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An average mouse in midlife weighs between 25 and 30 g, with about a gram of tissue in the largest adipose depot (gonadal), and the weight of this depot differs between inbred strains. Specifically, C57BL/6ByJ mice have heavier gonadal depots on average than do 129P3/J mice. To understand the genetic contributions to this trait, we mapped several quantitative trait loci (QTLs) for gonadal depot weight in an F2 intercross population. Our goal here was to fine-map one of these QTLs, Adip20 (formerly Adip5), on mouse chromosome 9. To that end, we analyzed the weight of the gonadal adipose depot from newly created congenic strains. Results from the sequential comparison method indicated at least four rather than one QTL; two of the QTLs were less than 0.5 Mb apart, with opposing directions of allelic effect. Different types of evidence (missense and regulatory genetic variation, human adiposity/body mass index orthologues, and differential gene expression) implicated numerous candidate genes from the four QTL regions. These results highlight the value of mouse congenic strains and the value of this sequential method to dissect challenging genetic architecture. [ABSTRACT FROM AUTHOR]

Obesity is a heritable trait caused by complex interactions between genes and environment, including diet. Gene-by-diet interactions are difficult to study in humans because the human diet is hard to control. Here, we used mice to study dietary obesity genes, by four methods. First, we bred 213 F2 mice from strains that are susceptible [C57BL/6ByJ (B6)] or resistant [129P3/J (129)] to dietary obesity. Percent body fat was assessed after mice ate low-energy diet and again after the same mice ate high-energy diet for 8 weeks. Linkage analyses identified QTLs associated with dietary obesity. Three methods were used to filter candidate genes within the QTL regions: (a) association mapping was conducted using >40 strains; (b) differential gene expression and (c) comparison of genomic DNA sequence, using two strains closely related to the progenitor strains from Experiment 1. The QTL effects depended on whether the mice were male or female or which diet they were recently fed. After feeding a low-energy diet, percent body fat was linked to chr 7 (LOD = 3.42). After feeding a high-energy diet, percent body fat was linked to chr 9 (Obq5; LOD = 3.88), chr 12 (Obq34; LOD = 3.88), and chr 17 (LOD = 4.56). The Chr 7 and 12 QTLs were sex dependent and all QTL were diet-dependent. The combination of filtering methods highlighted seven candidate genes within the QTL locus boundaries: Crx, Dmpk, Ahr, Mrpl28, Glo1, Tubb5, and Mut. However, these filtering methods have limitations so gene identification will require alternative strategies, such as the construction of congenics with very small donor regions. [ABSTRACT FROM AUTHOR]

Abstract: Compared with mice from the 129P3/J (129) inbred strain, mice from the C57BL/6ByJ (B6) inbred strain have higher consumption of several sweet-tasting amino acids and carbohydrates. To examine the relative contribution of taste and nutritive properties in these strain differences, we measured responses of B6 and 129 mice to eight sweet and non-sweet amino acids and carbohydrates in two-bottle preference tests with water. Mice from the two strains did not differ in consumption of non-sweet l-valine and l-histidine. Compared with 129 mice, B6 mice had higher consumption and lower preference thresholds for sweet amino acids l-glutamine, l-alanine and l-threonine, monosaccharides glucose and fructose, and maltooligosaccharide. These data suggest that differences in gustatory responsiveness are an important factor underlying higher consumption of some amino acids and carbohydrates by B6 mice compared with 129 mice. It is likely that in B6 mice, higher sweet taste responsiveness results in increased consumption of sweet-tasting amino acids and sugars, and higher taste responsiveness to complex carbohydrates results in increased consumption of maltooligosaccharide. However, postingestive processes also influence nutrient consumption and may be responsible for higher intake of carbohydrates compared with sweet-tasting amino acids. Results of this study set the stage for genetic analysis of differences between B6 and 129 mice in taste responsiveness and macronutrient consumption. [Copyright &y& Elsevier]

The Tas1r3 gene encodes the T1R3 receptor protein, which is involved in sweet taste transduction. To characterize ligand specificity of the T1R3 receptor and the genetic architecture of sweet taste responsiveness, we analyzed taste responses of 129.B6-Tas1r3 congenic mice to a variety of chemically diverse sweeteners and glucose polymers with three different measures: consumption in 48-h two-bottle preference tests, initial licking responses, and responses of the chorda tympani nerve. The results were generally consistent across the three measures. Allelic variation of the Tas1r3 gene influenced taste responsiveness to nonnutritive sweeteners (saccharin, acesulfame-K, sucralose, SC-45647), sugars (sucrose, maltose, glucose, fructose), sugar alcohols (erythritol, sorbitol), and some amino acids (D-tryptophan, D-phenylalanine, L-proline). Tas1r3 genotype did not affect taste responses to several sweet-tasting amino acids (L-glutamine, L-threonine, L-alanine, glycine), glucose polymers (Polycose, maltooligosaccharide), and nonsweet NaCl, HCl, quinine, monosodium glutamate, and inosine 5'-monophosphate. Thus Tas1r3 polymorphisms affect taste responses to many nutritive and nonnutritive sweeteners (all of which must interact with a taste receptor involving T1R3), but not to all carbohydrates and amino acids. In addition, we found that the genetic architecture of sweet taste responsiveness changes depending on the measure of taste response and the intensity of the sweet taste stimulus. Variation in the T1R3 receptor influenced peripheral taste responsiveness over a wide range of sweetener concentrations, but behavioral responses to higher concentrations of some sweeteners increasingly depended on mechanisms that could override input from the peripheral taste system. [ABSTRACT FROM AUTHOR]

