Agouti - Explore the Science & Experts | ideXlab

Scan Science and Technology

Contact Leading Edge Experts & Companies

Agouti

The Experts below are selected from a list of 13731 Experts worldwide ranked by ideXlab platform

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

  • An Agouti mutation lacking the basic domain induces yellow pigmentation but not obesity in transgenic mice
    Proceedings of the National Academy of Sciences of the United States of America, 1999
    Co-Authors: R. J. Miltenberger, Randall L. Mynatt, Richard P. Woychik, William O. Wilkison, B. D. Bruce, E. J. Michaud

    Abstract:

    Chronic antagonism of melanocortin receptors by the paracrine-acting Agouti gene product induces both yellow fur and a maturity-onset obesity syndrome in mice that ubiquitously express wild-type Agouti. Functional analysis of Agouti mutations in transgenic mice indicate that the cysteine-rich C terminus, signal peptide, and glycosylation site are required for Agouti activity in vivo. In contrast, no biological activity has been ascribed to the conserved basic domain. To examine the functional significance of the Agouti basic domain, the entire 29-aa region was deleted from the Agouti cDNA, and the resulting mutation (AgoutiΔbasic) was expressed in transgenic mice under the control of the β-actin promoter (BAPaΔbasic). Three independent lines of BAPaΔbasic transgenic mice all developed some degree of yellow pigment in the fur, indicating that the AgoutiΔbasic protein was functional in vivo. However, none of the BAPaΔbasic transgenic mice developed completely yellow fur, obesity, hyperinsulinemia, or hyperglycemia. High levels of AgoutiΔbasic expression in relevant tissues exceeded the level of Agouti expression in obese viable yellow mice, suggesting that suboptimal activity or synthesis of the AgoutiΔbasic protein, rather than insufficient RNA synthesis, accounts for the phenotype of the BAPaΔbasic transgenic mice. These findings implicate a functional role for the Agouti basic domain in vivo, possibly influencing the biogenesis of secreted Agouti protein or modulating protein–protein interactions that contribute to effective antagonism of melanocortin receptors.

  • 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, R. J. Miltenberger, Mitchell L. Klebig, Michael B. Zemel, 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.

  • Molecular Pharmacology of Agouti Protein in Vitro and in Vivo
    Annals of the New York Academy of Sciences, 2006
    Co-Authors: Gregory S. Barsh, Michael Martin Ollmann, Brent D Wilson, Kimberly A. Miller, Teresa M. Gunn

    Abstract:

    Agouti protein and Agouti-related protein (Agrp) are paracrine signaling molecules that act by antagonizing the effects of melanocortins, and several alternatives have been proposed to explain their mechanisms of action. Genetic crosses in a sensitized background uncover a phenotypic difference between overexpression of Agouti and loss of Mc1r function, demonstrate that a functional Mc1r is required for the pigmentary effects of Agouti, and suggest that Agouti protein can act as an agonist of the Mc1r in a way that differs from alpha-MSH stimulation. In vitro, Agouti protein inhibits melanocortin action by two mechanisms: competitive antagonism that depends on the carboxyterminus of the protein, and downregulation of melanocortin receptor signaling that depends on the aminoterminus. Our findings provide evidence of a novel signaling mechanism whereby alpha-MSH and Agouti protein function as independent ligands that inhibit each other’s binding and transduce opposite signals through a single receptor.

  • Association of an Agouti allele with fawn or sable coat color in domestic dogs
    Mammalian Genome, 2005
    Co-Authors: Tom G. Berryere, Gregory S. Barsh, Julie A. Kerns, Sheila M. Schmutz

    Abstract:

    The type of pigment synthesized in mammalian hair, yellow–red pheomelanin or black–brown eumelanin, depends on the interaction between Agouti protein and the Melanocortin 1 receptor. Although the genetics of pigmentation is broadly conserved across most mammalian species, pigment type-switching in domestic dogs is unusual because a yellow–tan coat with variable amounts of dark hair is thought to be caused by an allele of the Agouti locus referred to as fawn or sable ( a ^ y ). In a large survey covering thirty seven breeds, we identified an Agouti allele with two missense alterations, A82S and R83H, which was present (heterozygous or homozygous) in 41 dogs (22 breeds) with a fawn or sable coat, but was absent from 16 dogs (8 breeds) with a black-and-tan or tricolor phenotype. In an additional 33 dogs (14 breeds) with a eumelanic coat, 8 (German Shepherd Dogs, Groenendaels, Schipperkes, or Shetland Sheepdogs) were homozygous for a previously reported mutation, non-Agouti R96C; the remainder are likely to have carried dominant black, which is independent of and epistatic to Agouti . This work resolves some of the complexity in dog coat color genetics and provides diagnostic opportunities and practical guidelines for breeders.

