Rat obesity gene fatty (fa) maps to chromosome 5: evidence for homology with the mouse gene diabetes (db).

Abstract

The autosomal recessive mutations fa (rat) and db (mouse) cause obesity syndromes that develop early and ultimately become severe. Although bothfa/fa rats and db/db mice have been studied extensively as models of human obesity and diabetes, the molecular bases of these phenotypes remain unknown. We have mappedfa in 50fa/fa (obese) offspring of a (13M x Brown Norway) Ffa/+ intercross relative to two molecular markers, Ifa and Glut-i, which flank db on mouse chromosome 4 and which are located on rat chromosome 5. Ifa and Glut-] are linked tofa, with a gene order, Ifa-fa-Glut-1, that is identical to that for the region around db in the mouse genome. These results place fa on rat chromosome 5 and suggest that db and fa are mutations in homologous genes.Experimental models of obesity are abundant and include seven rodent obesities that are determined by single-gene mutations: yellow (AY), adipose (Ad), diabetes (db), fat (fat), obese (ob), and tubby (tub) in the mouse (1) and fatty (fa) in the rat (2). The obese phenotypes caused by these mutations differ by age of onset, severity, and degree of insulin resistance and thus present a range of phenotypes similar to that seen in obese humans. Although the molecular bases of these mutations remain unknown, the chromosomal locations of the six mouse obesity genes have been determined (1, 3), and efforts to clone several of these genes by positional genetics have been undertaken (4, 5). As a first step toward cloning the rat genefa, we set out to determine its chromosomal location and here present evidence that it maps to rat chromosome 5 in a region ofconserved synteny with the mouse chromosome 4 region containing db.Thefa mutation arose spontaneously in the Zucker (13M) rat strain (2). Obese (fa/fa) rats can be visually distinguished from their lean littermates by 5 weeks of age, although increased adiposity develops earlier (6). Additional aspects of the phenotype include hyperphagia, hyperinsulinemia, hyperlipemia, and multiple endocrine abnormalities (7, 8). A second occurrence of the mutation, originally designatedf(9) and later renamed cp (10), was identified as afa allele (fai) by the demonstration that crosses between individuals carrying fa and those carrying f yield obese progeny (11).One consideration in mapping fa was the prospect thatfa may be a homolog of one of the mouse obesity genes. Any of the six mouse obesity genes might be considered a candidate for homology with fa, but the early onset and severity of obesity mark the ob and db mutations as most similar tofa (1). However, the results of parabiosis experiments have been interpreted as evidence that both fa/fa rats and db/db mice fail to respond to a circulating factor that suppresses body weight or body fat, whereas ob/ob mice appear to lack the activity of this factor (12,13 Genotypes at Ifa and Glut-i. 13MBN F2 rats identified as fa/fa by phenotype were further characterized for 13M and BN alleles at two additional loci, interferon a (Ifa) and facilitative glucose transporter (Glut-l) §, ...

Effect of starvation on gene expression of regulatory enzymes of glycolysis/gluconeogenesis in genetically obese (fa/fa) Zucker rats

“…1 The fa locus, linked to obesity in the rat, has been mapped to a region syntenic with the mouse db locus, 2,3 implying that the fa mutation lies within the rat ob-receptor.…”

The Leptin Receptor

“…pA, poly(A) adenylation site. (43). Sequencing of OB-R in the fa rat revealed a single amino acid substitution in the extracellular domain (41,42).…”

Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: Role of tumor necrosis factor α and IL-18

“…Defects in leptin production, such as those observed in ob͞ob mice, or in the long isoform of the leptin receptor (db͞db mice and fa͞fa rats), cause severe hereditary obesity in rodents and humans (2)(3)(4)(5)(6). In addition to its effects on body weight, leptin has a variety of other functions, including the regulation of hematopoiesis, angiogenesis, wound healing, and the immune and inflammatory response (7)(8)(9)(10)(11)(12)(13)(14).…”