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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The results of extensive breeding experiments indicate that the phenotypic differentiation of embryos carrying the viable yellow, A( vy), or mottled, a(m), mutations is influenced to a major extent by the agouti locus genotype and the strain genome of the dam. The A(vy)/a and a(m)/a genotypes are each expressed in a spectrum of coat color phenotypes. These can be grouped into two classes, mottled and pseudoagouti.-In a reciprocal cross of C57BL/6JNIcrWf and AM/Wf-a(m)/a(m) mice, 29.5% of the offspring of C57BL/6 dams were of the pseudoagouti phenotype, whereas no pseudoagouti offspring were produced by AM strain dams.-Mottled yellow A(vy)/a mice become obese and tumor formation is enhanced in these mice in comparison with the lean pseudoagouti A(vy)/a siblings.-In two different reciprocal crosses using four different inbred strains, the proportion of pseudoagouti A(vy)/a offspring differed according to the strain of the dam. Regardless of strain, mottled yellow A( vy)/a dams produced significantly fewer pseudoagouti A( vy)/a offspring than did black a/a dams.-The data suggest that metabolic differentiation of A(vy)/a zygotes into phenotypic classes with different susceptibilities to obesity and tumor formation is influenced to a considerable degree by the metabolic characteristics of the oviductal and uterine environment of the dam.
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PMID:Influence of maternal phenotype on metabolic differentiation of agouti locus mutants in the mouse. 64 Mar 77

Is abnormal regulation of phaeomelanin synthesis, which results in yellow coat color, inextricably linked to the development of obesity in viable yellow (Avy) house mice? To answer this question, black male mice of genotypes Avy/A eso/e+ and A/ae eso/e+ were produced from (DFT/Wf X C3H-1 vyfB/HeWf X SO/LeWf matings. The sombre (eso) mutation prevents phaeomelanin synthesis; therefore, all mice carrying this dominant allele are black regardless of the alleles present at the agouti locus. These black males were weighed weekly to 18 weeks of age. Simultaneously the agouti locus genotype of each male was determined by test matings to a/a e+/e+ females. The results of these test matings indicated that the two genotypes could be classified rather accurately by the intensity of pigmentation of the belly hair. Black Avy mice tended to have more dilute belly pigmentation that black A/ae mice. These gross observations were confirmed by microscopic examination of several hair types. Black Avy males reached a mean body weight of 44.2 +/- 0.6 g at 18 weeks, while black A males had a mean weight of 30.7 +/- 0.4 g at the same age. It is concluded that excessive weight gain resulting in obesity is induced by the Avy gene even when phaeomelanin synthesis is completely inhibited.
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PMID:Phaeomelanin synthesis and obesity in mice. Interaction of the viable yellow (Avy) and sombre (eso) mutations. 74 71

The agouti (a) locus acts within the microenvironment of the hair follicle to regulate coat color pigmentation in the mouse. We have characterized a gene encoding a novel 131 amino acid protein that we propose is the one gene associated with the agouti locus. This gene is normally expressed in a manner consistent with a locus function, and, more importantly, its structure and expression are affected by a number of representative alleles in the agouti dominance hierarchy. In addition, we found that the pleiotropic effects associated with the lethal yellow (Ay) mutation, which include pronounced obesity, diabetes, and the development of neoplasms, are accompanied by deregulated overexpression of the agouti gene in numerous tissues of the adult animal.
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PMID:Molecular characterization of the mouse agouti locus. 147 52

The agouti locus regulates a switch in pigment synthesis by hair bulb melanocytes between eumelanosomes and phaeomelanosomes. The agouti locus appears to encode a trans-acting product that acts within the hair follicle to direct the pigment synthesis of melanocytes. In addition to coat color, several agouti mutations affect development, obesity, and susceptibility to neoplasms. The genomic organization of the agouti region suggests that there are three functional units involved in prenatal lethality flanking the agouti coat color locus. Molecular probes for the agouti region are needed to identify and study the genes responsible for these pleiotropic effects. Classical genetic crosses coupled with molecular genetic analyses have been used to determine the map distance and orientation of molecular loci in the agouti region of mouse chromosome 2. The proximity of some of these molecular probes to the agouti region enables the use of molecular markers designed to clone sequences from the agouti locus. Pulsed-field gel electrophoresis is being used to establish long-range restriction maps surrounding the agouti region. Identification of DNA alterations corresponding to specific agouti mutations will enable determination of the molecular basis of agouti locus phenotypes. The mechanism by which the agouti gene product(s) tells the melanocyte what type of pigment to produce may involve cell-cell communication and signal transduction pathways. Future experiments will determine the type of protein(s) encoded by the agouti coat color locus and establish the mechanism by which these protein(s) control the nature and timing of pigment production by melanocytes in the hair follicle.
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PMID:Genomic organization and molecular genetics of the agouti locus in the mouse. 180 96

