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      Hepatic Metabolic Profile Reveals the Adaptive Mechanisms of Ewes to Severe Undernutrition during Late Gestation

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          Abstract

          The mechanisms underlying the adaption of liver metabolism to the undernutrition in ewes during late gestation remain unclear. This research aimed to explore the adaptive mechanisms of liver metabolism by hepatic metabolome analysis in pregnant ewes to the negative energy balance induced by severe feed restriction. Twenty ewes carrying multiple fetuses and gestating for 115 days were fed normally or restricted to a 30% feed level (10 ewes in each group) for 15 days. All ewes were sacrificed and hepatic samples were collected and analyzed by liquid chromatography-mass spectrometry. Both the principal components analysis and partial least squares of discriminant analysis of hepatic metabolites showed the clear separation between ewes in the control and severely feed-restricted groups. The metabolic profile demonstrated that the proportions of differential metabolites between the two groups in fatty acids and lipids, organic acids, and amino acids and derivatives were 61.11%, 16.67%, and 11.11%, respectively. Enriched pathways of differential metabolites were mainly involved in fatty acids and amino acids metabolism and biosynthesis. Correlation networks of differential metabolites revealed that general metabolic pattern was changed apparently and mainly based on fatty acids and lipids in the livers of feed-restricted ewes. The accumulation and oxidation of long-chain fatty acids were intensified in the livers of feed-restricted ewes, while those of medium-chain fatty acids were the opposite. In general, severe feed restriction significantly affected the levels of hepatic metabolites and altered the overall metabolic pattern. Furthermore, fatty acids oxidation as well as the utilization of amino acids and organic acids were intensified to adapt to the negative energy balance during late gestation.

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          Most cited references 26

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          MetaboAnalyst: a web server for metabolomic data analysis and interpretation

          Metabolomics is a newly emerging field of ‘omics’ research that is concerned with characterizing large numbers of metabolites using NMR, chromatography and mass spectrometry. It is frequently used in biomarker identification and the metabolic profiling of cells, tissues or organisms. The data processing challenges in metabolomics are quite unique and often require specialized (or expensive) data analysis software and a detailed knowledge of cheminformatics, bioinformatics and statistics. In an effort to simplify metabolomic data analysis while at the same time improving user accessibility, we have developed a freely accessible, easy-to-use web server for metabolomic data analysis called MetaboAnalyst. Fundamentally, MetaboAnalyst is a web-based metabolomic data processing tool not unlike many of today's web-based microarray analysis packages. It accepts a variety of input data (NMR peak lists, binned spectra, MS peak lists, compound/concentration data) in a wide variety of formats. It also offers a number of options for metabolomic data processing, data normalization, multivariate statistical analysis, graphing, metabolite identification and pathway mapping. In particular, MetaboAnalyst supports such techniques as: fold change analysis, t-tests, PCA, PLS-DA, hierarchical clustering and a number of more sophisticated statistical or machine learning methods. It also employs a large library of reference spectra to facilitate compound identification from most kinds of input spectra. MetaboAnalyst guides users through a step-by-step analysis pipeline using a variety of menus, information hyperlinks and check boxes. Upon completion, the server generates a detailed report describing each method used, embedded with graphical and tabular outputs. MetaboAnalyst is capable of handling most kinds of metabolomic data and was designed to perform most of the common kinds of metabolomic data analyses. MetaboAnalyst is accessible at http://www.metaboanalyst.ca
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            New insights concerning the role of carnitine in the regulation of fuel metabolism in skeletal muscle.

            In skeletal muscle, carnitine plays an essential role in the translocation of long-chain fatty-acids into the mitochondrial matrix for subsequent beta-oxidation, and in the regulation of the mitochondrial acetyl-CoA/CoASH ratio. Interest in these vital metabolic roles of carnitine in skeletal muscle appears to have waned over the past 25 years. However, recent research has shed new light on the importance of carnitine as a regulator of muscle fuel selection. It has been established that muscle free carnitine availability may be limiting to fat oxidation during high intensity submaximal exercise. Furthermore, increasing muscle total carnitine content in resting healthy humans (via insulin-mediated stimulation of muscle carnitine transport) reduces muscle glycolysis, increases glycogen storage and is accompanied by an apparent increase in fat oxidation. By increasing muscle pyruvate dehydrogenase complex (PDC) activity and acetylcarnitine content at rest, it has also been established that PDC flux and acetyl group availability limits aerobic ATP re-synthesis at the onset of exercise (the acetyl group deficit). Thus, carnitine plays a vital role in the regulation of muscle fuel metabolism. The demonstration that its availability can be readily manipulated in humans, and impacts on physiological function, will result in renewed business and scientific interest in this compound.
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              Evidence for altered placental blood flow and vascularity in compromised pregnancies.

              The placenta is the organ that transports nutrients, respiratory gases, and wastes between the maternal and fetal systems. Consequently, placental blood flow and vascular development are essential components of normal placental function and are critical to fetal growth and development. Normal fetal growth and development are important to ensure optimum health of offspring throughout their subsequent life course. In numerous sheep models of compromised pregnancy, in which fetal or placental growth, or both, are impaired, utero-placental blood flows are reduced. In the models that have been evaluated, placental vascular development also is altered. Recent studies found that treatments designed to increase placental blood flow can 'rescue' fetal growth that was reduced due to low maternal dietary intake. Placental blood flow and vascular development are thus potential therapeutic targets in compromised pregnancies.
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                Author and article information

                Journal
                Metabolites
                Metabolites
                metabolites
                Metabolites
                MDPI
                2218-1989
                27 November 2018
                December 2018
                : 8
                : 4
                Affiliations
                Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, Laboratory of Gastrointestinal Microbiology, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; xueyanfeng1990@ 123456163.com (Y.X.); 2017205025@ 123456njau.edu.cn (C.G.); 2016105046@ 123456njau.edu.cn (F.H.); liujunhua0011@ 123456163.com (J.L.)
                Author notes
                [* ]Correspondence: maoshengyong@ 123456njau.edu.cn ; Tel.: +86-25-8439-5523
                Article
                metabolites-08-00085
                10.3390/metabo8040085
                6316483
                30486444
                © 2018 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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