Publications by authors named "Lutz Bünger"

31 Publications

PHOSPHO1 is a skeletal regulator of insulin resistance and obesity.

BMC Biol 2020 10 22;18(1):149. Epub 2020 Oct 22.

Roslin Institute, R(D)SVS, University of Edinburgh, Edinburgh, Scotland, UK.

Background: The classical functions of the skeleton encompass locomotion, protection and mineral homeostasis. However, cell-specific gene deletions in the mouse and human genetic studies have identified the skeleton as a key endocrine regulator of metabolism. The bone-specific phosphatase, Phosphatase, Orphan 1 (PHOSPHO1), which is indispensable for bone mineralisation, has been recently implicated in the regulation of energy metabolism in humans, but its role in systemic metabolism remains unclear. Here, we probe the mechanism underlying metabolic regulation by analysing Phospho1 mutant mice.

Results: Phospho1 mice exhibited improved basal glucose homeostasis and resisted high-fat-diet-induced weight gain and diabetes. The metabolic protection in Phospho1 mice was manifested in the absence of altered levels of osteocalcin. Osteoblasts isolated from Phospho1 mice were enriched for genes associated with energy metabolism and diabetes; Phospho1 both directly and indirectly interacted with genes associated with glucose transport and insulin receptor signalling. Canonical thermogenesis via brown adipose tissue did not underlie the metabolic protection observed in adult Phospho1 mice. However, the decreased serum choline levels in Phospho1 mice were normalised by feeding a 2% choline rich diet resulting in a normalisation in insulin sensitivity and fat mass.

Conclusion: We show that mice lacking the bone mineralisation enzyme PHOSPHO1 exhibit improved basal glucose homeostasis and resist high-fat-diet-induced weight gain and diabetes. This study identifies PHOSPHO1 as a potential bone-derived therapeutic target for the treatment of obesity and diabetes.
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http://dx.doi.org/10.1186/s12915-020-00880-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584094PMC
October 2020

Genetic parameters associated with meat quality of Nellore cattle at different anatomical points of longissimus: Brazilian standards.

Meat Sci 2021 Jan 18;171:108281. Epub 2020 Aug 18.

University of São Paulo, College of Veterinary Medicine and Animal Science, Av. Duque de Caxias Norte, 225, Postal Code: 13635-900 Pirassununga, Brazil. Electronic address:

The present study estimated genetic parameters and evaluated the genetic and phenotypic correlations between meat quality characteristics of Nellore cattle evaluated at different anatomical points of the longissimus. Data from 1329 Nellore young bulls were used to evaluate, in the 5th and 12th ribs, marbling score (MAR), shear force (SF), cooking weight losses (CWL) and intramuscular fat (IMF). In addition, the subcutaneous fat thickness was measured at the 12th rib (SFT) and between the last lumbar and the first sacral vertebrae (SFT), in the separation of loin and round. Results yielded moderate heritability coefficients for evaluated characteristics, except CWL. High genetic correlations (0.61) were found between measurements of SFT and SFT. MAR, IMF and SF were evaluated at the 5th and 12th rib. Meat quality and subcutaneous fat thickness measured at different anatomical points of the longissimus are genetically correlated and can be used in genetic selection programs to improve meat quality characteristics in Nellore cattle.
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http://dx.doi.org/10.1016/j.meatsci.2020.108281DOI Listing
January 2021

Predicting the shear value and intramuscular fat in meat from Nellore cattle using Vis-NIR spectroscopy.

Meat Sci 2020 May 1;163:108077. Epub 2020 Feb 1.

College of Veterinary Medicine and Animal Science, Av. Duque de Caxias Norte, 225, 13635-900 Pirassununga, Brazil. Electronic address:

Visible and near-infrared spectroscopy (Vis-NIRS) was tested for its effectiveness in predicting intramuscular fat (IMF) and WBSF in Nellore steers. Beef samples from longissimus thoracis, aged for either 2 or 7 days, had their spectra collected for wavelengths ranging from 400 to 1395 nm. Partial least squares regression models were developed for each trait. Determination coefficients of calibration models for WBSF ranged from 0.17 to 0.53. Considering WBSF in samples aged for 2 days, Vis-NIR correctly classified 100% of tough samples (>45 N), but wrongly classified all tender samples (≤45 N) as tough. Determination coefficients of calibration models for IMF ranged from 0.12 to 0.14. Vis-NIRS is a useful tool for identifying tough beef, but it is less effective in predicting tender samples and IMF. Additional studies are necessary to generate more robust models for the prediction of intramuscular fat in intact meat samples of Nellore cattle.
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http://dx.doi.org/10.1016/j.meatsci.2020.108077DOI Listing
May 2020

Effects of feed allowance and indispensable amino acid reduction on feed intake, growth performance and carcass characteristics of growing pigs.

PLoS One 2018 5;13(4):e0195645. Epub 2018 Apr 5.

Department of Agronomy, Food, Natural Resources, Animals and Environment, University of Padova, Legnaro, Padova, Italy.

The hypothesis that pigs placed on diets with reduced indispensable amino acid (AA) content attempts to offset the reduction in the nutrient density with increased feed intake was tested. In the experiment, feeds with a high or a low AA content were administrated to pigs fed ad-libitum or restrictively according to a 2 × 2 factorial design. Ninety-six barrows were housed in 8 pens (12 pigs/pen) equipped with automatic feeders. Within pen, and from 47 body weight (BW) onwards, 6 pigs were fed ad libitum. The others pigs were allowed to consume, as a maximum, the feed amounts indicated by the breeding company feeding plane to optimize the feed efficiency. In early (86-118 kg BW) and late (118-145 kg BW) finishing, the pigs of 4 pens received feeds with high indispensable AA contents (8.1 and 7.5 g lysine/kg in the two periods, respectively). The other pigs received feeds with reduced indispensable AA contents (lysine, methionine, threonine and tryptophan) by 9 and 18% in early and late finishing, respectively. Body lipid and protein (Pr) retentions were estimated from BW and back-fat depth measures recorded at the beginning and the end of each period. Nitrogen excretion was estimated as actual intake minus estimated N-retention (Pr/6.25). Pigs were slaughtered at 144 kg BW. Restricted feeding decreased feed intake (-7%), daily gain (-5%), carcass weight (-2.6%) and back-fat depth (-8.0%) but increased gain:feed ratio (+2%). The AA restriction increased feed intake (+5.9%), carcass weight (+4.9%) and intramuscular fat (+17.6%), and reduced carcass weight variation (-36%), with no effects on the feed efficiency and the estimated Pr (142 g/d). N excreted was reduced by feed (-9%) and dietary AA (-15%) restrictions. Irrespectively of the feeding level, the pigs responded to a reduction of the dietary essential AA content by increasing their feed intake.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195645PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886589PMC
July 2018

Baseline Muscle Mass Is a Poor Predictor of Functional Overload-Induced Gain in the Mouse Model.

