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NMR-based metabolic profiling in healthy individuals overfed different types of fat: links to changes in liver fat accumulation and lean tissue mass.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
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2015 (English)In: Nutrition & Diabetes, ISSN 2044-4052, E-ISSN 2044-4052, Vol. 5, no 19, e182- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Overeating different dietary fatty acids influence the amount of liver fat stored during weight gain, however, the mechanisms responsible are unclear. We aimed to identify non-lipid metabolites that may differentiate between saturated (SFA) and polyunsaturated fatty acid (PUFA) overfeeding using a non-targeted metabolomic approach. We also investigated the possible relationships between plasma metabolites and body fat accumulation.

METHODS: In a randomized study (LIPOGAIN study), n=39 healthy individuals were overfed with muffins containing SFA or PUFA. Plasma samples were precipitated with cold acetonitrile and analyzed by nuclear magnetic resonance (NMR) spectroscopy. Pattern recognition techniques were used to overview the data, identify variables contributing to group classification and to correlate metabolites with fat accumulation.

RESULTS: We previously reported that SFA causes a greater accumulation of liver fat, visceral fat and total body fat, whereas lean tissue levels increases less compared with PUFA, despite comparable weight gain. In this study, lactate and acetate were identified as important contributors to group classification between SFA and PUFA (P<0.05). Furthermore, the fat depots (total body fat, visceral adipose tissue and liver fat) and lean tissue correlated (P(corr)>0.5) all with two or more metabolites (for example, branched amino acids, alanine, acetate and lactate). The metabolite composition differed in a manner that may indicate higher insulin sensitivity after a diet with PUFA compared with SFA, but this needs to be confirmed in future studies.

CONCLUSION: A non-lipid metabolic profiling approach only identified a few metabolites that differentiated between SFA and PUFA overfeeding. Whether these metabolite changes are involved in depot-specific fat storage and increased lean tissue mass during overeating needs further investigation.

Place, publisher, year, edition, pages
2015. Vol. 5, no 19, e182- p.
National Category
Medical and Health Sciences Nutrition and Dietetics
Identifiers
URN: urn:nbn:se:uu:diva-267034DOI: 10.1038/nutd.2015.31ISI: 000368899900002PubMedID: 26479316OAI: oai:DiVA.org:uu-267034DiVA: diva2:871811
Funder
Swedish Research Council, K2015-54X-22081-04-3Swedish Diabetes Association
Note

Rosqvist, Engskog, Haglöf, Riséus and Pettersson contributed equally to this work.

Available from: 2015-11-17 Created: 2015-11-17 Last updated: 2017-12-01Bibliographically approved
In thesis
1. Dietary Fatty Acids, Body Composition and Ectopic Fat : Results from Overfeeding Studies in Humans
Open this publication in new window or tab >>Dietary Fatty Acids, Body Composition and Ectopic Fat : Results from Overfeeding Studies in Humans
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aim of this thesis was to investigate the effects of dietary fatty acids on body composition and ectopic fat in humans, with emphasis on the role of the omega-6 polyunsaturated fatty acid (PUFA) linoleic acid (18:2n-6) and the saturated fatty acid (SFA) palmitic acid (16:0). The overall hypothesis was that linoleic acid would be beneficial compared with palmitic acid during overfeeding, as previously indicated in animals.

Papers I, II and IV were double-blinded, randomized interventions in which different dietary fats were provided to participants and Paper III was a cross-sectional study in a community-based cohort (PIVUS) in which serum fatty acid composition was assessed as a biomarker of dietary fat intake.

In Paper I, overfeeding with sunflower oil (n-6 PUFA) for 7 weeks caused less accumulation of liver fat, visceral fat and total body fat (as assessed by MRI) compared with palm oil (SFA) in young and lean subjects despite similar weight gain among groups. Instead, sunflower oil caused a larger accumulation of lean tissue.

In Paper II, plasma from Paper I was analyzed with NMR-based metabolomics, aiming to identify metabolites differentially affected by the two dietary treatments. Acetate decreased by PUFA and increased by SFA whereas lactate increased by PUFA and decreased by SFA.

In Paper III, the proportion of linoleic acid in serum was inversely associated with contents of visceral-, subcutaneous- and total body adipose tissue whereas the proportion of palmitic acid was directly associated with visceral- and total body adipose tissue in 70-year old men and women.