  • Induction of brain-region-specific forms of obesity by Agouti.
    The Journal of Neuroscience, 2004
    Co-Authors: Martien J H Kas, Gregory S. Barsh, Birgitte Tiesjema, Gertjan Van Dijk, Keith M. Garner, Olivier Ter Brake, Joost Verhaagen, Roger A.h. Adan

    Abstract:

    Disruption of melanocortin (MC) signaling, such as by ectopic Agouti overexpression, leads to an obesity syndrome with hyperphagia, obesity, and accelerated body weight gain during high-fat diet. To investigate where in the brain disruption of MC signaling results in obesity, long-term Agouti expression was induced after local injections of recombinant adeno-associated viral particles in selected brain nuclei of adult rats. Agouti expression in the paraventricular nucleus, a hypothalamic region with a high density of MC receptors, induced acute onset hyperphagia and rapid weight gain that persisted for at least 6 weeks. In contrast, obesity and hyperphagia developed with a 3 week delay when Agouti was expressed in the dorsal medial hypothalamus. Agouti expression in the lateral hypothalamus (LH) did not affect food intake and body weight during regular diet, despite the presence of MC receptors in this region. However, during exposure to a high-fat diet, animals with Agouti expression in the LH exhibited a marked increase in body weight. Here we show that the LH is important for the protection against diet-induced obesity by controlling caloric intake during consumption of a high-fat diet. Together, this study provides evidence that different aspects of the Agouti-induced obesity syndrome, such as hyperphagia and diet responsiveness, are mediated by distinct brain regions and opens challenging opportunities for further understanding of pathophysiological processes in the development of the obesity syndrome.

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

  • Interactions of alpha-melanotropin and Agouti on B16 melanoma cells: evidence for inverse agonism of Agouti.
    Journal of Receptors and Signal Transduction, 2009
    Co-Authors: Walter Siegrist, William O. Wilkison, Roma Drozdz, Renato Cotti, Derril H. Willard, Alex N. Eberle

    Abstract:

    Abstractα-Melanocyte-stimulating hormone (α-MSH, α-melanotropin) and Agouti control the switch between eumelanin and pheomelanin synthesis in mammalian melanocytes. Here we investigated interactions between α-MSH, Agouti protein, cAMP elevating agents and phorbol ester on mouse B16 melanoma cells. Agouti (Kd 3.7nmol/l) and α-MSH (Kd 2.3 nmol/l) had similar affinities to the MC1 melanocortin receptor. Both α-MSH and Agouti induced MC1 receptor down-regulation. Agouti antagonized melanogenesis induced by α-MSH, forskolin, cholera toxin (CT), and pertussis toxin (PT). It also reduced the constitutive melanin formation of long-term cultures. Cell proliferation was inhibited by Agouti (43% at 100 nM). This effect was reversed by α-MSH, forskolin, or CT. B16-G4F cells, a cell variant that lacks the MC1 receptor, did not respond to Agouti. From these results we conclude that Agouti shows the characteristics of an inverse agonist acting through the MC1 receptor.

  • 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.

  • An Agouti mutation lacking the basic domain induces yellow pigmentation but not obesity in transgenic mice
    Proceedings of the National Academy of Sciences of the United States of America, 1999
    Co-Authors: R. J. Miltenberger, Randall L. Mynatt, Richard P. Woychik, William O. Wilkison, B. D. Bruce, E. J. Michaud

    Abstract:

    Chronic antagonism of melanocortin receptors by the paracrine-acting Agouti gene product induces both yellow fur and a maturity-onset obesity syndrome in mice that ubiquitously express wild-type Agouti. Functional analysis of Agouti mutations in transgenic mice indicate that the cysteine-rich C terminus, signal peptide, and glycosylation site are required for Agouti activity in vivo. In contrast, no biological activity has been ascribed to the conserved basic domain. To examine the functional significance of the Agouti basic domain, the entire 29-aa region was deleted from the Agouti cDNA, and the resulting mutation (AgoutiΔbasic) was expressed in transgenic mice under the control of the β-actin promoter (BAPaΔbasic). Three independent lines of BAPaΔbasic transgenic mice all developed some degree of yellow pigment in the fur, indicating that the AgoutiΔbasic protein was functional in vivo. However, none of the BAPaΔbasic transgenic mice developed completely yellow fur, obesity, hyperinsulinemia, or hyperglycemia. High levels of AgoutiΔbasic expression in relevant tissues exceeded the level of Agouti expression in obese viable yellow mice, suggesting that suboptimal activity or synthesis of the AgoutiΔbasic protein, rather than insufficient RNA synthesis, accounts for the phenotype of the BAPaΔbasic transgenic mice. These findings implicate a functional role for the Agouti basic domain in vivo, possibly influencing the biogenesis of secreted Agouti protein or modulating protein–protein interactions that contribute to effective antagonism of melanocortin receptors.