Front Physiol 2016 15;7:534. Epub 2016 Nov 15.

School of Medicine, Medical Sciences and Nutrition, College of Life Sciences and Medicine, University of Aberdeen Aberdeen, UK.

Genetic background contributes substantially to individual variability in muscle mass. Muscle hypertrophy in response to resistance training can also vary extensively. However, it is less clear if muscle mass at baseline is predictive of the hypertrophic response. The aim of this study was to examine the effect of genetic background on variability in muscle mass at baseline and in the adaptive response of the mouse fast- and slow-twitch muscles to overload. Males of eight laboratory mouse strains: C57BL/6J (B6, = 17), BALB/cByJ ( = 7), DBA/2J (D2, = 12), B6.A-()/Kjn (B6.A, = 9), C57BL/6J-Chr10/NaJ (B6.A10, = 8), BEH+/+ ( = 11), BEH ( = 12), and DUHi ( = 12), were studied. Compensatory growth of soleus and plantaris muscles was triggered by a 4-week overload induced by synergist unilateral ablation. Muscle weight in the control leg (baseline) varied from 5.2 ± 07 mg soleus and 11.4 ± 1.3 mg plantaris in D2 mice to 18.0 ± 1.7 mg soleus in DUHi and 43.7 ± 2.6 mg plantaris in BEH ( < 0.001 for both muscles). In addition, soleus in the B6.A10 strain was ~40% larger ( < 0.001) compared to the B6. Functional overload increased muscle weight, however, the extent of gain was strain-dependent for both soleus ( < 0.01) and plantaris ( < 0.02) even after accounting for the baseline differences. For the soleus muscle, the BEH strain emerged as the least responsive, with a 1.3-fold increase, compared to a 1.7-fold gain in the most responsive D2 strain, and there was no difference in the gain between the B6.A10 and B6 strains. The BEH strain appeared the least responsive in the gain of plantaris as well, 1.3-fold, compared to ~1.5-fold gain in the remaining strains. We conclude that variation in muscle mass at baseline is not a reliable predictor of that in the overload-induced gain. This suggests that a different set of genes influence variability in muscle mass acquired in the process of normal development, growth, and maintenance, and in the process of adaptive growth of the muscle challenged by overload.
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http://dx.doi.org/10.3389/fphys.2016.00534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108802PMC
November 2016

Oxidative costs of reproduction in mouse strains selected for different levels of food intake and which differ in reproductive performance.

Sci Rep 2016 11 14;6:36353. Epub 2016 Nov 14.

Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen AB24 2TZ, UK.

Oxidative damage caused by reactive oxygen species has been hypothesised to underpin the trade-off between reproduction and somatic maintenance, i.e., the life-history-oxidative stress theory. Previous tests of this hypothesis have proved equivocal, and it has been suggested that the variation in responses may be related to the tissues measured. Here, we measured oxidative damage (protein carbonyls, 8-OHdG) and antioxidant protection (enzymatic antioxidant activity and serum antioxidant capacity) in multiple tissues of reproductive (R) and non-reproductive (N) mice from two mouse strains selectively bred for high (H) or low (L) food intake, which differ in their reproductive performance, i.e., H mice have increased milk energy output (MEO) and wean larger pups. Levels of oxidative damage were unchanged (liver) or reduced (brain and serum) in R versus N mice, and no differences in multiple measures of oxidative protection were found between H and L mice in liver (except for Glutathione Peroxidase), brain or mammary glands. Also, there were no associations between an individual's energetic investment (e.g., MEO) and most of the oxidative stress measures detected in various tissues. These data are inconsistent with the oxidative stress theory, but were more supportive of, but not completely consistent, with the 'oxidative shielding' hypothesis.
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http://dx.doi.org/10.1038/srep36353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107891PMC
November 2016

Myostatin dysfunction impairs force generation in extensor digitorum longus muscle and increases exercise-induced protein efflux from extensor digitorum longus and soleus muscles.

Appl Physiol Nutr Metab 2015 Aug 6;40(8):817-21. Epub 2015 Apr 6.

a Institute of Sports Sciences and Innovation, Lithuanian Sports University, Sporto 6, LT-44221, Kaunas, Lithuania.

Myostatin dysfunction promotes muscle hypertrophy, which can complicate assessment of muscle properties. We examined force generating capacity and creatine kinase (CK) efflux from skeletal muscles of young mice before they reach adult body and muscle size. Isolated soleus (SOL) and extensor digitorum longus (EDL) muscles of Berlin high (BEH) mice with dysfunctional myostatin, i.e., homozygous for inactivating myostatin mutation, and with a wild-type myostatin (BEH+/+) were studied. The muscles of BEH mice showed faster (P < 0.01) twitch and tetanus contraction times compared with BEH+/+ mice, but only EDL displayed lower (P < 0.05) specific force. SOL and EDL of age-matched but not younger BEH mice showed greater exercise-induced CK efflux compared with BEH+/+ mice. In summary, myostatin dysfunction leads to impairment in muscle force generating capacity in EDL and increases susceptibility of SOL and EDL to protein loss after exercise.
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http://dx.doi.org/10.1139/apnm-2014-0513DOI Listing
August 2015

Genome-wide association study of footrot in Texel sheep.

Genet Sel Evol 2015 Apr 30;47:35. Epub 2015 Apr 30.

Animal and Veterinary Sciences, Scotland's Rural College, Easter Bush, Midlothian, EH25 9RG, , Scotland, UK.

Background: This is the first study based on a genome-wide association approach that investigates the links between ovine footrot scores and molecular polymorphisms in Texel sheep using the ovine 50 K SNP array (42 883 SNPs (single nucleotide polymorphisms) after quality control). Our aim was to identify molecular predictors of footrot resistance.

Methods: This study used data from animals selected from a footrot-phenotyped Texel sheep population of 2229 sheep with an average of 1.60 scoring records per animal. From these, a subset of 336 animals with extreme trait values for footrot was selected for genotyping based on their phenotypic records. De-regressed estimated breeding values (EBV) for footrot were used as pseudo-phenotypes in the genome-wide association analysis.

