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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) §, ...

Loci linked to sensitivity to dietary obesity were identified by Quantitative Trait Locus (QTL) analysis of two mapping populations derived from a cross between AKR/J and SWR/J mice. AKR/J mice are sensitive to dietary obesity when fed a high fat diet while SWR/J mice are resistant. Intercrosses between these strains segregate the phenotype of sensitivity to dietary obesity. Using an F2 mapping population of 931 male mice we found significant linkage with a QTL on chromosome 9 (Likelihood of the Odds [LOD] ratio of 4.85) and another QTL on chromosome 15 (LOD = 3.93). The presence of a QTL on chromosome 15 was confirmed in a separate mapping population of 375 male F1 x SWR/J mice (LOD = 3.82). These two loci are designated dietary obese 2 (Do2) and dietary obese 3 (Do3) for the chromosome 9 and 15 loci, respectively. Both of these chromosomal regions contain candidate genes which may contribute to variation in the phenotype. These loci also exert a significant control over individual adipose depot weights. (J. Clin. Invest. 1994. 94:1410-1416

The onset of hyperphagia in the Zucker fatty (fa/fa) rat occurs on a single day in postnatal development and could be driven by an increase in insulin sensitivity. To test this hypothesis, we performed insulin tolerance tests at several points in development. In rapidly growing juvenile rats, fatty rats are as insulin sensitive as lean rats at 4 wk of age but become increasingly insulin resistant as they became obese. During the suckling to weaning transition, fatty rats are insulin resistant at 2 wk of age, when they are exclusively suckling; they are also insulin resistant at 3 wk of age, when they are suckling and consuming solid food, but not hyperphagic. By 4 wk of age, when fatty rats are hyperphagic, they are as insulin sensitive as their lean littermates. These data indicate that fatty rats experience two phases of insulin resistance, punctuated by a brief period of insulin sensitivity that follows the onset of hyperphagia. To determine whether the increase in insulin sensitivity could be driving the onset of hyperphagia, insulin tolerance tests were performed from 21 to 27 days of age. Obese and lean rats became increasingly insulin resistant from 21 to 23 days of age and then became as insulin sensitive as lean rats by 25 days of age. These data show that increased insulin resistance precedes the onset of hyperphagia and increased insulin sensitivity follows the onset of hyperphagia. This pattern suggests that developmental perturbations in insulin signaling are likely to be involved in the onset of hyperphagia.

Expression of a single copy of the rat obesity fatty (fa) gene may affect energy balance. To test this hypothesis, the effects of zero, one, and two copies of fa on early growth were evaluated, using a molecular genetic method for counting fa alleles inherited by 7- and 14-day-old F2 offspring of a BN/Crl x Crl:ZUC-fa F1 intercross. Litter and sex effects were controlled by multiple-regression analysis, allowing genotype effects on the weights of body, inguinal adipose pads, interscapular brown adipose tissue, and liver to be isolated. At 7 days of age, the fa copy number had linear effects on body and inguinal adipose pads weight. At 14 days of age, the fa copy number had linear effects on body, inguinal adipose pads, and interscapular brown adipose tissue weights and an additional quadratic effect on inguinal adipose pads weight. Thus fa has codominant effects on growth during the first week of life. The recessive effects of fa on growth appear during the second week of life.