SMXA-5 mouse as a diabetic model susceptible to feeding a high-fat diet

The SMXA-5 strain, a new mouse model for type 2 diabetes, is a recombinant inbred strain derived from non-diabetic SM/J and A/J strains. As dietary fat is a key component in the development of diabetes, we compared the glucose tolerance and diabetes-related traits among the SMXA-5, SM/J, and A/J strains while feeding a high-fat diet for 10 weeks. SMXA-5 fed on a high-fat diet showed an increased serum insulin concentration. Judging from the hyperinsulinemia in SMXA-5, this strain showed insulin resistance, an inability of peripheral tissues to respond to insulin, which was strengthened by feeding with a high-fat diet. When fed on a high-fat diet for 5 weeks, the SMXA-5 mice showed severely impaired glucose tolerance. On the other hand, SM/J showed mildly impaired glucose tolerance, even when fed on a high-fat diet for 10 weeks. These results indicate that SMXA-5 would be available for use as a diabetic model susceptible to a high-fat diet.     

The Nxsm Recombinant Inbred Strains of Mice: Genetic Profile for 58 Loci Including the Mtv Proviral Loci

We report the construction of 17 recombinant inbred (RI) strains of mice derived from the progenitor strains NZB/BINRe and SM/J and the typing of this RI strain set, designated NXSM, for 58 loci distributed on 16 autosomes and the X chromosome. Two backcrosses involving NZB/BINJ and SM/J were constructed to confirm chromosomal assignments and determine gene orders suggested from NXSM RI strain data. From these results we recommend that chromosomal assignments and gene orders suggested from analyses of RI strain sets be confirmed using data obtained by other means. We also typed NZB/BINJ and SM/J for mammary tumor proviral (Mtv) loci. Both strains share three previously described Mtv loci: Mtv-7, Mtv-14 and Mtv-17. In addition, NZB/BINJ contains the previously described Mtv-3 and Mtv-9 loci and two new Mtv proviral loci: Mtv-27 located on chromosome (Chr) 1 and Mtv-28 located on the X chromosome. SM/J contains the previously described loci Mtv-6 and Mtv-8. Four LTR, mink cell focus-forming murine leukemia viral loci were identified and mapped: Ltrm-1 on Chr 12, Ltrm-2 on Chr 16, Ltrm-3 on Chr 5, and Ltrm-4 on Chr 13. The Tgn locus was positioned proximal to the Ly-6 locus on Chr 15.     

Searching for genetic factors of fatty liver in SMXA-5 mice by quantitative trait loci analysis under a high-fat diet

Fatty liver is strongly associated with the metabolic syndrome characterized by obesity, insulin resistance, and type 2 diabetes, but the genetic basis and functional mechanisms linking fatty liver with the metabolic syndrome are largely unknown. The SMXA-5 mouse is one of the SMXA recombinant inbred substrains established from SM/J and A/J strains and is a model for polygenic type 2 diabetes, characterized by moderately impaired glucose tolerance, hyperinsulinemia, and mild obesity. SMXA-5 mice also developed fatty liver, and a high-fat diet markedly worsened this trait, although SM/J and A/J mice are resistant to fatty liver development under a high-fat diet. To dissect loci for fatty liver in the A/J regions of the SMXA-5 genome, we attempted quantitative trait loci (QTLs) analysis in (SM/JxSMXA-5)F2 intercross mice fed a high-fat diet. We mapped a major QTL for relative liver weight and liver lipid content near D12Mit270 on chromosome 12 and designated this QTL Fl1sa. The A/J allele at this locus contributes to the increase in these traits. We confirmed the effect of Fl1sa on lipid accumulation in liver using the A/J-Chr12(SM) consomic strain, which showed significantly less accumulation than A/J mice. This suggests that the SM/J and A/J strains, neither of which develops fatty liver, possess loci causing fatty liver and that the coexistence of these loci causes fatty liver in SMXA-5 mice.     

