Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Heterozygosity for the mouse lethal yellow (Ay) mutation leads to obesity, increased tumor susceptibility and increased activity of the agouti coat color gene; homozygosity for Ay results in embryonic death around the time of implantation. Although these pleiotropic effects have not been separated by recombination, previous studies have suggested that the dominant and recessive effects result from distinct genetic lesions. Here we use a combination of genomic and cDNA cloning experiments to demonstrate that the Ay mutation is caused by a 120 kb deletion which lies centromere-proximal to the agouti coat color gene. The deletion removes coding but not 5' untranslated sequences for a ubiquitously expressed gene predicted to encode a protein similar in sequence to an RNA-binding protein, which we named Merc, for maternally expressed hnRNP C-related gene, but have renamed Raly, since the gene is nearly identical to one reported recently by Michaud et al. (Gene Dev. 7, 1203-1213, 1993). The Ay deletion results in the splicing of Merc/Raly 5' untranslated sequences to agouti protein-coding sequences, which suggests that ectopic expression of the normal agouti protein by the Ay fusion RNA is responsible for the pleiotropic effects associated with heterozygosity for Ay. We find that Merc/Raly RNA is present in the unfertilized egg and is also transcribed in preimplantation embryos. Using a PCR-based assay to determine the genotype of individual embryos from an Ay/a x Ay/a intercross, we show that, in the absence of zygotic Merc/Raly expression, Ay/Ay embryos develop to the blastocyst stage, but do not hatch from the zona pellucida or form trophoblastic outgrowths. Injection of a Merc/Raly antisense oligonucleotide into non-mutant embryos blocks development prior to the blastocyst stage, and can be rescued by coinjection of a Merc/Raly transgene. These results suggest that maternal expression of Merc/Raly plays an important role in preimplantation development and that its deletion of is sufficient to explain Ay-associated embryonic lethality.
 ...
PMID:Pleiotropic effects of the mouse lethal yellow (Ay) mutation explained by deletion of a maternally expressed gene and the simultaneous production of agouti fusion RNAs. 805 Mar 75

Lethal yellow (Ay) is a mutation at the mouse agouti locus in chromosome 2 that causes a number of dominant pleiotropic effects, including a completely yellow coat color, obesity, an insulin-resistant type II diabetic condition, and an increased propensity to develop a variety of spontaneous and induced tumors. Additionally, homozygosity for Ay results in preimplantation lethality, which terminates development by the blastocyst stage. The Ay mutation is the result of a 170-kb deletion that removes all but the promoter and noncoding first exon of another gene called Raly, which lies in the same transcriptional orientation as agouti and maps 280 kb proximal to the 3' end of the agouti gene. We present a model for the structure of the Ay allele that can explain the dominant pleiotropic effects associated with this mutation, as well as the recessive lethality, which is unrelated to the agouti gene.
 ...
PMID:A molecular model for the genetic and phenotypic characteristics of the mouse lethal yellow (Ay) mutation. 814 54

The viable yellow A(vy) mutation results in a mottled yellow mouse that is obese, slightly larger than its nonyellow sibs, and more susceptible to tumor formation in those tissues sensitized by the strain genome. The mutation exhibits variable expressivity resulting in a continuum of coat color phenotypes, from clear yellow to pseudoagouti. The mouse agouti protein is a paracrine signaling molecule that induces hair follicle melanocytes to switch from the synthesis of black pigment to yellow pigment. Molecular cloning studies indicate that the obesity and growth effects of the A(vy) mutation result from ectopic expression of the normal agouti gene product. This review seeks to summarize the current state of knowledge regarding the obesity, stimulation of somatic growth, and enhancement of tumor formation caused by the A(vy) mutation, and to interpret these pleiotropic effects in terms of the normal function of the agouti protein.
 ...
PMID:Obesity, diabetes, and neoplasia in yellow A(vy)/- mice: ectopic expression of the agouti gene. 818 66

