Eugene J. Eisen

Conjugated linoleic acid evokes de‐lipidation through the regulation of genes controlling lipid metabolism in adipose and liver tissue

Conjugated linoleic acid (CLA) is a unique lipid that elicits dramatic reductions in adiposity in several animal models when included at ≤ 1% of the diet. Despite a flurry of investigations, the precise mechanisms by which conjugated linoleic acid elicits its dramatic effects in adipose tissue and liver are still largely unknown. In vivo and in vitro analyses of physiological modifications imparted by conjugated linoleic acid on protein and gene expression suggest that conjugated linoleic acid exerts its de‐lipidating effects by modulating energy expenditure, apoptosis, fatty acid oxidation, lipolysis, stromal vascular cell differentiation and lipogenesis. The purpose of this review shall be to examine the recent advances and insights into conjugated linoleic acids effects on obesity and lipid metabolism, specifically focused on changes in gene expression and physiology of liver and adipose tissue.

A large-sample QTL study in mice: II. Body composition

Using lines of mice having undergone long-term selection for high and low growth, a large-sample (n = ~1,000 F2) experiment was conducted to gain further understanding of the genetic architecture of complex polygenic traits. Composite interval mapping on data from male F2 mice (n = 552) detected 50 QTL on 15 chromosomes impacting weights of various organ and adipose subcomponents of growth, including heart, liver, kidney, spleen, testis, and subcutaneous and epididymal fat depots. Nearly all aggregate growth QTL could be interpreted in terms of the organ and fat subcomponents measured. More than 25% of QTL detected map to MMU2, accentuating the relevance of this chromosome to growth and fatness in the context of this cross. Regions of MMU7, 15, and 17 also emerged as important obesity “hot-spots.” Average degrees of directional dominance are close to additivity, matching expectations for body composition traits. A strong QTL congruency is evident among heart, liver, kidney, and spleen weights. Liver and testis are organs whose genetic architectures are, respectively, most and least aligned with that for aggregate body weight. In this study, growth and body weight are interpreted in terms of organ subcomponents underlying the macro aggregate traits, and anchored on the corresponding genomic locations.

A large-sample QTL study in mice: I. Growth.

By use of long-term selection lines for high and low growth, a large-sample (n = ~1,000 F2) experiment was conducted in mice to further understand the genetic architecture of complex polygenic traits. In combination with previous work, we conclude that QTL analysis has reinforced classic polygenic paradigms put in place prior to molecular analysis. Composite interval mapping revealed large numbers of QTL for growth traits with an exponential distribution of magnitudes of effects and validated theoretical expectations regarding gene action. Of particular significance, large effects were detected on Chromosome (Chr) 2. Regions on Chrs 1, 3, 6, 10, 11, and 17 also harbor loci with significant contributions to phenotypic variation for growth. Despite the large sample size, average confidence intervals of ~20 cM exhibit the poor resolution for initial estimates of QTL location. Analysis with genome-wide and chromosomal polygenic models revealed that, under certain assumptions, large fractions of the genome may contribute little to phenotypic variation for growth. Only a few epistatic interactions among detected QTL, little statistical support for gender-specific QTL, and significant age effects on genetic architecture were other primary observations from this study.

Inbred lines of mice derived from long-term growth selected lines: unique resources for mapping growth genes.

Abstract. Lines of mice selected for many generations for high or low growth in several laboratories around the world have been collected, and from these, inbred lines are being developed by recurrent full-sib mating in Edinburgh. There are seven high selected lines and four low lines (each low line is from the same base population as one of the high lines), and the histories of each are summarized. Mean body weight of males at 70 days of age in the Edinburgh laboratory in the heaviest inbred line (77 g) is 4.8-fold higher than in the lightest line (16 g), and 1.9-fold higher than in the least extreme high line (41 g). Litter size, food intake, and fat content also differ substantially. These inbred extreme selected lines are a uniquely valuable resource for QTL or gene mapping, candidate gene identification, and elucidation of epistatic effects.

The contribution of epistatic pleiotropy to the genetic architecture of covariation among polygenic traits in mice

SUMMARY The contribution that pleiotropic effects of individual loci make to covariation among traits is well understood theoretically and is becoming well documented empirically. However, little is known about the role of epistasis in determining patterns of covariation among traits. To address this problem we combine a quantitative trait locus (QTL) analysis with a two‐locus model to assess the contribution of epistasis to the genetic architecture of variation and covariation of organ weights and limb bone lengths in a backcross population of mice created from the M16i and CAST/Ei strains. Significant epistasis was exhibited by 14 pairwise combinations of QTL for organ weights and 10 combinations of QTL for limb bone lengths, which contributed, on average, about 5% of the variation in organ weights and 8% in limb bone lengths beyond that of single‐locus QTL effects. Epistatic pleiotropy was much more common in the limb bones (seven of 10 epistatic combinations affecting limb bone lengths were pleiotropic) than the organs (three of the 14 epistatic combinations affecting organ weights were pleiotropic). In both cases, epistatic pleiotropy was less common than single‐locus pleiotropy. Epistatic pleiotropy accounted for an average of 6% of covariation among organ weights and 21% of covariation among limb bone lengths, which represented an average of one‐fifth (for organ weights) and one‐third (for limb bone lengths) of the total genetic covariance between traits. Thus, although epistatic pleiotropy made a smaller contribution than single‐locus pleiotropy, it clearly made a significant contribution to the genetic architecture of variation/covariation.

Quantitative trait loci for directional but not fluctuating asymmetry of mandible characters in mice.