Low expression of Neu2 sialidase in the thymus of SM/J mice—existence of neuraminidase positive cells “Neu-medullocyte” in the murine thymus

We have already reported that the homogenate of the A/J mouse thymus shows a high sialidase activity at the neutral pH region and that in both soluble and membrane fractions optimal pH was 6.5–7 (Kijimoto-Ochiai et al., Glycoconj. J., 20:375–384, 2004). In the present study, we investigated the level of sialidase activities in the thymus of the SM/J mouse, a mouse strain that we know to have a Neu1^a allele that reveals a low level of sialidase activity in the liver. We found that while in the A/J thymus the soluble sialidase activity at pH 6.5 was high, the SM/J thymus lacked all such activity. A QTL analysis of SMXA recombinant inbred strains showed that soluble sialidase activity correlated well with the D1Mit8/9 marker on chromosome 1. The murine whole DNA-sequence data and the results of our FISH analysis (Kotani et al., Biochem. Biophys. Res. Comm., 286:250–258, 2001) showed that this location is consistent with the position of Neu2 gene. We confirmed that it is hard to detect the Neu2 enzyme of the SM/J mouse thymus by an anti-Neu2 antibody using a Western blot analysis. We also found that while the mRNA expression of Neu2 was quite normal in the SM/J mouse liver, it was very low in the SM/J mouse thymus. We therefore conclude that the lack of soluble sialidase activity in the SM/J mouse thymus is due to the thymus-specific low expression level of the Neu2 gene. We have previously shown that the sialidase positive cell which contains the Mac-1 and immunoglobulin, and which is located sparsely in the corticomedullar region or medullary region of the A/J mouse thymus (Kijimoto-Ochiai et al., Glycoconj. J., 20:375–384, 2004). We showed now in this paper that the detection of this cell in the SM/J mouse thymus at pH 7.0 was difficult. We propose, therefore, to name the cell “Neu-medullocyte”.     

Establishment of consomic strains derived from A/J and SM/J mice for genetic analysis of complex traits

Consomic strains, in which one chromosome is derived from a donor strain and the other chromosomes are derived from the recipient strain, provide a powerful tool for the dissection of complex genetic traits. In this study we established ten consomic strains (A-2^SM, A-6^SM, A-11^SM, A-12^SM, A-13^SM, A-15^SM, A-17^SM, A-18^SM, A-19^SM, A-Y^SM) using the SM/J strain as the donor and the A/J strain as the recipient; these are the parental strains of a set of SMXA recombinant inbred (RI) strains that we had developed previously. We analyzed body weights and blood lipid levels in the consomic and parental strains. The mean values for each trait showed a continuous range of variation in the consomic strains suggesting that they are controlled by multiple genes. We previously identified suggestive QTLs for body weight on chromosome 6 in SMXA RI strains and (SM/J?×?A/J)F₂ mice. The observation that the A-6^SM consomic strain had a significantly lower mean body weight than the A/J strain supports the presence of this QTL on chromosome 6. Similarly, the higher blood triglyceride level in the A-11^SM strain shows the existence of a previously mapped QTL on chromosome 11, and the A-12^SM strain provides evidence of a QTL for blood total cholesterol level on chromosome 12. These consomic strains, along with the previously developed set of SMXA RI strains from A/J and SM/J mice, offer an invaluable and powerful resource for the analysis of complex genetic traits in mice.     

Searching for Genomic Region of High-Fat Diet-Induced Type 2 Diabetes in Mouse Chromosome 2 by Analysis of Congenic Strains

SMXA-5 mice are a high-fat diet-induced type 2 diabetes animal model established from non-diabetic SM/J and A/J mice. By using F2 intercross mice between SMXA-5 and SM/J mice under feeding with a high-fat diet, we previously mapped a major diabetogenic QTL (T2dm2sa) on chromosome 2. We then produced the congenic strain (SM.A-T2dm2sa (R0), 20.8–163.0 Mb) and demonstrated that the A/J allele of T2dm2sa impaired glucose tolerance and increased body weight and body mass index in the congenic strain compared to SM/J mice. We also showed that the combination of T2dm2sa and other diabetogenic loci was needed to develop the high-fat diet-induced type 2 diabetes. In this study, to narrow the potential genomic region containing the gene(s) responsible for T2dm2sa, we constructed R1 and R2 congenic strains. Both R1 (69.6–163.0 Mb) and R2 (20.8–128.2 Mb) congenic mice exhibited increases in body weight and abdominal fat weight and impaired glucose tolerance compared to SM/J mice. The R1 and R2 congenic analyses strongly suggested that the responsible genes existed in the overlapping genomic interval (69.6–128.2 Mb) between R1 and R2. In addition, studies using the newly established R1A congenic strain showed that the narrowed genomic region (69.6–75.4 Mb) affected not only obesity but also glucose tolerance. To search for candidate genes within the R1A genomic region, we performed exome sequencing analysis between SM/J and A/J mice and extracted 4 genes (Itga6, Zak, Gpr155, and Mtx2) with non-synonymous coding SNPs. These four genes might be candidate genes for type 2 diabetes caused by gene-gene interactions. This study indicated that one of the genes responsible for high-fat diet-induced diabetes exists in the 5.8 Mb genomic interval on mouse chromosome 2.     