Results: Seven SNPs were significant on a chromosome-wise level but the association analysis did not reveal any genome-wise significant SNPs associated with footrot. Based on the current state of knowledge of the ovine genome, it is difficult to clearly link the function of the genes that contain these significant SNPs with a potential role in resistance/susceptibility to footrot. Linkage disequilibrium (LD) was analysed as one of the factors that influence the power of detecting QTL (quantitative trait loci). A mean LD of 0.20 (r(2) at a distance of 50 kb between two SNPs) in the population analysed was estimated. LD declined from 0.15 to 0.07 and to 0.04 at distances between two SNPs of 100, 1000 and 2000 kb, respectively.

Conclusions: Based on a relatively small number of genotyped animals, this study is a first step to search for genomic regions that are involved in resistance to footrot using the ovine 50 K SNP array. Seven SNPs were found to be significant on a chromosome-wise level. No major genome-wise significant QTL were identified.
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http://dx.doi.org/10.1186/s12711-015-0119-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4415250PMC
April 2015

Limits to sustained energy intake. XXII. Reproductive performance of two selected mouse lines with different thermal conductance.

J Exp Biol 2014 Oct 11;217(Pt 20):3718-32. Epub 2014 Sep 11.

Institute of Biological and Environmental Sciences, University of Aberdeen, Aberdeen AB24 2TZ, UK Institute of Genetics and Developmental Biology, State Key Laboratory of Molecular Developmental Biology, Chinese Academy of Sciences, Bei Chen Xi Lu, Chaoyang, Beijing 100101, People's Republic of China

Maximal sustained energy intake (SusEI) appears limited, but the factors imposing the limit are disputed. We studied reproductive performance in two lines of mice selected for high and low food intake (MH and ML, respectively), and known to have large differences in thermal conductance (29% higher in the MH line at 21°C). When these mice raised their natural litters, their metabolisable energy intake significantly increased over the first 13 days of lactation and then reached a plateau. At peak lactation, MH mice assimilated on average 45.3% more energy than ML mice (222.9±7.1 and 153.4±12.5 kJ day(-1), N=49 and 24, respectively). Moreover, MH mice exported on average 62.3 kJ day(-1) more energy as milk than ML mice (118.9±5.3 and 56.6±5.4 kJ day(-1), N=subset of 32 and 21, respectively). The elevated milk production of MH mice enabled them to wean litters (65.2±2.1 g) that were on average 50.2% heavier than litters produced by ML mothers (43.4±3.0 g), and pups that were on average 27.2% heavier (9.9±0.2 and 7.8±0.2 g, respectively). Lactating mice in both lines had significantly longer and heavier guts compared with non-reproductive mice. However, inconsistent with the 'central limit hypothesis', the ML mice had significantly longer and heavier intestines than MH mice. An experiment where the mice raised litters of the opposing line demonstrated that lactation performance was not limited by the growth capacity of offspring. Our findings are consistent with the idea that the SusEI at peak lactation is constrained by the capacity of the mothers to dissipate body heat.
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http://dx.doi.org/10.1242/jeb.103705DOI Listing
October 2014

Genetic and genomic analyses of musculoskeletal differences between BEH and BEL strains.

Physiol Genomics 2013 Oct 20;45(20):940-7. Epub 2013 Aug 20.

School of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom;

Berlin high (BEH) and Berlin low (BEL) strains selected for divergent growth differ threefold in body weight. We aimed at examining muscle mass, which is a major contributor to body weight, by exploring morphological characteristics of the soleus muscle (fiber number and cross sectional area; CSA), by analyzing the transcriptome of the gastrocnemius and by initiating quantitative trait locus (QTL) mapping. BEH muscles were four to eight times larger than those of BEL. In substrain BEH+/+, mutant myostatin was replaced with a wild-type allele; however, BEH+/+muscles still were two to four times larger compared with BEL. BEH soleus muscle fibers were two times more numerous (P < 0.0001) and CSA was two times larger (P < 0.0001) compared with BEL. In addition, soleus femoral attachment anomaly (SFAA) was observed in all BEL mice. One significant (Chr 1) and four suggestive (Chr 3, 4, 6, and 9) muscle weight QTLs were mapped in a 21-day-old F2 intercross (n = 296) between BEH and BEL strains. The frequency of SFAA incidence in the F2 and in the backcross to BEL strain (BCL) suggested the presence of more than one causative gene. Two suggestive SFAA QTLs were mapped in BCL; however, their peak markers were not associated with the phenotype in F2. RNA-Seq analysis revealed 2,148 differentially expressed (P < 0.1) genes and 45,673 single nucleotide polymorphisms and >2,000 indels between BEH+/+ and BEL males. In conclusion, contrasting muscle traits and genomic and gene expression differences between BEH and BEL strains provide a promising model for the search for genes involved in muscle growth and musculoskeletal morphogenesis.
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http://dx.doi.org/10.1152/physiolgenomics.00109.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798766PMC
October 2013

Analyses of muscle spindles in the soleus of six inbred mouse strains.

J Anat 2013 Sep 8;223(3):289-96. Epub 2013 Jul 8.

School of Medical Sciences, University of Aberdeen, Aberdeen, UK.

Adult muscle size and fibre-type composition are heritable traits that vary substantially between individuals. We used inbred mouse strains in which soleus muscle mass varied by an order of magnitude to explore whether properties of muscle spindles can also be influenced by genetic factors. Skip-serial cross-sections of soleus muscles dissected from 15 male mice of BEH, BEL, C57BL/6J, DUH, LG/J and SM/J strains were analysed for number of muscle spindles and characteristics of intrafusal and extrafusal fibres following ATPase staining. The BEL and DUH strains determined the range of: soleus mean size, a 10-fold difference from 2.1 to 22.3 mg, respectively; the mean number of extrafusal fibres, a 2.5-fold difference from 497 to 1249; and mean fibre-cross-sectional area, three-fold difference, e.g. for type 1 fibres, from 678 to 1948 μm². The range of mean proportion of type 1 fibres was determined by C57BL/6J (31%) and DUH (64%) strains. The mean number of spindles per muscle ranged between nine (LG/J) and 13 (BEL) (strain effect P < 0.02). Genetic correlations between spindle count and muscle weight or properties of extrafusal fibres were weak and not statistically significant. However, there was a strong correlation between the proportion of spindles with more than one bag2 fibre and the proportion of extrafusal fibres that were of type 1, and strain-dependent variation in the numbers of such spindles was statistically significant. The numbers of intrafusal fibres per spindle ranged from 2 to 8, with the most common complement of four found in 75.6% of spindles. There were no significant differences between the strains in the mean numbers of intrafusal fibres; however, the variance of the number was significantly less for the C57BL/6J strain than for any of the others. We conclude that abundance of muscle spindles and their intrafusal-fibre composition are substantially determined by genetic factors, which are different from those affecting muscle size and properties of the extrafusal fibres.
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http://dx.doi.org/10.1111/joa.12076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972049PMC
September 2013

Parallel selection mapping using artificially selected mice reveals body weight control loci.