The Ay allele is a recessive lethal mutation at the mouse agouti locus, which results in embryonic death around the time of implantation. In the heterozygous state, Ay produces several dominant pleiotropic effects, including an increase in weight gain and body length, a susceptibility to hepatic, pulmonary and mammary tumors, and a suppression of the agouti phenotype, which results in a yellow coat color. To investigate the cellular action of Ay with regard to its effects upon embryonic viability and adult-onset obesity, we generated a series of aggregation chimeras using embryos that differ in their agouti locus genotype. Embryos derived from Ay/a x Ay/a matings were aggregated with those derived from A/A x A/A matings, and genotypic identification of the resultant chimeras was accomplished using a molecular probe at the Emv-15 locus that distinguishes among the three different alleles, Ay, A, and a. Among 50 chimeras, 25 analyzed as liveborns and 25 as 9.5 day embryos, 29 were a/a in equilibrium A/A and 21 were Ay/a in equilibrium A/A. The absence of Ay/Ay in equilibrium A/A chimeras demonstrates that Ay/Ay cells cannot be rescued in a chimeric environment, and the relative deficiency of Ay/a in equilibrium A/A chimeras suggests that, under certain conditions, Ay heterozygosity may partially affect cell viability or proliferation. In the 25 liveborn chimeras, Ay/a in equilibrium A/A animals became obese as adults and a/a in equilibrium A/A animals did not. There was no correlation between genotypic proportions and rate of weight gain, which shows that, with regard to its effects on weight gain, Ay heterozygosity is cell non-autonomous.
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PMID:Effects of the lethal yellow (Ay) mutation in mouse aggregation chimeras. 240 Dec 19

We investigated the anti-obesity effects of the adrenal androgen, dehydroepiandrosterone (DHEA), on genetically predisposed obese lethal yellow mice (Ay/Aw). Secondly, we tested the hypothesis that DHEA promotes its anti-obesity effects by decreasing the activity of glucose-6-phosphate dehydrogenase (G6PDH). We subjected four genotype-sex combinations of yellow and agouti (control) mice to four dietary treatments and determined weight changes, food consumption, and G6PDH activity. Although G6PDH activities of yellow mice were considerably decreased in the 0.4% DHEA treatment group, they were elevated in the 0.0 and 0.1% DHEA treatment groups. In contrast, G6PDH activities of DHEA-treated control agouti mice remained relatively constant. These studies confirm that DHEA prevents the Ay gene from promoting excess fat deposition via some mechanism(s) other than reduced dietary intake. However, the overall absence of agreement between weight change (gain or loss) and G6PDH activity suggests that the anti-obesity activity of DHEA is not mediated via G6PDH. Since yellow obese (Ay/Aw) mice were found to be more susceptible to DHEA's effects than their agouti (Aw/Aw) littermates, Ay appears to induce an altered metabolism in Ay/Aw mice which is more susceptible to the effects of DHEA than the normal metabolism of Aw/Aw mice.
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PMID:Effects of dehydroepiandrosterone on obesity and glucose-6-phosphate dehydrogenase activity in the lethal yellow mouse (strain 129/Sv-Ay/Aw). 295 75

Maturity-onset obesity and elevated circulating insulin levels are characteristic of some, but not all, mice bearing the viable yellow mutation (Avy) at the agouti locus. The expression of the Avy/a genotype in individual mice, which become obese and which remain lean is determined during prenatal development by as yet unidentified conditions in the dam's reproductive tract. One Avy/a phenotype is identified by a mottled yellow coat and characterized by adult obesity, elevated circulating insulin levels, and impaired glucose tolerance. These mice are notably more susceptible to hyperplasia and neoplasia. The alternative Avy/ a phenotype has a pseudoagouti coat, remains lean, is normoinsulinemic and normoglycemic, and in numerous other characteristics resembles congeneic lean black (a/a) littermates. Obese mottled yellow and lean pseudoagouti Avy/a mice differ in capacity to support the growth of ascites cells, in the growth response to castration, and in hepatic glutathione S-transferase activity, erythrocyte fragility, immune function, and susceptibility to Plasmodium yoelii pathogenesis. Our working hypothesis is that the constellation of characteristics, except coat color pattern, which differentiate the obese yellow mice from their lean littermates, is largely a consequence of the elevated circulating insulin levels that induce increased lipogenesis and decreased lipolysis, increased DNA and protein synthesis, increased mitosis in sensitive tissues, and increased proliferation of transformed cells.
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PMID:Prenatal determination of obesity, tumor susceptibility, and coat color pattern in viable yellow (Avy/a) mice. The yellow mouse syndrome. 373 4