This review focuses on behavioral genetic studies of sweet, umami, bitter and salt taste responses in mammals. Studies involving mouse inbred strain comparisons and genetic analyses, and their impact on elucidation of taste receptors and transduction mechanisms are discussed. Finally, the effect of genetic variation in taste responsiveness on complex traits such as drug intake is considered. Recent advances in development of genomic resources make behavioral genetics a powerful approach for understanding mechanisms of taste. [ABSTRACT FROM AUTHOR]

To identify the gene or genes on mouse Chromosome 9 that contribute to strain differences in fatness, we conducted an expanded mapping analysis to better define the region where suggestive linkage was found, using the F2 generation of an intercross between the C57BL/6ByJ and 129P3/J mouse strains. Six traits were studied: the summed weight of two adipose depots, the weight of each depot, analyzed individually (the gonadal and retroperitoneal depot), and the weight of each depot (summed and individual) relative to body size. We found significant linkage (LOD = 4.6) that accounted for the relative weight of the summed adipose depots, and another for the relative weight of the gonadal (LOD = 5.3) but not retroperitoneal (LOD = 0.9) adipose depot. This linkage is near marker rs30280752 (61.1 Mb, Build 34) and probably is equivalent to the quantitative trait locus (QTL) Adip5. Because the causal gene is unknown, we identified and evaluated several candidates within the confidence interval with functional significance to the body fatness phenotype ( Il18, Acat1, Cyp19a1, Crabp1, Man2c1, Neil1, Mpi1, Csk, Lsm16, Adpgk, Bbs4, Hexa, Thsd4, Dpp8, Anxa2, and Lipc). We conclude that the Adip5 locus is specific to the gonadal adipose depot and that a gene or genes near the linkage peak may account for this QTL. [ABSTRACT FROM AUTHOR]

In long-term two-bottle tests, mice from the C57BL/6ByJ (B6) strain drink more monosodium l-glutamate (MSG) and inosine-5′-monophosphate (IMP) compared with mice from the 129P3/J (129) strain. The goal of this study was to assess the role of afferent gustatory input in these strain differences. We measured integrated responses of the mouse chorda tympani and glossopharyngeal nerves to lingual application of compounds that evoke umami taste in humans: MSG, monoammonium l-glutamate (NH4 glutamate), IMP and guanosine-5′-monophosphate (GMP) and also to other taste stimuli. Chorda tympani responses to MSG and NH4 glutamate were similar in B6 and 129 mice. Chorda tympani responses to IMP and GMP were lower in B6 than in 129 mice. Responses to umami stimuli in the glossopharyngeal nerve did not differ between the B6 and 129 strains. Responses to MSG, IMP and GMP were not affected by sodium present in these compounds because B6 and 129 mice had similar neural taste responses to NaCl. This study has demonstrated that the increased ingestive responses to the umami stimuli in B6 mice are accompanied by either unchanged or decreased neural responses to these stimuli. Lack of support for the role of the chorda tympani or glossopharyngeal nerves in the enhanced consumption of MSG and IMP by B6 mice suggests that it is due to some other factors. Although results of our previous study suggest that postingestive effects of MSG can affect its intake, contribution of other gustatory components (e.g. greater superficial petrosal nerve or central gustatory processing) to the strain differences in consumption of umami compounds also cannot be excluded. Strain differences in gustatory neural responses to nucleotides but not glutamate suggest that these compounds may activate distinct taste transduction mechanisms. [ABSTRACT FROM AUTHOR]

Recent studies have shown that the T1R3 receptor protein encoded by the Taslr3 gene is involved in transduction of sweet taste. To assess ligand specificity of the T1R3 receptor, we analyzed the association of Taslr3 allelic variants with taste responses in mice. In the F2 hybrids between the C57BL/6ByJ (B6) and 129P3/J (129) inbred mouse strains, we determined genotypes of markers on chromosome 4, where Taslr3 resides, measured consumption of taste solutions presented in two-bottle preference tests, and recorded integrated responses of the chorda tympani gustatory nerve to lingual application of taste stimuli. For intakes and preferences, significant linkages to Taslr3 were found for the sweeteners sucrose, saccharin, and D-phenylalanine but not glycine. For chorda tympani responses, significant linkages to Taslr3 were found for the sweeteners sucrose, saccharin, D-phenylalanine, D-tryptophan, and SC-45647 but not glycine, L-proline, L-alanine, or L-glutamine. No linkages to distal chromosome 4 were detected for behavioral or neural responses to non-sweet quinine, citric acid, HC1, NaC1, KC1, monosodium glutamate, inosine 5'-monophosphate, or ammonium glutamate. These results demonstrate that allelic variation of the Taslr3 gene affects gustatory neural and behavioral responses to some, but not all, sweeteners. This study describes the range of ligand sensitivity of the T 1R3 receptor using an in vivo approach and, to our knowledge, is the first genetic mapping study of activity in gustatory nerves. [ABSTRACT FROM AUTHOR]

