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Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance.

ABSTRACT: Dietary intake of saturated fat is a likely contributor to nonalcoholic fatty liver disease (NAFLD) and insulin resistance, but the mechanisms that initiate these abnormalities in humans remain unclear. We examined the effects of a single oral saturated fat load on insulin sensitivity, hepatic glucose metabolism, and lipid metabolism in humans. Similarly, initiating mechanisms were examined after an equivalent challenge in mice.Fourteen lean, healthy individuals randomly received either palm oil (PO) or vehicle (VCL). Hepatic metabolism was analyzed using in vivo 13C/31P/1H and ex vivo 2H magnetic resonance spectroscopy before and during hyperinsulinemic-euglycemic clamps with isotope dilution. Mice underwent identical clamp procedures and hepatic transcriptome analyses.PO administration decreased whole-body, hepatic, and adipose tissue insulin sensitivity by 25%, 15%, and 34%, respectively. Hepatic triglyceride and ATP content rose by 35% and 16%, respectively. Hepatic gluconeogenesis increased by 70%, and net glycogenolysis declined by 20%. Mouse transcriptomics revealed that PO differentially regulates predicted upstream regulators and pathways, including LPS, members of the TLR and PPAR families, NF-?B, and TNF-related weak inducer of apoptosis (TWEAK).Saturated fat ingestion rapidly increases hepatic lipid storage, energy metabolism, and insulin resistance. This is accompanied by regulation of hepatic gene expression and signaling that may contribute to development of NAFLD.REGISTRATION. ClinicalTrials.gov NCT01736202.Germany: Ministry of Innovation, Science, and Research North Rhine-Westfalia, German Federal Ministry of Health, Federal Ministry of Education and Research, German Center for Diabetes Research, German Research Foundation, and German Diabetes Association. Portugal: Portuguese Foundation for Science and Technology, FEDER - European Regional Development Fund, Portuguese Foundation for Science and Technology, and Rede Nacional de Ressonância Magnética Nuclear.

SUBMITTER: Hernandez EA

PROVIDER: S-EPMC5272194 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance.

Hernández Elisa Álvarez EÁ Kahl Sabine S Seelig Anett A Begovatz Paul P Irmler Martin M Kupriyanova Yuliya Y Nowotny Bettina B Nowotny Peter P Herder Christian C Barosa Cristina C Carvalho Filipa F Rozman Jan J Neschen Susanne S Jones John G JG Beckers Johannes J de Angelis Martin Hrabě MH Roden Michael M

The Journal of clinical investigation 20170123 2

<h4>Background</h4>Dietary intake of saturated fat is a likely contributor to nonalcoholic fatty liver disease (NAFLD) and insulin resistance, but the mechanisms that initiate these abnormalities in humans remain unclear. We examined the effects of a single oral saturated fat load on insulin sensitivity, hepatic glucose metabolism, and lipid metabolism in humans. Similarly, initiating mechanisms were examined after an equivalent challenge in mice.<h4>Methods</h4>Fourteen lean, healthy individual ...[more]