Quantitative trait loci for body weight in the intercross between SM/J and A/J mice.

We performed a genome-wide quantitative trait locus (QTL) analysis of body weight at 10 weeks of age in a population of 321 intercross offspring from SM/J and A/J mice, progenitor strains of SMXA recombinant inbred strains. Interval mapping revealed two significant QTLs, Bwq3 (body weight QTL3) and Bwq4, on Chromosomes (Chrs) 8 and 18 respectively, and five suggestive QTLs on Chrs 2, 6, 7, 15 and 19. Bwq3 and Bwq4 explained 6% of the phenotypic variance. The SM/J alleles at both QTLs increased body weight, though the SM/J mouse was smaller than the A/J mouse. On the other hand, four of the five suggestive QTLs detected had male-specific effects on body weight and the remainder was female-specific. These suggestive QTLs explained 5-6% of the phenotypic variance and all the SM/J alleles decreased body weight.     

Establishment of consomic strains derived from A/J and SM/J mice for genetic analysis of complex traits

Consomic strains, in which one chromosome is derived from a donor strain and the other chromosomes are derived from the recipient strain, provide a powerful tool for the dissection of complex genetic traits. In this study we established ten consomic strains (A-2^SM, A-6^SM, A-11^SM, A-12^SM, A-13^SM, A-15^SM, A-17^SM, A-18^SM, A-19^SM, A-Y^SM) using the SM/J strain as the donor and the A/J strain as the recipient; these are the parental strains of a set of SMXA recombinant inbred (RI) strains that we had developed previously. We analyzed body weights and blood lipid levels in the consomic and parental strains. The mean values for each trait showed a continuous range of variation in the consomic strains suggesting that they are controlled by multiple genes. We previously identified suggestive QTLs for body weight on chromosome 6 in SMXA RI strains and (SM/J × A/J)F₂ mice. The observation that the A-6^SM consomic strain had a significantly lower mean body weight than the A/J strain supports the presence of this QTL on chromosome 6. Similarly, the higher blood triglyceride level in the A-11^SM strain shows the existence of a previously mapped QTL on chromosome 11, and the A-12^SM strain provides evidence of a QTL for blood total cholesterol level on chromosome 12. These consomic strains, along with the previously developed set of SMXA RI strains from A/J and SM/J mice, offer an invaluable and powerful resource for the analysis of complex genetic traits in mice.

     

The SMXA: a new set of recombinant inbred strain of mice consisting of 26 substrains and their genetic profile

A new set of recombinant inbred (RI) strain SMXA consisting of 26 substrains was established between SM/J and A/J. The history of the SMXA RI strains and their genetic prolife covering 158 genetic marker loci are reported. From the strain distribution pattern among SMXA RI strains, the chromosomal location of salivary and tear protein genes Spel-r, Spel-s, Spe2, and Tpe1 were newly determined.     

Visual detection, pattern discrimination and visual acuity in 14 strains of mice

Based on the procedure of Prusky et al. (2000, Vision Research, 40, 2201-2209), we used a computer-based, two-alternative swim task to evaluate visual detection, pattern discrimination and visual acuity in 14 strains of mice from priority groups A and B of the JAX phenome project (129S1/SvImJ, A/J, AKR/J, BALB/cByJ, BALB/cJ, C3H/HeJ, C57BL/6J, CAST/Ei, DBA/2J, FVB/NJ, MOLF/Ei, SJL/J, SM/J and SPRET/Ei). Each mouse was tested for eight trials/day for 8 days on each of the three tests. There was a significant strain difference in visual ability in all three tests. Mice with reported normal vision (129S1/SvImJ, C57BL/6J and DBA/2J) and one albino strain (AKR/J) performed very well in these tasks. The other albino strains (A/J, BALB/cByJ and BALB/cJ) took longer to learn the tasks than mice with normal vision and did not reach the criterion of 70% correct. Mice with retinal degeneration (C3H/HeJ, FVB/NJ, MOLF/Ei and SJL/J) performed only at chance levels as did the three strains with unknown visual abilities (CAST/Ei, SM/J and SPRET/Ei). Because many behavioral tasks for rodents rely on visual cues, we suggest that the visual abilities of mice should be evaluated before they are tested in commonly used visuo-spatial learning and memory tasks.     