Identification of the fundamental polypeptide difference between yellow (A(y)/-, A(vy)/-) and non-yellow mice is important for biomedical research because of the influence of the yellow genotype on normal and neoplastic growth and obesity. The complexity of the "yellow mouse syndrome" makes attainment of this objective dependent on the separation of those pleiotropic enzyme differences which are secondary, and depend on the background genome, from those which are primary, and depend primarily on the agouti locus genotype.-Four of nine hepatic enzyme activities assayed simultaneously differed between eight-week-old yellow (A(y)/-, A(vy)/-) and non-yellow (A/-, a/a) male inbred and F(1) hybrid mice. Among these four, only cytoplasmic malic enzyme activity was elevated in all yellow mice, as compared with the non-yellow sibs, regardless of background genome. Glucokinase, serine dehydratase, and tyrosine alpha-ketoglutarate transaminase activities were also changed in yellow mice, but these alterations depended on the background genome.-The ratio of malic enzyme activity to citrate-cleavage enzyme activity, possibly related to the altered fat metabolism of yellow mice, was influenced by background genome as well as by the yellow genotype.--Significant deviations of enzyme activities from mid-parent values among F(1) hybrids were associated with particular background genomes; the number of such deviations was larger among yellow mice than among non-yellows and this difference was greater among C3H F(1) hybrids than among C57BL/6 F(1) hybrids.
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PMID:Influence of background genome on enzymatic characteristics of yellow (A v -, A vy -) mice. 440 52

Several dominant mutations at the murine agouti locus result in the expression of a number of phenotypic changes, including a predominantly yellow coat color, obesity, and hyperinsulinemia. The mutants exhibit ectopic overexpression of normal agouti protein, suggesting that agouti regulates coat coloration by direct antagonism of the alpha-melanocyte-stimulating hormone receptor. We have tested this hypothesis by examining agouti inhibition of both melanocortin-stimulated cyclic adenosine monophosphate production and the binding of a radioactive melanocortin analog in the murine B16F10 melanoma cell line. Inhibition of melanocortin-induced cyclic nucleotide accumulation did not require preincubation of the cells with agouti and was independent of the agonist used. Furthermore, inhibition of both agonist binding to and activation of melanocortin receptor could be described by a simple competitive model with similar inhibition constants of 1.9 and 0.9 nM, respectively. The mutually exclusive binding of agouti and melanocortin was verified by cross-linking experiments using a radiolabeled alpha-melanocyte-stimulating hormone analog. Competitive inhibition of alpha-melanocyte-stimulating hormone binding can account for the effects of agouti on coat coloration and suggests the possibility that the other phenotypic changes observed on agouti overexpression may be due to direct action of agouti at a novel melanocortin receptor(s).
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PMID:Agouti antagonism of melanocortin binding and action in the B16F10 murine melanoma cell line. 754 13

The agouti locus on mouse chromosome 2 encodes a secreted cysteine-rich protein of 131 amino acids that acts as a molecular switch to instruct the melanocyte to make either yellow pigment (phaeomelanin) or black pigment (eumelanin). Mutations that up-regulate agouti expression are dominant to those causing decreased expression and result in yellow coat color. Other associated effects are obesity, diabetes, and increased susceptibility to tumors. To try to define important functional domains of the agouti protein, we have analyzed the molecular defects present in a series of recessive viable agouti mutations. In total, six alleles (amJ, au, ada, a16H, a18H, ae) were examined at both the RNA and DNA level. Two of the alleles, a16H and ae, result from mutations in the agouti coding region. Four alleles (amJ, au, a18H, and ada) appear to represent regulatory mutations that down-regulate agouti expression. Interestingly, one of these mutations, a18H, also appears to cause an immunological defect in the homozygous condition. This immunological defect is somewhat analogous to that observed in motheaten (me) mutant mice. Short and long-range restriction enzyme analyses of homozygous a18H DNA are consistent with the hypothesis that a18H results from a paracentric inversion where one end of the inversion maps in the 5' regulatory region of agouti and the other end in or near a gene that is required for normal immunological function. Cloning the breakpoints of this putative inversion should allow us to identify the gene that confers this interesting immunological disorder.
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PMID:Molecular genetic characterization of six recessive viable alleles of the mouse agouti locus. 763 90


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