Curr Biol 2012 May 22;22(9):794-800. Epub 2012 Mar 22.

Max Planck Institute for Evolutionary Biology, August-Thienemann-Str. 2, 24306 Plön, Germany.

Understanding how polygenic traits evolve under selection is an unsolved problem, because challenges exist for identifying genes underlying a complex trait and understanding how multilocus selection operates in the genome. Here we study polygenic response to selection using artificial selection experiments. Inbred strains from seven independent long-term selection experiments for extreme mouse body weight ("high" lines weigh 42-77 g versus 16-40 g in "control" lines) were genotyped at 527,572 SNPs to identify loci controlling body weight. We identified 67 parallel selected regions (PSRs) where high lines share variants rarely found among the controls. By comparing allele frequencies in one selection experiment against its unselected control, we found classical selective sweeps centered on the PSRs. We present evidence supporting two G protein-coupled receptors GPR133 and Prlhr as positional candidates controlling body weight. Artificial selection may mimic natural selection in the wild: compared to control loci, we detected reduced heterozygosity in PSRs in unusually large wild mice on islands. Many PSRs overlap loci associated with human height variation, possibly through evolutionary conserved functional pathways. Our data suggest that parallel selection on complex traits may evoke parallel responses at many genes involved in diverse but relevant pathways.
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http://dx.doi.org/10.1016/j.cub.2012.03.011DOI Listing
May 2012

Factors affecting dystocia and offspring vigour in different sheep genotypes.

Prev Vet Med 2012 Mar 28;103(4):257-64. Epub 2011 Sep 28.

Sustainable Livestock Systems Group, Scottish Agricultural College, King's Building, Edinburgh, UK.

Birth difficulty and poor lamb vigour are significant causes of perinatal lamb mortality. In this study we investigated whether sheep breeds differing in appearance, muscularity and selection history also had differences in dystocia and lamb vigour, and considered some of the factors that may contribute to the variation in these traits. Data were collected at birth from a total of 3252 lambs of two terminal sire breeds selected for lean growth (Suffolk [S], n=500 and Texel [T], n=1207), from a Hill breed (Scottish Blackface [B], n=610), which has been mainly selected for hardiness, and a crossbred (Mule×T [M], n=935) representing a maternal line. For each lamb the degree of assistance at delivery, lamb presentation, amount of assistance to achieve successful sucking, sex, litter size and birth weight were recorded. T lambs required the most, and B and M lambs the least assistance at birth, S lambs were intermediate (% lambs assisted: T=55.7, S=30.7, B=22.7, M=24.9, P<0.001). T and S lambs were equally likely to be malpresented at birth (29% of births) and more likely to be malpresented than B or M lambs (20%; P<0.001). In T and S breeds lambs requiring veterinary assistance at delivery were mainly heavy and singleton lambs, whereas in B and M breeds these were exclusively low birth weight lambs in multiple litters. Although heavier lambs needed greater birth assistance, T lambs were lighter than S and M lambs, but heavier than B lambs (birth weight (kg): S=4.66, M=4.56, T=4.32, B=3.67, P<0.001). S lambs were more likely to require assistance with sucking than other breeds, and T lambs also required more assistance than B or M lambs (% lambs assisted to suck: S=56.0, T=31.6, M=19.8, B=18.4, P<0.001). Heavier lambs were more likely to suck unaided than lighter lambs (P<0.001). The data suggest that the two terminal sire breeds, selected narrowly for greater productivity (muscle growth and conformation), are more likely to experience birth difficulty and poorer lamb vigour than the breed selected for hardiness, or the cross breed. Whether these effects arise as a consequence of genetic selection (e.g. for specific lamb conformation), or as a result of management practices to achieve selection goals (e.g. increased intervention at lambing) is unknown. Specific actions to improve birth difficulty and lamb vigour, such as including these traits in the selection index, would be beneficial in improving the welfare of ewes and lambs of the terminal sire breeds.
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http://dx.doi.org/10.1016/j.prevetmed.2011.09.002DOI Listing
March 2012

A stratified transcriptomics analysis of polygenic fat and lean mouse adipose tissues identifies novel candidate obesity genes.

PLoS One 2011 7;6(9):e23944. Epub 2011 Sep 7.

Molecular Metabolism Group, BHF/University Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.

Background: Obesity and metabolic syndrome results from a complex interaction between genetic and environmental factors. In addition to brain-regulated processes, recent genome wide association studies have indicated that genes highly expressed in adipose tissue affect the distribution and function of fat and thus contribute to obesity. Using a stratified transcriptome gene enrichment approach we attempted to identify adipose tissue-specific obesity genes in the unique polygenic Fat (F) mouse strain generated by selective breeding over 60 generations for divergent adiposity from a comparator Lean (L) strain.

Results: To enrich for adipose tissue obesity genes a 'snap-shot' pooled-sample transcriptome comparison of key fat depots and non adipose tissues (muscle, liver, kidney) was performed. Known obesity quantitative trait loci (QTL) information for the model allowed us to further filter genes for increased likelihood of being causal or secondary for obesity. This successfully identified several genes previously linked to obesity (C1qr1, and Np3r) as positional QTL candidate genes elevated specifically in F line adipose tissue. A number of novel obesity candidate genes were also identified (Thbs1, Ppp1r3d, Tmepai, Trp53inp2, Ttc7b, Tuba1a, Fgf13, Fmr) that have inferred roles in fat cell function. Quantitative microarray analysis was then applied to the most phenotypically divergent adipose depot after exaggerating F and L strain differences with chronic high fat feeding which revealed a distinct gene expression profile of line, fat depot and diet-responsive inflammatory, angiogenic and metabolic pathways. Selected candidate genes Npr3 and Thbs1, as well as Gys2, a non-QTL gene that otherwise passed our enrichment criteria were characterised, revealing novel functional effects consistent with a contribution to obesity.