猪瘟病毒感染性cDNA克隆的构建及其致病性

为了建立研究猪瘟病毒的技术平台,利用RT-PCR技术构建了猪瘟病毒中国石门株(Shimen)的全长有感染性cDNA克隆pT7SM。通过体外转录线性化的pT7SM并将转录的RNA转染至PK-15细胞中,获得了猪瘟病毒粒子。再用间接免疫荧光法测定了其生长曲线,通过电镜观察到重组病毒呈球形,具有囊膜结构。进一步把获得的猪瘟病毒粒子感染非免疫实验猪,结果子代病毒与石门株类似,对非免疫实验猪有强烈的致病性,证明该全长cDNA克隆可靠稳定,忠实地保留了石门株病毒的感染性和致病特征。由此为进一步探讨猪瘟病毒的致弱机制及病毒与机体相互作用的机制打下了良好的基础。     

Genetic regulation of alcohol dehydrogenase C2 in the mouse. Developmental consequences of the temporal locus (Adh-3t) and positioning of Adh-3 on chromosome 3

The tissue specificity of a proposed cis-acting temporal locus (Adh-3t), which regulates alcohol dehydrogenase C₂ (ADH-C₂) activity in mouse reproductive tissue extracts, has been examined in C5 7BL/6J, SM/J, F₁ (SM/J × C5 7BL/6J) mice as well as in progeny of an (F₁ [SM/J × C5 7BL/6J] × C5 7BL/6J) back-cross. Electrophoretic variants for ADH-C₂, previously used to localize the gene (Adh-3) encoding this enzyme on chromosome 3, enabled the relative parental contributions to ADH-C₂ phenotype in F¹ and backcross mouse tissues to be determined. These analyses demonstrated that (1) stomach, kidney, lung, adrenals, seminal vesicles, epididymis, uterus, and ovary ADH-C₂ is encoded by a single locus (Adh-3); Adh-3t is differentially active in various tissues, eg, lung exhibits no apparent activity whereas the temporal locus is fully active in seminal vesicles; (3) Adh-3t is probably differentically active in different cells of some tissues, eg, adrenals. Specific activity profiles of stomach and epididymal ADH-C₂ during the neonatal development of C5 7BL/6J, SM/J, and F₁ (SM/J × C5 7BL/6J) male mice supported the proposal for a cis-acting temporal locus for this enzyme. Genetic analyses examining segregation of Adh-3 and Adh-3t among backcross progeny suggested that these are distinct but closely linked loci, since one recombinant among 256 progeny was observed. Linkage data of Adh-3 with Va (varitint-waddler) and de (droopy ear) was also obtained, which suggested that Adh-3 is localized on chromosome 3 between Va and de.     

Lysosomal Acid phosphatase deficiency: liver specific variant in the mouse

The number and classes of genes responsible for the final expression of lysosomal acid phosphatase were investigated in the mouse (Mus musculus ). In mouse tissues, lysosomal acid phosphatase activity was separated by gel electrophoresis into two major zones of activity. The cathodal zone of activity in liver of the SM/J inbred strain was almost completely absent, while the anodal zone was increased in activity. Other tissues from SM/J were not affected, nor were livers and other tissues in 27 inbred mouse strains. Genetic studies indicated that this deficiency variant segregated as an autosomal codominant gene which has been designated Apl to symbolize the acid phosphatase liver phenotype. The Apl gene was not linked to markers on chromosomes 1, 2, 4, 5, 7, 8, or X. Electrophoretic, heat denaturation, neuraminidase treatment, tartrate inhibition studies and tissue mixing experiments suggested that the Apl gene was not a structural gene for acid phosphatase, but a separate gene that functions in liver and is responsible for controlling or modifying an acid phosphatase structural gene product.     

