Changes in metabolite profiles caused by genetically determined obesity in mice.

The Berlin Fat Mouse Inbred (BFMI) line harbors a major recessive gene defect on chromosome 3 (jobes1) leading to juvenile obesity and metabolic syndrome. The present study aimed at the identification of metabolites that might be linked to recessively acting genes in the obesity locus. Firstly, serum metabolites were analyzed between obese BFMI and lean B6 and BFMI × B6 F1 mice to identify metabolites that are different. In a second step, a metabolite-protein network analysis was performed linking metabolites typical for BFMI mice with genes of the jobes1 region. The levels of 22 diacyl-phosphatidylcholines (PC aa), two lyso-PC and three carnitines were found to be significantly lower in obese mice compared with lean mice, while serine, glycine, arginine and hydroxysphingomyelin were higher for the same comparison. The network analysis identified PC aa C42:1 as functionally linked with the genes Ccna2 and Trpc3 via the enzymes choline kinase alpha and phospholipase A2 group 1B (PLA2G1B), respectively. Gene expression analysis revealed elevated Ccna2 expression in adipose tissue of BFMI mice. Furthermore, unique mutations were found in the Ccna2 promoter of BFMI mice which are located in binding sites for transcription factors or micro RNAs and could cause differential Ccna2 mRNA levels between BFMI and B6 mice. Increased expression of Ccna2 was consistent with higher mitotic activity of adipose tissue in BFMI mice. Therefore, we suggest a higher demand for PC necessary for adipose tissue growth and remodeling. This study highlights the relationship between metabolite profiles and the underlying genetics of obesity in the BFMI line.

ATR-FTIR spectroscopy reveals genomic loci regulating the tissue response in high fat diet fed BXD recombinant inbred mouse strains.

BACKGROUND: Obesity-associated organ-specific pathological states can be ensued from the dysregulation of the functions of the adipose tissues, liver and muscle. However, the influence of genetic differences underlying gross-compositional differences in these tissues is largely unknown. In the present study, the analytical method of ATR-FTIR spectroscopy has been combined with a genetic approach to identify genetic differences responsible for phenotypic alterations in adipose, liver and muscle tissues. RESULTS: Mice from 29 BXD recombinant inbred mouse strains were put on high fat diet and gross-compositional changes in adipose, liver and muscle tissues were measured by ATR-FTIR spectroscopy. The analysis of genotype-phenotype correlations revealed significant quantitative trait loci (QTL) on chromosome 12 for the content of fat and collagen, collagen integrity, and the lipid to protein ratio in adipose tissue and on chromosome 17 for lipid to protein ratio in liver. Using gene expression and sequence information, we suggest Rsad2 (viperin) and Colec11 (collectin-11) on chromosome 12 as potential quantitative trait candidate genes. Rsad2 may act as a modulator of lipid droplet contents and lipid biosynthesis; Colec11 might play a role in apoptopic cell clearance and maintenance of adipose tissue. An increased level of Rsad2 transcripts in adipose tissue of DBA/2J compared to C57BL/6J mice suggests a cis-acting genetic variant leading to differential gene activation. CONCLUSION: The results demonstrate that the analytical method of ATR-FTIR spectroscopy effectively contributed to decompose the macromolecular composition of tissues that accumulate fat and to link this information with genetic determinants. The candidate genes in the QTL regions may contribute to obesity-related diseases in humans, in particular if the results can be verified in a bigger BXD cohort.

Body weight and energy homeostasis was not affected in C57BL/6 mice fed high whey protein or leucine-supplemented low-fat diets.

BACKGROUND: Leucine is suggested to act as nutrient signal of high-protein diets regulating pathways associated with an alleviation of metabolic syndrome parameters. However, the subject remains controversial. AIM OF THE STUDY: The aim of this study was to assess and to compare the effects of high-protein diets with dietary leucine supplementation in mice, particularly on energy homeostasis, body composition, and expression of uncoupling protein (UCP), which are suggested to decrease food energy efficiency. METHODS: Male C57BL/6 mice were exposed for 14 weeks to semi-synthetic diets containing either 20% (adequate protein content, AP) or 50% whey protein (high-protein content, HP). A third group was fed the AP diet supplemented with L-leucine (AP + L) corresponding to the leucine content of the HP diet. The total fat content was 5% (w/w). RESULTS: Body weight gain, body composition, energy expenditure, and protein expression of UCP1 in brown adipose tissue, and UCP3 in skeletal muscle were not different between groups. In HP-fed mice, a stronger increase in blood glucose levels was detected during glucose tolerance tests compared to AP and AP + L, whereas plasma insulin was similar in all groups. Leucine supplementation did not affect glucose tolerance. Plasma cholesterol was significantly decreased in HP and AP + L when compared to AP. Plasma triglyceride concentrations were increased twofold in HP-fed mice when compared to AP + L and AP groups. Liver and skeletal muscle triglyceride and glycogen concentrations were similar in all groups. Postabsorptive plasma concentrations of branched-chain amino acids were not significantly increased after exposure to HP and AP + L diets, whereas those of lysine were decreased in HP and AP + L mice when compared to AP (P < 0.001). Plasma methionine concentrations were lower after HP intake when compared to AP and AP + L (P < 0.05). CONCLUSIONS: We suggest that an exposure of mice to HP diets or a corresponding leucine supplementation has no significant effect on energy homeostasis and UCP expression compared with AP diets when feeding a low-fat diet. The use of high-quality whey protein might at least in part explain the results obtained.