Non-directional variation in right minus left differences in bilateral characters, referred to as fluctuating asymmetry (FA), often has been assumed to be largely or entirely environmental in origin. FA increasingly has been used as a measure of developmental stability, and its presumed environmental origin has facilitated the comparisons of populations believed to differ in their levels of stability. Directional asymmetry (DA), in which one side is consistently larger than the other, has been assumed to be at least partially heritable. Both these assumptions were tested with interval mapping techniques designed to detect any quantitative trait loci (QTLs) affecting FA or DA in 15 bilateral mandible characters in house mice resulting from a cross of the F1 between CAST/Ei (wild strain) and M16i (selected for rapid growth rate) back to M16i. For purposes of the analysis, all mandibles were triply measured and 92 microsatellite markers were scored in a total of 350 mice. No significant QTLs were found for FA, but three QTLs significantly affected DA in several characters, confirming both assumptions. The QTLs for DA were similar in location to those affecting the size of several of the mandible characters, although they accounted for an average of only 1% of the total phenotypic variation in DA.

Bayesian Analyses of Multiple Epistatic QTL Models for Body Weight and Body Composition in Mice

To comprehensively investigate the genetic architecture of growth and obesity, we performed Bayesian analyses of multiple epistatic quantitative trait locus (QTL) models for body weights at five ages (12 days, 3, 6, 9 and 12 weeks) and body composition traits (weights of two fat pads and five organs) in mice produced from a cross of the F1 between M16i (selected for rapid growth rate) and CAST/Ei (wild-derived strain of small and lean mice) back to M16i. Bayesian model selection revealed a temporally regulated network of multiple QTL for body weight, involving both strong main effects and epistatic effects. No QTL had strong support for both early and late growth, although overlapping combinations of main and epistatic effects were observed at adjacent ages. Most main effects and epistatic interactions had an opposite effect on early and late growth. The contribution of epistasis was more pronounced for body weights at older ages. Body composition traits were also influenced by an interacting network of multiple QTLs. Several main and epistatic effects were shared by the body composition and body weight traits, suggesting that pleiotropy plays an important role in growth and obesity.

The mouse in animal genetics and breeding research

* The Beginnings: Ode to a Wee Mouse (E J Eisen) * Testing Quantitative Genetic Selection Theory (E J Eisen) * Maternal Effects, Genomic Imprinting and Evolution (J Funk-Keenan & W R Atchley) * Inbreeding and Crossbreeding (G A Brockmann) * Genotype by Environment Interaction: Lessons From the Mouse (W D Hohenboken) * Genetics of Growth in the Mouse (J M Cheverud) * Genetics of Body Composition and Metabolic Rate (L Bunger & W G Hill) * Genetics of Reproduction (M K Nielsen) * Genetics of Behavior (R J Hitzemann) * Genetics of Disease Resistance (S L Ewart & R A Ramadas) * Genomic Dissection of Complex Trait Predisposition (D Pomp) * Mouse Mutagenesis (D R Beier) * Embryo Biotechnologies (C A Pinkert & M J Martin) * Transgenics (J D Murray & E A Maga) * The Mouse in Biomedical Research (R B Roberts & D W Threadgill) * The Mouse Genome Sequencing Project: An Overview (M C Wendl et al.)

A large-sample QTL study in mice: III. Reproduction

Using lines of mice having undergone long-term selection for high and low growth, a large-sample (n ≈ 1000 F2) experiment was conducted to gain further understanding of the genetic architecture of complex polygenic traits. Composite interval mapping on data from 10-week-old F2 females (n = 439) detected 15 quantitative trait loci (QTLs) on 5 chromosomes that influence reproduction traits characterized at day 16 of gestation. These QTL are broadly categorized into two groups: those where effects on the number of live fetuses (LF) were accompanied by parallel effects on the number of dead fetuses (DF), and those free of such undesirable effects. QTL for ovulation rate (OR) did not overlap with QTL for litter size, potentially indicating the importance of uterine capacity. Large dominance effects were identified for most QTL detected, and overdominance was also present. The QTL of largest effects were detected in regions of Chromosome 2, where large QTL effects for growth and fatness have also been found and where corroborating evidence from other studies exists. Considerable overlap between locations of QTL for reproductive traits and for growth traits corresponds well with the positive correlations usually observed among these sets of phenotypes. Some support for the relevance of QTL × genetic background interactions in reproduction was detected. Traits with low heritability demand considerably larger sample sizes to achieve effective power of QTL detection. This is unfortunate as traits with low heritability are among those that could most benefit from QTL-complemented breeding and selection strategies in food animal production.

Trans-10, cis-12-conjugated linoleic acid alters hepatic gene expression in a polygenic obese line of mice displaying hepatic lipidosis.

The trans-10, cis-12 isomer of conjugated linoleic acid (CLA) causes a rapid reduction of body and adipose mass in mice. In addition to changes in adipose tissue, numerous studies have reported alterations in hepatic lipid metabolism. Livers of CLA-fed mice gain mass, partly due to lipid accumulation; however, the precise molecular mechanisms are unknown. To elucidate these mechanisms, we examined fatty acid composition and gene expression profiles of livers from a polygenic obese line of mice fed 1% trans-10, cis-12-CLA for 14 days. Analysis of gene expression data led to the identification of 1393 genes differentially expressed in the liver of CLA-fed male mice at a nominal P value of .01, and 775 were considered significant using a false discovery rate (FDR) threshold of .05. While surprisingly few genes in lipid metabolism were impacted, pathway analysis found that protein kinase A (PKA) and cyclic adenosine monophosphate (cAMP) pathways signaling pathways were affected by CLA treatment and 98 of the 775 genes were found to be regulated by hepatocyte nuclear factor 4alpha, a transcription factor important in controlling liver metabolic status.