Genetic loci that regulate healing and regeneration in LG/J and SM/J mice

MRL mice display unusual healing properties. When MRL ear pinnae are hole punched, the holes close completely without scarring, with regrowth of cartilage and reappearance of both hair follicles and sebaceous glands. Studies using (MRL/lpr × C57BL/6)F₂ and backcross mice first showed that this phenomenon was genetically determined and that multiple loci contributed to this quantitative trait. The lpr mutation itself, however, was not one of them. In the present study we examined the genetic basis of healing in the Large (LG/J) mouse strain, a parent of the MRL mouse and a strain that shows the same healing phenotype. LG/J mice were crossed with Small (SM/J) mice and the F₂ population was scored for healing and their genotypes determined at more than 200 polymorphic markers. As we previously observed for MRL and (MRL × B6)F₂ mice, the wound-healing phenotype was sexually dimorphic, with female mice healing more quickly and more completely than male mice. We found quantitative trait loci (QTLs) on chromosomes (Chrs) 9, 10, 11, and 15. The heal QTLs on Chrs 11 and 15 were linked to differential healing primarily in male animals, whereas QTLs on Chrs 9 and 10 were not sexually dimorphic. A comparison of loci identified in previous crosses with those in the present report using LG/J × SM/J showed that loci on Chrs 9, 11, and 15 colocalized with those seen in previous MRL crosses, whereas the locus on Chr 10 was not seen before and is contributed by SM/J.     

A second gene affecting the sialylation of lysosomal α-mannosidase in mouse liver

We have previously reported on a mouse liver-specific genetic polymorphism associated with altered sialylation of lysosomal a-mannosidase. A second electrophoretic polymorphism for liver lysosomal a-mannosidase has now been found and characterized. This variation, between SWR/J and SM/JCv inbred mice, is determined by a single genetic locus (Map-2) on chromosome 17 and appears to be the result of further differences in sialylation of the lysosomal enzyme. The Map-2 gene appears to affect the processing of liver, spleen, and lung lysosomal a-mannosidase, whereas the Map-1 gene appears to be specific to the processing of liver lysosomal a-mannosidase (Dizik and Elliott, 1977). The more negatively charged electrophoretic liver phenotype (MA-A) characteristic of the SM/JCv strain is recessive to the phenotype (MA-B) characteristic of the SWR/J strain. In contrast, at the Map-1 locus, the more negatively charged phenotype is dominant. The electrophoretic pattern of development of the liver enzyme from SM/JCv mice is described.This work was supported in part by Grant GM-19521 from the U.S. Public Health Service. One of the authors (M. D.) was supported in part by USPHS Grant TAO-CA05016.In partial fulfillment of the requirements for the Ph.D. degree.     

Ileal smooth muscle dysfunction and remodeling in cystic fibrosis

Patients with cystic fibrosis (CF) often suffer from gastrointestinal cramps and intestinal obstruction. The CF transmembrane conductance regulator (CFTR) channel has been shown to be expressed in vascular and airway smooth muscle (SM). We hypothesized that the absence of CFTR expression alters the gastrointestinal SM function and that these alterations may show strain-related differences in the mouse. The aim of this study was to measure the contractile properties of the ileal SM in two CF mouse models. CFTR(-/-) and CFTR(+/+) mice were studied on BALB/cJ and C57BL/6J backgrounds. Responsiveness of ileal strips to electrical field stimulation (EFS), methacholine (MCh), and isoproterenol was measured. The mass and the cell density of SM layers were measured morphometrically. Finally, the maximal velocity of shortening (Vmax) and the expression of the fast (+)insert myosin isoform were measured in the C57BL/6J ileum. Ileal hyperreactivity was observed in response to EFS and MCh in CFTR(-/-) compared with CFTR(+/+) mice in C57BL/6J background. This latter observation was not reproduced by acute inhibition of CFTR with CFTR(inh)172. BALB/cJ CFTR(-/-) mice exhibited a significant increase of SM mass with a lower density of cells compared with CFTR(+/+), whereas no difference was observed in the C57BL/6J background. In addition, in this latter strain, ileal strips from CFTR(-/-) exhibited a significant increase in Vmax compared with control and expressed a greater proportion of the fast (+)insert SM myosin isoform with respect to total myosin. BALB/cJ CFTR(-/-) ilium had a greater relaxation to isoproterenol than the CFTR(+/+) mice when precontracted with EFS, but no difference was observed in response to exogeneous MCh. In vivo, the lack of CFTR expression induces a different SM ileal phenotype in different mouse strains, supporting the importance of modifier genes in determining intestinal SM properties.     