Conclusions: A focussed candidate gene enrichment strategy in the unique F and L model has identified novel adipose tissue-enriched genes contributing to obesity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0023944PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3168488PMC
February 2012

Interactive effects of protein nutrition, genetic growth potential and Heligmosomoides bakeri infection pressure on resilience and resistance in mice.

Parasitology 2011 Sep 18;138(10):1305-15. Epub 2011 Jul 18.

Animal Health, SAC, West Mains Road, Edinburgh EH9 3JG, UK.

The ability of animals to cope with an increasing parasite load, in terms of resilience and resistance, may be affected by both nutrient supply and demand. Here, we hypothesized that host nutrition and growth potential interact and influence the ability of mice to cope with different parasite doses. Mice selected for high (ROH) or low (ROL) body weight were fed a low (40 g/kg; LP) or high (230 g/kg; HP) protein diet and infected with 0, 50, 100, 150, 200 or 250 L3 infective Heligmosomoides bakeri larvae. ROH-LP mice grew less at doses of 150 L3 and above, whilst growth of ROH-HP and of ROL mice was not affected by infection pressure. Total worm burdens reached a plateau at doses of 150L3, whilst ROH mice excreted fewer worm eggs than ROL mice. Serum antibodies increased with infection dose and ROH mice were found to have higher parasite-specific IgG1 titres than ROL mice. In contrast, ROL had higher total IgE titres than ROH mice, only on HP diets. The interaction between host nutrition and growth potential appears to differentially affect resilience and resistance in mice. However, the results support the view that parasitism penalises performance in animals selected for higher growth.
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http://dx.doi.org/10.1017/S0031182011000990DOI Listing
September 2011

The effect of gestational undernutrition on maternal weight change and fetal weight in lines of mice selected for different growth characteristics.

Br J Nutr 2011 Feb;105(4):539-48

Sustainable Livestock Systems Group, Scottish Agricultural College, King's Buildings, West Mains Road, Edinburgh EH9 3JG, UK.

The present study investigated whether the genetic growth characteristics (fast or slow growing, lean or fat) of a mother influences her ability to partition nutrients to developing offspring. A total of sixty-one pregnant mice of three selected lines were used: fast-growing, relatively fat (FF, n 19); fast-growing, relatively lean (FL, n 23); and normal growth, relatively lean (NL, n 19). On day 1 of pregnancy, mice were given either ad libitum access to food (control (C): n 32) or pair-fed at 80 % of C intake (restricted (R): n 29). Feed intake and dam weight were measured daily. The weight of the mouse, organs, mammary tissue and the weight of fetuses and placentas were determined at day 18 of gestation. Overall, R dams gained less than half the weight of C dams during gestation. NL dams gained the most weight, and FF dams gained the least weight (P < 0·001). R dams in the fast-growing lines mobilised significantly more body fat during gestation than the NL line (P < 0·001) and had a greater reduction in mammary tissue growth. The relative weight of the litter increased in R dams of the FF line but was reduced in both the lean lines. Undernutrition reduced fetal and placental weight, and reduced placental efficiency in all the lines. The reduction was least in the FF line and greatest in the FL line. The data suggest that selection of animals for different growth characteristics alters their response to undernutrition during pregnancy, the relatively fat line was better able to buffer its offspring from the effects of undernutrition than the lean lines, regardless of their underlying rate of growth.
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http://dx.doi.org/10.1017/S0007114510004022DOI Listing
February 2011

Divergent physical activity and novel alternative responses to high fat feeding in polygenic fat and lean mice.

Behav Genet 2008 May 18;38(3):292-300. Epub 2008 Mar 18.

Biotechnical Faculty, Zootechnical Department, University of Ljubljana, 1230, Domzale, Slovenia.

We determined whether altered physical activity levels might underlie the contrasting adiposity of a divergently selected polygenic murine model of metabolic syndrome (Fat; F) and leanness (Lean; L) mice. We measured physical activity with a long term running wheel experiment and performed an additional high fat diet intervention. Further, we measured posture allocation by visual monitoring within the home cage as a non-exercise correlate of 'normal' physical activity. Whilst initially similar, running wheel activity of the F line declined with age, while the activity of the L line increased. Food intake was higher in the L line and increased with wheel exposure. Vertical rearing measured by video quantification in the home cage, without the stimulus of a running wheel was also significantly higher in the L line. The two lines developed novel alternate strategies to defend their body weight when exposed to high fat diets with a running wheel. F mice increased their running wheel activity, and despite unaltered food intake, still gained weight. L mice reduced their food intake and maintained activity levels without a significant change in body weight. Phenotypic selection for divergence in body fat content has co-segregated with a genetic predisposition for divergent physical activity levels and different strategies for coping with exposure to high fat diets that will facilitate the discovery of the genes underlying these important obesity related traits.
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http://dx.doi.org/10.1007/s10519-008-9199-yDOI Listing
May 2008

Quantitative trait Loci for regional adiposity in mouse lines divergently selected for food intake.

Obesity (Silver Spring) 2007 Dec;15(12):2994-3004

Aberdeen Centre for Energy Regulation and Obesity, School of Biological Sciences, University of Aberdeen, UK.

Objective: Obesity is thought to result from an interaction between genotype and environment. Excessive adiposity is associated with a number of important comorbidities; however, the risk of obesity-related disease varies with the distribution of fat throughout the body. The aim of this study was to map quantitative trait loci (QTLs) associated with regional fat depots in mouse lines divergently selected for food intake corrected for body mass.

Research Methods And Procedures: Using an F2 intercross design (n = 457), the dry mass of regional white (subcutaneous, gonadal, retroperitoneal, and mesenteric) adipose tissue (WAT) and brown adipose tissue (BAT) depots were analyzed to map QTLs.

Results: The total variance explained by the mapped QTL varied between 12% and 39% for BAT and gonadal fat depots, respectively. Using the genome-wide significance threshold, nine QTLs were associated with multiple fat depots. Chromosomes 4 and 19 were associated with WAT and BAT and chromosome 9 with WAT depots. Significant sex x QTL interactions were identified for gonadal fat on chromosomes 9, 16, and 19. The pattern of QTLs identified for the regional deposits showed the most similarity between retroperitoneal and gonadal fat, whereas BAT showed the least similarity to the WAT depots. Analysis of total fat mass explained in excess of 40% of total variance.

Discussion: There was limited concordance between the QTLs mapped in our study and those reported previously. This is likely to reflect the unique nature of the mouse lines used. Results provide an insight into the genetic basis of regional fat distribution.
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http://dx.doi.org/10.1038/oby.2007.357DOI Listing
December 2007

Fine mapping of mouse QTLs for fatness using SNP data.