In Paper IV, overfeeding with sunflower oil for 8 weeks caused less accumulation of liver fat compared with palm oil also in overweight and obese subjects. SFA increased visceral fat in men only. Accumulation of lean tissue was similar between groups.

In conclusion, SFA (palmitic acid) from palm oil promotes marked liver fat accumulation in both normal-weight and overweight/obese subjects during overeating, whereas n-6 PUFA (linoleic acid) from sunflower oil prevents such liver fat accumulation. Diverging effects of SFA and PUFA on visceral adipose tissue and lean tissue may only be applicable in some groups and/or circumstances. These results imply that negative effects associated with weight gain (e.g. fatty liver) may be partly counteracted by the type fat in the diet, overall supporting a beneficial role of diets higher in unsaturated fat compared with saturated fat for preventing liver fat accumulation. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 94 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1358
Keyword
Linoleic acid, Palmitic acid, SFA, PUFA, Fatty acids, Body composition, Liver fat, Ectopic fat, Adipose tissue
National Category
Nutrition and Dietetics
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-280949 (URN)978-91-554-9523-7 (ISBN)
Public defence
2016-05-13, Auditorium Minus, Museum Gustavianum, Akademigatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-04-22 Created: 2016-03-16 Last updated: 2016-04-29
2. Selectivity in NMR and LC-MS Metabolomics: The Importance of Sample Preparation and Separation, and how to Measure Selectivity in LC-MS Metabolomics.
Open this publication in new window or tab >>Selectivity in NMR and LC-MS Metabolomics: The Importance of Sample Preparation and Separation, and how to Measure Selectivity in LC-MS Metabolomics.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Until now, most metabolomics protocols have been optimized towards high sample throughput and high metabolite coverage, parameters considered to be highly important for identifying influenced biological pathways and to generate as many potential biomarkers as possible. From an analytical point of view this can be troubling, as neither sample throughput nor the number of signals relates to actual quality of the detected signals/metabolites. However, a method’s selectivity for a specific signal/metabolite is often closely associated to the quality of that signal, yet this is a parameter often neglected in metabolomics.

This thesis demonstrates the importance of considering selectivity when developing NMR and LC-MS metabolomics methods, and introduces a novel approach for measuring chromatographic and signal selectivity in LC-MS metabolomics.

Selectivity for various sample preparations and HILIC stationary phases was compared. The choice of sample preparation affected the selectivity in both NMR and LC-MS. For the stationary phases, selectivity differences related primarily to retention differences of unwanted matrix components, e.g. inorganic salts or glycerophospholipids. Metabolites co-eluting with these matrix components often showed an incorrect quantitative signal, due to an influenced ionization efficiency and/or adduct formation.

A novel approach for measuring selectivity in LC-MS metabolomics has been introduced. By dividing the intensity of each feature (a unique mass at a specific retention time) with the total intensity of the co-eluting features, a ratio representing the combined chromatographic (amount of co-elution) and signal (e.g. in-source fragmentation) selectivity is acquired. The calculated co-feature ratios have successfully been used to compare the selectivity of sample preparations and HILIC stationary phases.

In conclusion, standard approaches in metabolomics research might be unwise, as each metabolomics investigation is often unique.  The methods used should be adapted for the research question at hand, primarily based on any key metabolites, as well as the type of sample to be analyzed. Increased selectivity, through proper choice of analytical methods, may reduce the risks of matrix-associated effects and thereby reduce the false positive and false negative discovery rate of any metabolomics investigation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 40 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 232
Keyword
Metabolomics, NMR, LC-MS, HILIC, UHPLC, Q-ToF, selectivity, co-feature ratio, method evaluation, data evaluation
National Category
Pharmaceutical Sciences Analytical Chemistry
Research subject
Analytical Pharmaceutical Chemistry
Identifiers
urn:nbn:se:uu:diva-318296 (URN)978-91-554-9879-5 (ISBN)
Public defence
2017-05-19, B41, BMC, Husargatan 3, Uppsala, 10:15 (Swedish)
Opponent
Supervisors
Available from: 2017-04-26 Created: 2017-03-30 Last updated: 2017-05-05

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