levels of Agouti in the liver under the regulatory control of the albumin promoter. Expression levels of the Agouti transGene in the liver were quantified by Northern blot analysis. Functional Agouti protein in the liver of transgenic mice was assayed by its ability to inhibit binding of the α-melanocyte stimulating hormone (αMSH) to the Mc1r. Body weight, plasma insulin and blood glucose levels were analyzed in control and transgenic mice. Control and transgenic male mice were given a single intraperitoneal injection (10 mg/kg) of the hepatocellular carcinogen, diethylnitrosamine (DEN), at 15 days of age. Mice were euthanized at 36 or 40 weeks after DEN injection and the number of tumors per liver and total liver weights were recorded.

  • Regulation of the Melanocortin Receptors by Agouti
    The Melanocortin Receptors, 2000
    Co-Authors: William O. Wilkison
    Abstract:

    The melanocortin family of receptors has been implicated in the regulation of a number of physiologic systems. Despite the cloning and characterization of these receptors, little is known about their regulation. I will summarize in this chapter what is known about a novel regulator of melanocortin receptor activity, the Agouti Gene product. Not only does the action of Agouti on these receptors explain or clarify the physiologic role of some of these receptors, Agouti function and regulation also imparts new possibilities for these receptors having a role in processes such as energy homeostasis.

  • The Agouti Gene product stimulates pancreatic β-cell Ca2+ signaling and insulin release
    Physiological genomics, 1999
    Co-Authors: Bingzhong Xue, R. L. Mynatt, William O. Wilkison, N. Moustaid, M. Goldman, Michael B. Zemel
    Abstract:

    Xue, B. Z., W. O. Wilkison, R. L. Mynatt, N. Moustaid, M. Goldman, and M. B. Zemel. The Agouti Gene product stimulates pancreatic β-cell Ca2+ signaling and insulin release. Physiol. Genomics 1: 11-…

George L. Wolff – One of the best experts on this subject based on the ideXlab platform.

  • Maternal methyl supplements in mice affect epiGenetic variation and DNA methylation of offspring.
    The Journal of nutrition, 2002
    Co-Authors: Craig A Cooney, Apurva A Dave, George L. Wolff
    Abstract:

    This study was designed to determine if maternal dietary methyl supplements increase DNA methylation and methylation-dependent epiGenetic phenotypes in mammalian offspring. Female mice of two strains were fed two levels of dietary methyl supplement or control diet prior to and during pregnancy. Offspring of these mice vary in phenotype, which is epiGenetically determined and affects health and 2-y survival. Phenotype and DNA methylation of a long terminal repeat (LTR) controlling expression of the Agouti Gene were assayed in the resulting offspring. Methyl supplements increase the level of DNA methylation in the Agouti LTR and change the phenotype of offspring in the healthy, longer-lived direction. This shows that methyl supplements have strong effects on DNA methylation and phenotype and are likely to affect long-term health. Optimum dietary supplements for the health and longevity of offspring should be intensively investigated. This should lead to public policy guidance that teaches optimal, rather than minimal, dose levels of maternal supplements.

  • Physiological consequences of ectopic Agouti Gene expression: the yellow obese mouse syndrome
    Physiological genomics, 1999
    Co-Authors: George L. Wolff, Dean W. Roberts, Kathleen G. Mountjoy
    Abstract:

    Wolff, George L., Dean W. Roberts, and Kathleen G. Mountjoy. Physiological consequences of ectopic Agouti Gene expression: the yellow obese mouse syndrome. Physiol. Genomics 1: 151–163, 1999.—This …

  • maternal epiGenetics and methyl supplements affect Agouti Gene expression in avy a mice
    The FASEB Journal, 1998
    Co-Authors: George L. Wolff, Ralph L Kodell, Stephen R Moore, Craig A Cooney
    Abstract:

    ‘Viable yellow’ (Avy/a) mice are larger, obese, hyperinsulinemic, more susceptible to cancer, and, on average, shorter lived than their non-yellow siblings. They are epiGenetic mosaics ranging from a yellow phenotype with maximum ectopic Agouti overexpression, through a continuum of mottled Agouti/yellow phenotypes with partial Agouti overexpression, to a pseudoAgouti phenotype with minimal ectopic expression. PseudoAgouti Avy/a mice are lean, healthy, and longer lived than their yellow siblings. Here we report that feeding pregnant black a/a dams methyl-supplemented diets alters epiGenetic regulation of Agouti expression in their offspring, as indicated by increased Agouti/black mottling in the direction of the pseudoAgouti phenotype. We also present confirmatory evidence that epiGenetic phenotypes are maternally heritable. Thus Avy expression, already known to be modulated by imprinting, strain-specific modification, and maternal epiGenetic inheritance, is also modulated by maternal diet. These observations suggest, at least in this special case, that maternal dietary supplementation may positively affect health and longevity of the offspring. Therefore, this experimental system should be useful for identifying maternal factors that modulate epiGenetic mechanisms, especially DNA methylation, in developing embryos.