Lethal yellow (Ay) is a mutation at the mouse agouti (a) locus that is associated with an all-yellow coat color, obesity, diabetes, tumors in heterozygotes, and preimplantation embryonic lethality in homozygotes. Previously, we cloned and characterized the wild-type agouti gene and demonstrated that it expresses a 0.8-kb mRNA in neonatal skin. In contrast, Ay expresses a 1.1-kb transcript that is ectopically overexpressed in all tissues examined. The Ay mRNA is identical to the wild-type a transcript for the entire coding region, but the 5'-untranslated sequence of the a gene has been replaced by novel sequence. Here, we demonstrate that the novel 5' sequence in the Ay mRNA corresponds to the 5'-untranslated sequence of another gene that is normally tightly linked to a in mouse chromosome 2. This other gene (Raly) has the potential to encode a novel RNA-binding protein that is normally expressed in the preimplantation embryo, throughout development, and in all adult tissues examined. Importantly, the Ay mutation disrupts the structure and expression of the Raly gene. The data suggest that the Ay mutation arose from a DNA structural alteration that affects the expression of both agouti and Raly. We propose that the dominant pleiotropic effects associated with Ay may result from the ectopic overexpression of the wild-type a gene product under the control of the Raly promoter and that the recessive embryonic lethality may be the result of the lack of Raly gene expression in the early embryo.
 ...
PMID:The embryonic lethality of homozygous lethal yellow mice (Ay/Ay) is associated with the disruption of a novel RNA-binding protein. 831 10

The mouse agouti gene controls the deposition of yellow and black pigment in developing hairs. Several dominant alleles, including lethal yellow (Ay), result in the exclusive production of yellow pigment and have pleiotropic effects that include obesity and increased tumor susceptibility. In an interspecific backcross, we established genetic limits for the agouti gene and found that the Ay and the lethal non-agouti (ax) allele were not separated from a previously identified probe at the breakpoint of the Is1GsO chromosomal rearrangement. Using the Is1GsO probe, we isolated the agouti gene, and find that it has the potential to code for a secreted protein expressed in hair follicles and the epidermis, and that the level of expression correlates with the synthesis of yellow pigment. In the Ay mutation, there is a chromosomal rearrangement that results in the production of a chimeric RNA expressed in nearly every tissue of the body. The 5' portion of this chimeric RNA contains highly expressed novel 5' sequences, but the 3' portion retains the protein-coding potential of the nonmutant allele. We speculate that dominant pleiotropic effects of Ay are caused by ectopic activation of a signaling pathway similar to that used during normal hair growth.
 ...
PMID:Cloning of the mouse agouti gene predicts a secreted protein ubiquitously expressed in mice carrying the lethal yellow mutation. 844 4

Mutations in the obese (ob) gene lead to obesity. This gene has been recently cloned, but the factors regulating its expression have not been elucidated. To address the regulation of the ob gene with regard to body weight and nutritional factors, Northern blot analysis was used to assess ob mRNA in adipose tissue from mice [lean, obese due to diet, or genetically (yellow agouti) obese] under different nutritional conditions. ob mRNA was elevated in both forms of obesity, compared to lean controls, correlated with elevations in plasma insulin and body weight, but not plasma glucose. In lean C57BL/6J mice, but not in mice with diet-induced obesity, ob mRNA decreased after a 48-hr fast. Similarly, in lean C57BL/6J controls, but not in obese yellow mice, i.p. glucose injection significantly increased ob mRNA. For up to 30 min after glucose injection, ob mRNA in lean mice significantly correlated with plasma glucose, but not with plasma insulin. In a separate study with only lean mice, ob mRNA was inhibited >90% by fasting, and elevated approximately 2-fold 30 min after i.p. injection of either glucose or insulin. These results suggest that in lean animals glucose and insulin enhance ob gene expression. In contrast to our results in lean mice, in obese animals ob mRNA is elevated and relatively insensitive to nutritional state, possibly due to chronic exposure to elevated plasma insulin and/or glucose.
 ...
PMID:Obese gene expression: reduction by fasting and stimulation by insulin and glucose in lean mice, and persistent elevation in acquired (diet-induced) and genetic (yellow agouti) obesity. 862 53