The subtelomeric region of mouse chromosome (Chr) 4 harbors loci with effects on behavior, development, and disease susceptibility. Regions near the telomeres are more difficult to map and characterize than other areas because of the unique features of subtelomeric DNA. As a result of these problems, the available mapping information for this part of mouse Chr 4 was insufficient to pursue candidate gene evaluation. Therefore, we sought to characterize the area in greater detail by creating a comprehensive genetic, physical, and comparative map. We constructed a genetic map that contained 30 markers and covered 13.3 cM; then we created a 1.2-Mb sequence-ready BAC contig, representing a 5.1-cM area, and sequenced a 246-kb mouse BAC from this contig. The resulting sequence, as well as approximately 40 kb of previously deposited genomic sequence, yielded a total of 284 kb of sequence, which contained over 20 putative genes. These putative genes were confirmed by matching ESTs or cDNA in the public databases to the genomic sequence and/or by direct sequencing of cDNA. Comparative genome sequence analysis demonstrated conserved synteny between the mouse and the human genomes (1p36.3). DNA from two strains of mice (C57BL/6ByJ and 129P3/J) was sequenced to detect single nucleotide polymorphisms (SNPs). The frequency of SNPs in this region was more than threefold higher than the genome-wide average for comparable mouse strains (129/Sv and C57BL/6J). The resulting SNP map, in conjunction with the sequence annotation and with physical and genetic maps, provides a detailed description of this gene-rich region. These data will facilitate genetic and comparative mapping studies and identification of a large number of novel candidate genes for the trait loci mapped to this region. [ABSTRACT FROM AUTHOR]

What an animal chooses to eat can either induce or retard the development of obesity; this review summarizes what is known about the genetic determinants of nutrient selection and its impact on obesity in humans and rodents. The selection of macronutrients in the diet appears to be, in part, heritable. Genes that mediate the consumption of sweet-tasting carbohydrate sources have been mapped and are being isolated and characterized. Excessive dietary fat intake is strongly tied to obesity, and several studies suggest that a preference for fat and the resulting obesity are partially genetically determined. Identifying genes involved in the excess consumption of dietary fat will be an important key to our understanding of the genetic disposition toward common dietary obesity. [ABSTRACT FROM AUTHOR]

We have begun to characterize the genetic basis of calcium consumption. Previously, we found that the PWK/PhJ mouse strain has stronger preferences for calcium solutions than do 39 other strains, including the C57BL/6J strain (see Mouse Phenome Database, project 103). To determine the cause of this variation, we phenotyped and genotyped 481 C57BL/6J x PWK/PhJ F2 hybrids. Phenotypes included a 96-h two-bottle preference test with a choice between water and 50 mM CaCl2. Genotypes were based on 116 SSLP markers. Interval mapping revealed two quantitative trait loci (QTLs) for calcium intake. One was on proximal chromosome 16 with a peak close to Casr, an extracellular calcium receptor. This QTL supports the hypothesis that CaSR detects oral and/or circulating calcium to control calcium intake. The other was on distal chromosome 4 with a peak close to Tas1r3, the sweet receptor. Taken with confirmatory evidence, this suggests that calcium interacts with the sweet receptor to stimulate calcium intake in some strains of mice. Perhaps PWK/PhJ mice drink calcium avidly because they perceive it to be sweet. [ABSTRACT FROM AUTHOR]

Abstract: Our previous studies have shown that in long-term two-bottle preference tests, mice from the C57BL/6ByJ (B6) inbred strain drink more monosodium glutamate (MSG) and inosine monophosphate (IMP) than mice from the 129P3/J (129) inbred strain. The goal of this study was to examine whether this variation in consumption could be attributed to strain differences in perception of the taste quality of MSG and IMP. We developed a conditioned taste aversion (CTA) in B6 and 129 mice to 100 mM MSG or 10 mM IMP and used a brief-access taste assay to examine CTA generalization. B6 and 129 mice did not differ in the generalization patterns following CTA to MSG: mice from both strains generalized CTA from MSG to NaCl. In contrast, strain differences in the generalization patterns were evident following the CTA to IMP: while mice from both strains generalized CTA from IMP to MSG, 129 mice tended to have stronger CTA generalization to saccharin and d-tryptophan, both of which are perceived as sweet by humans. These data suggest that the strain differences in MSG consumption are not due to variation in perception of the taste quality of MSG. Instead, the differential intake of IMP likely reflects strain differences in the way the taste quality of IMP is perceived. Our data suggest that mice perceive MSG and IMP as complex taste stimuli: some taste components are shared between these two substances, but their relative intensity seems to be different for MSG and IMP. The amiloride-sensitive salt taste component is more prevalent in MSG than in IMP taste, and in B6 compared with 129 mice. [Copyright &y& Elsevier]