OMICS 2007 ;11(4):341-50

Institute for Animal Sciences, Humboldt-Universität zu Berlin, Berlin, Germany.

Quantitative trait loci (QTLs), as determined in crossbred studies, are a valuable resource to identify genes responsible for the corresponding phenotypic variances. Due to their broad chromosomal extension of some dozens of megabases, further steps are necessary to bring the number of candidate genes that underlie the detected effects to a reasonable order of magnitude. We use a set of 13,370 SNPs to identify informative haplotype blocks in 22 mouse QTLs for fatness. About half of the genes in a typical QTL overlap with haplotype blocks, which are different for the two base mouse lines, and which, thus, qualify for further analysis. For these genes we collect four more pieces of evidence for association with fat accumulation, namely (1) homology to genes identified in a Caenorhabditis elegans knock-out experiment as fat decreasing or fat increasing, (2) the overexpression of the genes in mouse fat, liver, muscle, or hypothalamus tissues, (3) the occurrence of a gene in several independently found QTLs, and (4) the information provided by gene ontology, to achieve a ranked list of 131 candidate genes. Ten genes fulfill three or four of the above sketched criteria and are discussed briefly, 121 further genes fulfilling two criteria are provided as on-line material. Viewing the genomic region of fatness-related QTLs under several different aspects is appropriate to assess the many thousands of genes that reside in such QTLs and to produce lists of more robust candidate genes.
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http://dx.doi.org/10.1089/omi.2007.0015DOI Listing
March 2008

Lack of myostatin results in excessive muscle growth but impaired force generation.

Proc Natl Acad Sci U S A 2007 Feb 31;104(6):1835-40. Epub 2007 Jan 31.

Department of Paediatrics, University Hospital of Essen, Essen, Germany.

The lack of myostatin promotes growth of skeletal muscle, and blockade of its activity has been proposed as a treatment for various muscle-wasting disorders. Here, we have examined two independent mouse lines that harbor mutations in the myostatin gene, constitutive null (Mstn(-/-)) and compact (Berlin High Line, BEH(c/c)). We report that, despite a larger muscle mass relative to age-matched wild types, there was no increase in maximum tetanic force generation, but that when expressed as a function of muscle size (specific force), muscles of myostatin-deficient mice were weaker than wild-type muscles. In addition, Mstn(-/-) muscle contracted and relaxed faster during a single twitch and had a marked increase in the number of type IIb fibers relative to wild-type controls. This change was also accompanied by a significant increase in type IIB fibers containing tubular aggregates. Moreover, the ratio of mitochondrial DNA to nuclear DNA and mitochondria number were decreased in myostatin-deficient muscle, suggesting a mitochondrial depletion. Overall, our results suggest that lack of myostatin compromises force production in association with loss of oxidative characteristics of skeletal muscle.
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http://dx.doi.org/10.1073/pnas.0604893104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1794294PMC
February 2007

A polygenic model of the metabolic syndrome with reduced circulating and intra-adipose glucocorticoid action.

Diabetes 2005 Dec;54(12):3371-8

Endocrinology Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, UK.

Despite major advances in understanding monogenic causes of morbid obesity, the complex genetic and environmental etiology of idiopathic metabolic syndrome remains poorly understood. One hypothesis suggests that similarities between the metabolic disease of plasma glucocorticoid excess (Cushing's syndrome) and idiopathic metabolic syndrome results from increased glucocorticoid reamplification within adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1). Indeed, 11beta-HSD-1 is now a major therapeutic target. Because much supporting evidence for a role of adipose 11beta-HSD-1 comes from transgenic or obese rodents with single-gene mutations, we investigated whether the predicted traits of metabolic syndrome and glucocorticoid metabolism were coassociated in a unique polygenic model of obesity developed by long-term selection for divergent fat mass (Fat and Lean mice with 23 vs. 4% fat as body weight, respectively). Fat mice exhibited an insulin-resistant metabolic syndrome including fatty liver and hypertension. Unexpectedly, Fat mice had a marked intra-adipose (11beta-HSD-1) and plasma glucocorticoid deficiency but higher liver glucocorticoid action. Furthermore, metabolic disease was exacerbated only in Fat mice when challenged with exogenous glucocorticoids or a high-fat diet. Our data suggest that idiopathic metabolic syndrome might associate with such a novel pattern of glucocorticoid action and sensitivity in humans, with implications for tissue-specific therapeutic targeting of 11beta-HSD-1.
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http://dx.doi.org/10.2337/diabetes.54.12.3371DOI Listing
December 2005

A paternally imprinted QTL for mature body mass on mouse chromosome 8.

Mamm Genome 2005 Aug 14;16(8):567-77. Epub 2005 Sep 14.

Aberdeen Centre for Energy Regulation and Obesity (ACERO), School of Biological Sciences, University of Aberdeen, Tillydrone Avenue, Aberdeen, AB24 2TZ, UK.

Body mass (BM) is a classic polygenic trait that has been extensively investigated to determine the underlying genetic architecture. Many previous studies looking at the genetic basis of variation in BM in murine animal models by quantitative trait loci (QTL) mapping have used crosses between two inbred lines. As a consequence it has not been possible to explore imprinting effects which have been shown to play an important role in the genetic basis of early growth with persistent effects throughout the growth curve. Here we use partially inbred mouse lines to identify QTL for mature BM by applying both Mendelian and Imprinting models. The analysis of an F2 population (n approximately 500) identified a number of QTL at 14, 16, and 18 weeks explaining in total 31.5%, 34.4%, and 30.5% of total phenotypic variation, respectively. On Chromosome 8 a QTL of large effect (14% of the total phenotypic variance at 14 weeks) was found to be explained by paternal imprinting. Although Chromosome 8 has not been previously associated with imprinting effects, features of candidate genes within the QTL confidence interval (CpG islands and direct clustered repeats) support the hypothesis that Insulin receptor substrate 2 may be associated with imprinting, but as yet is unidentified as being so.
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http://dx.doi.org/10.1007/s00335-005-0012-4DOI Listing
August 2005

Relationships between quantitative and reproductive fitness traits in animals.

Philos Trans R Soc Lond B Biol Sci 2005 Jul;360(1459):1489-502

Scottish Agricultural College, Sustainable Livestock Systems Group, Bush Estate, Penicuik, EH26 0PH, UK.

