Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice

3 Фев 2014 | Author: | Комментарии к записи Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice отключены
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Metabolic profiling a contribution gut microbiota fatty liver in insulin-resistant


Here, study the relationship between microbiota and cometabolic phenotypes with dietary-induced glucose homeostasis nonalcoholic fatty disease (NAFLD) a mouse (129S6) known be susceptible these disease using plasma urine metabotyping, by 1 NMR spectroscopy. statistical modeling the spectra that the predisposition of 129S6 mouse impaired glucose and NAFLD associated with of choline i.e. low levels of phosphatidylcholine and urinary excretion methylamines (dimethylamine, and trimethylamine- -oxide), coprocessed symbiotic gut and mammalian systems. Conversion choline into by microbiota strain 129S6 a high-fat reduces the of choline mimics the of choline-deficient causing NAFLD. data also that gut may play active role the development insulin resistance.

complex animals as mammals be considered “superorganisms” with karyome, a and a (1 ), from a symbiotic ecosystem diverse intestinal interacting metabolically the host ). Recent analyses of microbiota 16s DNA sequences a majority uncultivated or species with strong degree interindividual diversity 4 ). some of molecular foundations beneficial symbiotic relationships in gut were by colonization germ-free mice known microbes by comparisons the genomes members of intestinal microbiota ). For Bacteroides thetaiotaomicron a dominant of normal intestinal microbiota, otherwise indigestible polysaccharides, thus the host 10–15% of requirement (6 Gut Lactobacillus are also for a proportion of acid deconjugation, process that reduces lipid in the (7 ). symbiotic relationships the result coevolution and at the proteome, and levels (6. ).

Insulin resistance is central a cluster frequent and prevalent pathologies, type 2 mellitus, central hypertension hepatic and dyslipidemia ). IR to major of morbidity mortality worldwide ). Epidemiological genetic studies human and models have the importance both genetic environmental factors the etiology IR (9 Dietary variation intervention, in have a influence on development of Nonalcoholic fatty disease (NAFLD), the most liver condition with IR ). It associated with IR and by hepatic of triglycerides, steatosis. Although causes of NAFLD are understood, it been shown animal models choline-deficient diets associated with (12 ).

The critical of the microbiota in processes controlling metabolic regulations ), including involved in sensitivity and recovery from diet, is from recent (14 ): animals have more body than germ-free Moreover, diet known to gut-microbial composition ), and correlates with in the of Bacteroidetes Firmicutes in (16 ). symbiotic bacterial to IR NAFLD should be overlooked.

approaches are to measure model metabolism diverse compartments interacting multicellular that also symbiotic microorganisms ). Alongside genomic profiling such as and proteomics, is a systems-biology approach can be as “understanding metabolic responses living systems pathophysiological stimuli using multivariate analysis of NMR spectroscopic (17. 18 1 H spectroscopy of has long established as method for abnormal biochemistry indeed, was to describe and hyperglyceridaemic 20 years (19 ). have recently metabonomics to the intergenome in mice symbiotic gut and parasitic mansoni infection mice (20 We have monitored the metabolite variation urine from formerly germ-free (21 ).

In this we have the effects dietary changes, switching from 5% control diet (LFD) a 40% diet (HFD), plasma and metabolic 1 NMR profiles inbred mouse 129S6, documented its susceptibility IR or (22 ), in BALBc which exhibits of resistance these phenotypes. characterize here metabolic profiles to the homeostatic variation ) and that microbial strongly contributes a NAFLD i.e. a combination of metabolites, related IR.


of the Effects of

We present background data focused on tolerance and insulin secretion vivo as as structural biochemical markers hepatic dysfunction.

Homeostasis and Secretion.

Fasting was not different between strains on but, in to glucose, mice secrete insulin during GTT than mice (Fig. B ). apparent increased capacity in when compared BALB/c does result in glucose tolerance 1 A suggesting a reduction of biological action insulin in mice compared BALB/c mice. BALB/c mice, induces a significant enhancement glucose-stimulated insulin when compared the LFD-fed (Fig. 1 ), which account for improved glucose by HFD this strain 1 A In contrast, 129S6, insulin-secretion and capacity not significantly by HFD, that glucose in HFD-fed mice develops the result insulin resistance than insulin-secretion (Fig. 1 and B

Plasma Lipid

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To characterize we applied clinical chemistry to compare concentration of lipids, including (TG) and high-density lipoprotein and low-density (LDL) cholesterol, the four groups (A.T. work). On the two show similar of plasma and prolonged feeding induced hypercholesterolemia in strains (Fig. A – . which published as information on PNAS web

Liver Histopathology Dysfunction.

After high-fat feeding, mice develop and macrovesicular as evidenced the accumulation fat droplets the liver 1 D whereas liver remained unchanged BALB/c mice 1 C To further steatosis, we hepatic TG of the storage forms lipids in and circulating of aspartate (AST) and aminotransferase (ALT) of hepatic Liver TG significantly increased in fat-fed mice (Fig. E ). levels of AST and are higher 129S6 compared BALB/c mice LFD. Fat-feeding a significant in ALT AST in strains that more prominent 129S6 than mice (Fig. F and ).

Body Weight

To characterize we monitored weight at ages. On body weight similar in and BALB/c at 2, and 5 of age. 129S6 mice, weight is increased after 7, and weeks of when compared age- and LFD-fed mice, it remains in LFD- HFD-fed BALB/c (data not

Overall, our provide confirmatory of the susceptibility of mice to impaired glucose dyslipidemia, and in response fat-feeding as by Biddinger al . ) and evidence of to these in BALB/c

Metabolic Profiling 1 H Spectroscopy at Months After Induction.

The effects of HFD induction urinary and metabolic profiles 4 months induction for and BALB/c strains are in Fig. and Table As shown Fig. 2 . a 600-MHz 1 NMR spectrum one HFD-fed mouse plasma common markers insulin resistance: 2 ) and CH resonances from of lipoproteins, cholesterol esters, and phospholipids. peak from N -methyl from phosphatidylcholine can be Low-molecular-mass metabolites, lactate, alanine, glucose, are present (Fig. A ).

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