Abstract
—Mouse lines long-term selected for high fatness offer the possibility to identify individual genes involved in the development of obesity. The Berlin Fat Mouse (BFM) line has been selected for low protein content and afterward for high fatness. Three Berlin Fat Mouse Inbred (BFMI) lines, which are derivates of the selection line BFM and an unselected control line (C57BL/6; B6) were systematically phenotyped between 3 and 20 wk. The body weights and body compositions were measured on a weekly basis. We demonstrated that the BFMI lines dispose of more body weight, body fat mass, and body lean mass than the control line B6 because of a better feed efficiency in these lines. In contrast to other growth-selected mouse lines, the BFMI lines exhibited a general increase in body fat mass but only a marginal increase in body lean mass. The three BFMI lines also showed line-and sex-specific patterns and varied in their response to high-fat diet. The phenotypic differences between the BFMI lines can be traced back to different sets of fixed alleles contributing to fat accumulation and diet-induced obesity. Our results demonstrate that the genetically related BFMI lines are novel models to study the genetic as well as the nutritional aspects of obesity. selection; inbreeding; fat distribution; growth; adiposity SEVERAL SINGLE-GENE MUTATIONS causing obesity or obesity-related phenotypes have been identified in mice to date (11, 12, 22). However, monogenic types of obesity are likely to account for only a small fraction of human obesity. Most genetically controlled types of obesity seem to be influenced by multiple gene loci. Individual genes only have a small effect, but the interaction of many genes causes extreme phenotypes (3, 5). In humans, the genetic analysis of such polygenic traits is difficult because of the effects of the environmental and genetic background ; therefore, polygenic mouse models are used to study the genetics of complex traits such as obesity. Mouse lines, long-term selected for the desired feature, and, more specifically , their inbred derivates offer the possibility to identify individual genes and to elucidate the complex network of interacting genes with regard to the interaction between genes and environment. Depending on the genetic variability in the particular founder population, the selected mouse lines differ not only in their phenotypes but also in their specific set of genes and alleles. Several different mouse lines derived from heterogeneous base populations have been selected either for body weight or fat content (9), for example, the lines LG/J, DU6, M16, New Zealand obese (NZO), KK, and F. The lines LG/J and DU6 were selected for high body weight (10, 19), whereas the mouse line M16 is a result of selection for rapid weight gain (15). The NZO line was bred for high body weight and obesity (4), while only the F line has been selected solely for high fat content (24). The KK line was originally established as a diabetic line developing moderate obesity (21). All of these mouse lines develop obesity on standard breeding diet, but in some lines the degree of body fat can be additionally increased by a high-fat diet. However, the specific genes that are responsible for determining sensitivity to dietary obesity are potentially different from those causing general obesity. Recently, interactions between genotype and diet composition have been detected in experiments with lean mouse lines where obesity was induced by high-caloric diets (13, 18, 25, 33). However, some of these mouse lines did not develop diet-induced obesity (DIO). To study the genetic basis of obesity, the intercross of phenotypically different inbred mouse lines provides an excellent multigenic model. Crosses between diverse growth-selected mouse lines as well as between different inbred lines have revealed many quantitative trait loci (QTLs) for body weight and obesity (5, 22). However, crosses between different line pairs showed a diverse pattern of QTLs. This indicates that many different genes contribute to obesity and related traits. Moreover, most of the above-mentioned mouse lines were selected primarily for high body weight. High body weight consists not only of fat, but also of a considerable proportion of body lean mass. It is therefore very likely that many QTLs merely affecting fat accumulation are still unknown. Thus the development of new animal models to identify genes responsible for common obesity is still important. To constitute a valuable model for studies of the genetic basis of fat accumulation, we have established the Berlin Fat Mouse Inbred (BFMI) lines BFMI856, BFMI860, and BFMI861, which are collectively termed BFMI lines in this article, as novel mouse models for obesity. In contrast to some of the above-mentioned models, the BFMI lines were generated from an outbred population selected for a high-fat phenotype with low body weight. The objectives of the primary experiment that we report here were 1) the phenotypic characterization of the genetically related BFMI lines as polygenic model for obesity and 2) the analysis of the response of the different BFMI lines to a high-fat diet. The genetic similarity between these lines on the one side and the different sensitivity to diet-induced obesity on the other make these mouse lines Article published online before print. See web site for date of publication