The relationships between quantitative and reproductive fitness traits in animals are of general biological importance for the development of population genetic models and our understanding of evolution, and of great direct economical importance in the breeding of farm animals. Two well investigated quantitative traits--body weight (BW) and litter size (LS)--were chosen as the focus of our review. The genetic relationships between them are reviewed in fishes and several mammalian species. We have focused especially on mice where data are most abundant. In mice, many individual genes influencing these traits have been identified, and numerous quantitative trait loci (QTL) located. The extensive data on both unselected and selected mouse populations, with some characterized for more than 100 generations, allow a thorough investigation of the dynamics of this relationship during the process of selection. Although there is a substantial positive genetic correlation between both traits in unselected populations, caused mainly by the high correlation between BW and ovulation rate, that correlation apparently declines during selection and therefore does not restrict a relatively independent development of both traits. The importance of these findings for overall reproductive fitness and its change during selection is discussed.
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http://dx.doi.org/10.1098/rstb.2005.1679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1569514PMC
July 2005

Effects of the compact mutant myostatin allele Mstn (Cmpt-dl1Abc) introgressed into a high growth mouse line on skeletal muscle cellularity.

J Muscle Res Cell Motil 2005 1;26(2-3):103-12. Epub 2005 Jul 1.

Department of Muscle Biology and Growth, Research Institute for the Biology of Farm Animals, Wilhelm-Stahl-Allee 2, D-18196 Dummerstorf, Germany.

The murine myostatin mutation Mstn(Cmpt-dl1Abc) (Compact; C) was introduced into an inbred mouse line with extreme growth (DUHi) by marker-assisted introgression. To study the allelic effects on muscle fibre hyperplasia and hypertrophy, myonuclear proliferation, protein accretion, capillary density, and muscle fibre metabolism, samples from M. rectus femoris (RF) and M. longissimus dorsi (LD) muscles of animals wild-type (+/+), heterozygous (C/+), and homozygous (C/C) for the Mstn(Cmpt-dl1Abc) allele were examined by histological and biochemical analyses. Homozygous C/C mice exhibited lower body (-12%) but higher muscle weights (+38%) than ++ mice. Total muscle fibre number was increased (+24%), whereas fibre size was not significantly affected. Protein and DNA concentrations and DNA:protein ratios as well as specific CK activity remained unchanged for higher mass muscle implying increases in the total contents of DNA and muscle specific protein. Fibre type distribution was markedly shifted to the white glycolytic muscle fibres (+16-17% units) at the expense of red oxidative fibres. Capillary density was substantially lower in C/C than in ++ mice as seen by lower number of capillaries per fibre (-35%) and larger fibre area per capillary (+77%). However, the Mstn(Cmpt-dl1Abc) allele was partially recessive in heterozygous C/+ mice for both fibre type frequencies and capillary density. The results show that hypermuscularity caused by mutations in the myostatin gene results from muscle fibre hyperplasia rather than hypertrophy, and from balanced increases in myonuclear proliferation and protein accretion. However, capillary supply is adversely affected and muscle metabolism shifted towards glycolysis, which could have negative consequences for physical fitness.
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http://dx.doi.org/10.1007/s10974-005-1099-7DOI Listing
July 2006

Mice with low metabolic rates are not susceptible to weight gain when fed a high-fat diet.

Obes Res 2005 Mar;13(3):556-66

School of Biological Sciences, Aberdeen Center for Energy Regulation and Obesity, University of Aberdeen, Aberdeen, UK.

Objective: Mice divergently selected for high or low food intake (FI) at constant body mass differ in their resting metabolic rates (RMRs). Low-intake individuals (ML) have significantly lower RMR (by 30%) compared with those from the high-intake line (MH). We hypothesized that MLs might, therefore, be more likely to increase their body and fat mass when exposed to a high-fat diet (HFD).

Research Methods And Procedures: We exposed both lines to a diet with 44.9% calories from fat for 3 weeks while measuring FI, fecal production, and body mass and then returned the mice to standard chow.

Results: When exposed to the HFD, both lines significantly decreased their FI (MH, 40% to 45%; ML, 31% to 35%). This decrease occurred simultaneously with a significant increase in apparent energy absorption efficiency (AEAE). When returned to chow, FI and AEAE returned to the levels observed prior to HFD exposure. Because of the adjustments in FI, the absorbed energy was maintained in the MLs and, thus, body mass remained constant. The MH individuals overcompensated for the elevated energy content and AEAE on the HFD and, therefore, absorbed lower energy than when feeding on chow. These mice also did not significantly change their body mass when on the HFD and must have made adjustments in their energy expenditures. Both lines and both sexes increased in fat content on the HFD, but these effects were not different between lines or sexes.

Discussion: We found no support for the hypothesis that mice with low RMRs were more susceptible to weight gain when fed the HFD.
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http://dx.doi.org/10.1038/oby.2005.59DOI Listing
March 2005

Marker-assisted introgression of the Compact mutant myostatin allele MstnCmpt-dl1Abc into a mouse line with extreme growth effects on body composition and muscularity.

Genet Res 2004 Dec;84(3):161-73

Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, Edinburgh, EH9 3JT, UK.

Myostatin is a negative regulator of muscle growth and mutations in its gene lead to muscular hypertrophy and reduced fat. In cattle, this is seen in 'double muscled' breeds. We have used marker-assisted introgression to introduce a murine myostatin mutation, MstnCmpt-dl1Abc [Compact (C)], into an inbred line of mice (DUHi) that had been selected on body weight and had exceptional growth. Compared with homozygous wild-type mice, homozygous (C/C) mice of this line were approximately 4-5 % lighter, had approximately 7-8 % shorter tails, substantially increased muscle weights (e.g. quadriceps muscle in males was 59 % heavier) and an increased 'dressing percentage' (approximately 49 % vs 39 %), an indicator of overall muscularity. The weights of several organs (e.g. liver, kidney, heart and digestive tract) were significantly reduced, by 12-20 %. Myostatin deficiency also resulted in drastic reductions of total body fat and of various fat depots, total body fat proportion falling from approximately 17.5 % in wild-type animals of both sexes to 9.5 % and 11.6% in homozygous (C/C) females and males, respectively. Males with a deficiency in myostatin had higher gains in muscle traits than females. Additionally, there was a strong distortion of the segregation ratio on the DUHi background. Of 838 genotyped pups from inter se matings 29 %, 63 % and 8 % were homozygous wild type (+/+), heterozygous (C/+) and homozygous (C/C), respectively, showing that MstnCmpt-dl1Abc has lower fitness on this background. This line, when congenic, will be a useful resource in gene expression studies and for finding modifying genes.
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http://dx.doi.org/10.1017/s0016672304007165DOI Listing
December 2004

Microarray gene expression analysis of the Fob3b obesity QTL identifies positional candidate gene Sqle and perturbed cholesterol and glycolysis pathways.

