Here, we study the intricate relationship between gut microbiota and host cometabolic phenotypes associated with dietary-induced impaired glucose homeostasis and nonalcoholic fatty liver disease (NAFLD) in a mouse strain (129S6) known to be susceptible to these disease traits, using plasma and urine metabotyping, achieved by 1 H NMR spectroscopy. Multivariate statistical modeling of the spectra shows that the genetic predisposition of the 129S6 mouse to impaired glucose homeostasis and NAFLD is associated with disruptions of choline metabolism, i.e., low circulating levels of plasma phosphatidylcholine and high urinary excretion of methylamines (dimethylamine, trimethylamine, and trimethylamine-Noxide), coprocessed by symbiotic gut microbiota and mammalian enzyme systems. Conversion of choline into methylamines by microbiota in strain 129S6 on a high-fat diet reduces the bioavailability of choline and mimics the effect of choline-deficient diets, causing NAFLD. These data also indicate that gut microbiota may play an active role in the development of insulin resistance.metabonomics ͉ NMR ͉ nonalcoholic fatty liver disease ͉ nutritional genomics ͉ metabolic syndrome H ighly complex animals such as mammals can be considered as ''superorganisms'' with a karyome, a chondriome, and a microbiome (1), resulting from a coevolutionary symbiotic ecosystem of diverse intestinal microbiota interacting metabolically with the host (2). Recent molecular analyses of human microbiota 16s ribosomal DNA sequences revealed a majority of uncultivated or unknown species with a strong degree of interindividual diversity (3, 4). Also, some of the molecular foundations of beneficial symbiotic host-bacteria relationships in the gut were revealed by colonization of germ-free mice with known microbes and by comparisons of the genomes of members of the intestinal microbiota (5). For instance, Bacteroides thetaiotaomicron, a dominant member of normal distal intestinal microbiota, hydrolyzes otherwise indigestible dietary polysaccharides, thus supplying the host with 10-15% of calorific requirement (6). Gut Lactobacillus spp. are also responsible for a significant proportion of bile acid deconjugation, a process that efficiently reduces lipid absorption in the gut (7). Such symbiotic relationships are the result of coevolution and operate at the genome, proteome, and metabolome levels (6,8).Insulin resistance (IR) is central to a cluster of frequent and increasingly prevalent pathologies, including type 2 diabetes mellitus, central obesity, hypertension hepatic steatosis, and dyslipidemia (9). IR contributes to major causes of morbidity and mortality worldwide (10). Epidemiological and genetic studies in human and animal models have demonstrated the importance of both genetic and environmental factors in the etiology of IR (9): Dietary variation and intervention, in particular, have a strong influence on the development of IR. Nonalcoholic fatty liver disease (NAFLD), is the most frequent liver condition associated with IR (11). It is associa...

Aims/hypothesis Complex changes in gene expression are associated with insulin resistance and non-alcoholic fatty liver disease (NAFLD) promoted by feeding a high-fat diet (HFD). We used functional genomic technologies to document molecular mechanisms associated with dietinduced NAFLD. Materials and Methods Male 129S6 mice were fed a diet containing 40% fat (high-fat diet, HFD) for 15 weeks. Glucose tolerance, in vivo insulin secretion, plasma lipid profile and adiposity were determined. Plasma metabonomics and liver transcriptomics were used to identify changes in gene expression associated with HFD-induced NAFLD.Results In HFD-fed mice, NAFLD and impaired glucose and lipid homeostasis were associated with increased hepatic transcription of genes involved in fatty acid uptake, intracellular transport, modification and elongation, whilst genes involved in beta-oxidation and lipoprotein secretion were, paradoxically, also upregulated. NAFLD developed despite strong and sustained downregulation of transcription of the gene encoding stearoyl-coenzyme A desaturase 1 (Scd1) and uncoordinated regulation of transcription of Scd1 and the gene encoding sterol regulatory element binding factor 1c (Srebf1c) transcription. Inflammatory mechanisms appeared to be stimulated by HFD. Conclusions/interpretation Our results provide an accurate representation of subtle changes in metabolic and gene expression regulation underlying disease-promoting and compensatory mechanisms, collectively contributing to dietinduced insulin resistance and NAFLD. They suggest that proposed models of NAFLD pathogenesis can be enriched with novel diet-reactive genes and disease mechanisms.

Background-Interstitial white matter neurons (IWMNs) may reflect immature neurons which migrate tangentially to the neocortex from the ganglionic eminence to form cortical interneurons. Alterations of interneuron markers have been detected in gray matter of dorsolateral prefrontal cortex (DLPFC) in schizophrenia and IWMNs are also reported to be altered in schizophrenia. In this study we asked if a potential link exists between these two pathological findings.