Genetic characterization of a new set of recombinant inbred lines (LGXSM) formed from the intercross of SM/J and LG/J inbred mouse strains

A new set of LGXSM recombinant inbred (RI) strains is presented. The RI strain panel consists of 18 remaining strains of the original 55 founding strains. Strain characterization is based on 506 polymorphic microsatellites and 4289 single nucleotide polymorphisms (SNPs) distributed across the genome. Average microsatellite intermarker distance is 4.80 ± 4.84 Mb or 2.91 ± 3.21 F₂ cM. SNPs are more densely spaced at 0.57 ± 1.27 Mb. Ninety-five percent of all microsatellite intermarker intervals are separated by less than 15.00 Mb or 8.50 F₂ cM, while 95% of the SNPs are less than 0.95 Mb apart. Strains show expected low levels of nonsyntenic association among loci and complete genomic independence. During inbreeding, the RI strains went through strong natural selection on the agouti locus on Chromosome 2, especially when the epistatically interacting tyrosinase locus on Chromosome 7 carried the wild-type allele. The LG/J and SM/J strains differ in a large number of biomedically important traits, and they and their intercross progeny have been used in multiple mapping studies. The LG×SM RI strain panel provides a powerful new resource for mapping the genetic bases of complex traits and should prove to be of great biomedical utility in modeling complex human diseases such as obesity and diabetes. Electronic Supplementary Material Electronic Supplementary material is available for this article at and accessible for authorised users.     

Characterization of hyperinsulinemic recombinant inbred (RI) strains (SMXA-5 and SMXA-9) derived from normoinsulinemic SM/J and A/J mice.

We discovered two mouse strains (SMXA-5 and SMXA-9) with hyperinsulinemia among the substrains and progenitor strains (SM/J and A/J) of the SMXA recombinant inbred (RI) strains, and characterized the two strains at 20 weeks of age. SMXA-5 (mean +/- S.E.M: 9.6 +/- 1.7 ng/ml) and SMXA-9 (7.7 +/- 1.3 ng/ml) males had higher serum immunoreactive insulin levels than SM/J (1.4 +/- 0.3 ng/ml) and A/J (1.1 +/- 0.1 ng/ml) males in the nonfasting condition. The hypoglycemic response to insulin at 30 min after injection was significantly less in SMXA-5 males than in SM/J mice. Glucose tolerance test revealed that the incidence of impaired glucose tolerant males was 58% (11/19) in SMXA-5 and 42% (10/24) in SMXA-9 strains, but none in SM/J and A/J strains. SMXA-5 (209 +/- 29 mg/dl) and SMXA-9 (235 +/- 31 mg/dl) had higher serum triglyceride levels than SM/J (126 +/- 14 mg/dl) and A/J (89 +/- 5 mg/dl) males in the nonfasting condition. Histologic examination revealed enlarged islets in the pancreas of hyperinsulinemic SMXA-5 male mice. Moreover, SMXA-5 and SMXA-9 mice exhibited mild obesity. SMXA-5 and SMXA-9 males were therefore characterized by hyperinsulinemia, impaired glucose tolerance, hypertriglyceridemia and mild obesity which resembled some of the phenotypes of human Syndrome X, although both progenitor strains were normal so far as we examined. Since the RI strains are a powerful tool to facilitate polygenic-trait analysis, SMXA-5 and SMXA-9 mice will be useful materials to investigate the genetic basis of complex diseases, and are possible new metabolic models in relation to hyperinsulinemia.     

Diet,Obesity, and Hyperglycemia in LG/J and SM/J Mice

Objective: To examine the differential response of obesity‐ and diabetes‐related traits to a high‐ or low‐fat diet in LG/J and SM/J mice. We also examined food consumption in these strains. Research Methods and Procedures: Mice were placed on a high‐ or low‐fat diet after weaning. Animals were weighed once per week and subjected to glucose tolerance tests at 20 weeks. At sacrifice, fat pads and internal organs were removed along with serum samples. For food consumption, LG/J and SM/J mice of each sex were assigned to a high‐fat or low‐fat diet after reaching maturity. Mice were weighed three times per week, and food consumed was determined by subtraction. Results: LG/J animals consume more total food, but SM/J animals consume more food per gram of body weight. LG/J mice grow faster to 10 weeks but slower from 10 to 20 weeks, have higher cholesterol and free fatty acid levels, and have lower basal glucose levels and better response to a glucose challenge than SM/J mice. For most traits, SM/J mice respond more strongly to a high‐fat diet than LG/J mice, including body weight and growth, basal glucose levels, organ weights, fat distribution, and circulating triglycerides and cholesterol levels. Discussion: Obesity‐related phenotypes, as well as response to increased dietary fat, differ genetically between LG/J and SM/J and can, therefore, be mapped. This study indicates that the cross of SM/J and LG/J mice would be an excellent model system for the study of gene‐by‐diet interaction in obesity.