Physiol Genomics 2005 Feb 14;20(3):224-32. Epub 2004 Dec 14.

Department of Gene Expression, Roslin Institute, Edinburgh, Scotland.

Obesity-related diseases are poised to become the primary cause of death in developed nations. While a number of monogenic causes of obesity have recently been identified, these are responsible for only a small proportion of human cases of obesity. Quantitative trait locus (QTL) studies using animal models have revealed hundreds of potential loci that affect obesity; however, few have been further analyzed beyond the original QTL scan. We previously mapped four QTL in an F(2) between divergently selected Fat (F) and Lean (L) lines. A QTL of large effect on chromosome 15 (Fob3) was subsequently mapped to a higher resolution into two smaller-effect QTL (Fob3a and Fob3b) using crosses between the F-line and a congenic line containing L-line alleles at the Fob3 QTL region. Here we report the gene expression characterization of Fob3b. Microarray expression analysis using the NIA-NIH 15K cDNA array set containing 14,938 mouse ESTs was employed to identify candidate genes and pathways that are differentially expressed between the F-line and a congenic line containing only the Fob3b QTL (Fob3b-line). Our study suggests squalene epoxidase (Sqle), a cholesterol biosynthesis enzyme, as a strong positional candidate gene for Fob3b. Several other cholesterol biosynthesis pathway genes unlinked to Fob3b were found to be differentially expressed, suggesting that a perturbation of this pathway could be in part responsible for the phenotypic difference between the F-line and Fob3b-line mice.
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http://dx.doi.org/10.1152/physiolgenomics.00183.2004DOI Listing
February 2005

Identification and reciprocal introgression of a QTL affecting body mass in mice.

Genet Sel Evol 2004 Sep-Oct;36(5):577-91

Institute of Cell, Animal and Population Biology, University of Edinburgh, Ashworth Laboratories, King's Buildings, West Mains Road, Edinburgh EH9 3JT, UK.

The aim of this study was to examine the effects of a QTL in different genetic backgrounds. A QTL affecting body mass on chromosome 6 was identified in an F(2) cross between two lines of mice that have been divergently selected for this trait. The effect of the QTL on mass increased between 6 and 10 weeks of age and was not sex-specific. Body composition analysis showed effects on fat-free dry body mass and fat mass. To examine the effect of this QTL in different genetic backgrounds, the high body mass sixth chromosome was introgressed into the low body mass genetic background and vice versa by repeated marker-assisted backcrossing. After three generations of backcrossing, new F(2) populations were established within each of the introgression lines by crossing individuals that were heterozygous across the sixth chromosome. The estimated additive effect of the QTL on 10-week body mass was similar in both genetic backgrounds and in the original F(2) population (i.e., approximately 0.4 phenotypic standard deviations); no evidence of epistatic interaction with the genetic background was found. The 95% confidence interval for the location of the QTL was refined to a region of approximately 7 cM between D6Mit268 and D6Mit123.
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http://dx.doi.org/10.1186/1297-9686-36-5-577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697194PMC
March 2005

Genetic complexity of an obesity QTL ( Fob3) revealed by detailed genetic mapping.

Mamm Genome 2004 Jun;15(6):472-81

Roslin Institute (Edinburgh), Roslin, EH25 9PS, Scotland, UK.

Obesity is proving to be a serious health concern in the developed world as well as an unwanted component of growth in livestock production. While recent advances in genetics have identified a number of monogenic causes of obesity, these are responsible for only a small proportion of human cases of obesity. By divergent selection for high and low fat content over 60 generations, we have created Fat (F) and Lean (L) lines of mice that represent a model of polygenic obesity similar to the situation in human populations. From previous crosses of these lines, four body fat quantitative trait loci (QTL) were identified. We have created congenic lines (F(chr15L)), by recurrent marker-assisted backcrossing, to introgress the QTL region with the highest LOD score, Fob3 on Chr 15, from the L-Iine into the F-line background. We have further mapped this QTL by progeny testing of recombinants, produced from crosses between the F-line and congenic F(chrl5L) mice, showing that the Fob3 QTL region is a composite of at least two smaller effect QTL-the proximal QTL Fob3a is a late-onset obesity QTL, whereas the distal Fob3b is an early-onset obesity QTL.
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http://dx.doi.org/10.1007/s00335-004-3039-zDOI Listing
June 2004

Growth selection in mice reveals conserved and redundant expression patterns of the insulin-like growth factor system.

Gen Comp Endocrinol 2004 Apr;136(2):248-59

Lehrstuhl für Molekulare Tierzucht und Biotechnologie/Genzentrum, Ludwig-Maximilians-Universität, 81377 Munich, Germany.

Transgenic and knockout models have been used successfully in order to attribute specific functions to distinct growth factors. However, it is not clear which from the different IGF-components are actually altered when growth is affected. Furthermore it is not clear if unique or redundant patterns of IGF-component expression are present under conditions of elevated or reduced growth. To address these questions we have used a unique set of mouse models generated by divergent selection for high and low body growth. The set of mouse models consisted of eight mouse lines established in different laboratories. We have studied systemic and local expression of growth relevant genes in these mouse lines highly diverging for body and carcass weights but also for nose-rump lengths. As a strictly conserved pattern, serum IGF-I levels were dramatically increased in all H-lines if compared with the respective L-lines. By contrast serum IGFBP concentrations did not reveal clear patterns of expression in response to growth selection: IGFBP-3 was elevated in some H-lines, IGFBP-2 was increased in H- or L-lines and IGFBP-4 was similar in H- and L-lines. The fact that IGFBP-2 was the only IGFBP elevated in part of the L-lines, identifies IGFBP-2 as an exclusive although facultative negative effector for growth in the circulation among all other IGFBPs. In muscle tissue from selected breeding groups characterized by specific increases of the carcass weights we found redundant patterns of gene expression indicating the absence of tissue-specific or uniquely fixed expression patterns during growth selection within muscle tissue. The finding that serum but not tissue IGF-I levels were strictly positively correlated with growth during growth selection argues for an important role of endocrine IGF-I for postnatal growth in mice.
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http://dx.doi.org/10.1016/j.ygcen.2003.12.019DOI Listing
April 2004