Mutant alleles of the agouti gene cause obesity in the mouse and the homologous gene in humans has been mapped to chromosome 20q11.2. An allelic variant of the agouti gene could account for obesity in humans and we tested this hypothesis by genotyping 210 sibling pairs from 45 families segregating an obesity phenotype. Using sibling pair linear regression analysis, evidence for linkage between obesity and markers flanking the agouti locus and other markers spanning chromosome 20q was assessed. We found no correlation between identity-by-descent at these markers and obesity differences within pairs. In the mouse, obesity caused by mutations of the agouti gene develops later in life, so a subset of families with adult-onset obesity were also tested for linkage, with negative results. Although it is not possible to exclude alleles of the agouti gene as a contributor to obesity in humans, the absence of positive linkage in this study suggests that either the agouti gene has small effects or the allele frequency is low.
 ...
PMID:Absence of linkage between human obesity and the mouse agouti homologous region (20q11.2) or other markers spanning chromosome 20q. 865 32

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.
 ...
PMID:Upregulation of adipocyte metabolism by agouti protein: possible paracrine actions in yellow mouse obesity. 877 92

The homologues of single genes that cause obesity in rodents are suggested as candidate genes for modulation of body composition in humans. Among these genes are the four mouse mutations-diabetes (db), obesity (ob), tubby (tub), and yellow agouti (Ay). Variation in the human counterparts to these genes (OB, DB, TUB, and ASP, respectively) may contribute to human obesity, which is thought to have a substantial genetic component. To initially assess the potential contribution of these genes to human obesity, we examined polymorphic DNA markers that, by virtue of syntenic relationships to appropriate regions of the mouse genome, should be closely linked to the human counterparts of these genes. Using combined data from 716 Pima Indians comprising 217 nuclear families, we have tested a number of polymorphic microsatellite markers (three at DB, two at OB, five at TUB, and three at ASP) for sib-pair linkage to BMI, percentage body fat, resting metabolic rate, 24-h energy expenditure, and 24-h respiratory quotient. No significant linkages were found in an analysis of all sibships or in an analysis restricted to discordant sib pairs.
 ...
PMID:Absence of linkage of obesity and energy metabolism to markers flanking homologues of rodent obesity genes in Pima Indians. 877 27

Neonatal treatment with monosodium glutamate (MSG) decreases proopiomelanocortin (POMC) peptides and results in obesity. The yellow mouse is a model of obesity induced by the viable yellow (Avy) gene at the agouti locus on Chromosome 2, which results in overproduction of a POMC receptor antagonist. Thus we hypothesized that MSG, when imposed on the genetically susceptible model, would alter the development of obesity. Both yellow obese (Avy) and black lean (alpha/alpha) males were injected on Postnatal Days 1, 3, 5, 7, and 9 with 2.0 mg/g body weight MSG or saline SC. Their food intake, growth parameters, and neurochemical status were examined. Paradoxically, MSG interacted with the yellow phenotype to delay the rapid rate of weight gain characteristic of this model (p < 0.05). Food intake was decreased (p < 0.05) in both phenotypes treated with MSG, as was hypothalamic content of dopamine (p < 0.05) and of the POMC peptide, beta-endorphin (p < 0.001). The yellow obese phenotype was more sensitive than the black lean phenotype to the neurochemical effect of early postnatal MSG administration. Recent reports suggest the agouti locus protein is an antagonist of the receptor for another POMC peptide, melanocyte-stimulating hormone (MSH). Therefore, the balance of functional activity between various POMC peptides appears to be an important factor in the development of both acquired and genetic obesity.
 ...
PMID:Neonatal MSG reduces hypothalamic DA, beta-endorphin, and delays weight gain in genetically obese (A viable yellow/alpha) mice. 880 53


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>