PMID: 28112681

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Project description:Purpose: Obesity is a global health issue. To investigate if protein and fat contents of the diets had effects on energy balance via the canonical hunger signaling pathways in the hypothalamus, RNAseq was performed on RNA extracted from the hypothalami of mice exposed to the different diets. A suggested mechanism by which animals may avoid obesity is by burning off excess energy via upregulation of white adipose tissue (WAT) browning. To investigate if protein and fat content of the diet had effects on energy balance via the browning related signaling pathways in the WAT, RNAseq was performed on RNA extracted from the subcutaneous WAT (sWAT) and epididymal WAT (eWAT) of mice exposed to the different diets. Methods: C57BL/6 male mice were used in this work. All mice were fed a standard diet with 10% fat and 20% protein (D12450B, Research Diets Ltd) for 2 weeks as the baseline period. Following 2 weeks of baseline monitoring (at age 12 weeks), all mice were randomly allocated to different groups and switched to the experimental diets for 12 weeks. After 12 weeks all mice were sacrificed and dissected. Methods: In total, mice were fed on 4 diet series, each series consisting of 6 different diets (total = 24 diets). In the first two series (Series 1: D14071601–D14071606 and series 2: D14071607 – D14071612) we fixed the level of fat by energy, and varied the protein content. The protein source was casein. The balance was made up by carbohydrate (roughly equal mix of corn starch and maltodextrose). The source of fat was a mix of cocoa butter, coconut oil, menhaden oil, palm oil and sunflower oil. This mix was designed to match the balance of saturated, mono-unsaturated and polyunsaturated fats (ratio 47.5: 36.8: 15.8) and the n-6: n-3 ratio (14.7: 1) in the typical western diet. The proportions of the different fat constituents and hence fatty acid distributions did not change as the total fat content changed. Sucrose and cellulose were both fixed 5% by energy and weight respectively, and all diets were supplemented with a standard vitamin and mineral mix. In the second two series of diets (series 3: D14071613 – D14071618 and series 4: D14071619 – D14071624) we fixed the level of protein by energy and then allowed the fat content to vary. In these diets the sucrose, cellulose and vitamin and mineral contents were the same as the diets in series 1 and 2. All these diets can be ordered direct from research diets (www.researchdiets.com) using the diet codes provided. Methods: From each diet group, the hypothalami of 8/20 individuals were collected. The left halves of two, and the right halves of another two, were pooled together as one sample, and the same was performed with the other 4 hypothalami, resulting in each diet group having 2 pooled samples of 4 hypothalami (n = 48 samples in total across 24 diets). From each diet group, the sWAT and eWAT of 12/20 individuals were also collected. A small piece from each of six sWAT collections were pooled together as one sample, and the same was performed with the other six eWAT collections. In this way each diet group had one pooled sWAT sample and one pooled eWAT sample (also n = 48 across 24 diets). Methods: The total RNA of the hypothalamus and WAT was isolated using the RNeasy Mini Kit (QIAGEN, 74104) according to manufacturer's protocol. All sequencing was carried out using the Illumina NextSeq 500 sequencer. RNA fragments were sequenced by 75 bp long reads from paired ends (PE 2 x 75 bp, 150 bp per fragment). Quality control checks for raw data FASTQ files were done by using FASTQC (a quality control tool for high throughput sequence data; http://www.bioinformatics.babraham.ac.uk/projects/fastqc/). Paired-end reads were mapped to the Mus musculus genome (GRCm38) using Bowtie 2-2.1.0, TopHat-2.0.10, and Samtools-0.1.19; uniquely mapped reads for each gene were counted against the GTF file of GRCm38 provided by Ensembl (release 83) using HTSeq-0.6.1p1 using the strand = reverse; after read count data were obtained from the TopHat-HTSeq pipeline, counts per million (CPM) value for each gene was calculated by using the R package ‘edgeR’ (version 3.12.0, R version 3.2.2) to normalize the count data by the size of the library of each sample. Genes with the CPM value ≥ 1 in at least one of the 24 diets group were retained (Anders et al., 2013). Generalized Linear Modelling (GLM) was applied by R (version 3.2.2). The GLM model used here was: ~p+f+p:f, which regresses gene expression (CPM) against the protein (p) and fat contents (f) of diets, as well as their interaction (p:f). However, when the effect of the interaction was not significant (p value ≥ 0.05), the interaction term was dropped and a revised model (~p+f) was utilized. Results: With TopHat-HTSeq pipeline, reads of each sample were mapped to 46,078 genes. In hypothalamus there were 15,371 genes with the counts per million (CPM) value ≥ 1 in at least one of the 24 diets group; in white adipose tissue there were 18,202 genes with the CPM value ≥ 1 in at least one of the 24 diets group. No major changes in hypothalamic gene expression levels were found in relation to different dietary protein levels at fixed fat contents, however hypothalamic gene expression showed increase in expression of genes in reward pathways in relation to dietary fat, while Agrp and Npy were both downregulated in relation to dietary fat levels. WAT gene expression showed decrease in expression of general thermogenic related genes and WAT browning related genes in relation to both dietary protein and dietary fat, while Tgfb1, Pdk4 and Fgf1 were all upregulated in relation to dietary fat levels. Conclusions: Significant positive associations were evident between the fat levels of the diet and the main hedonic signaling systems linked to food intake. Significant negative associations were found between both protein and fat levels of the diet and WAT browning or general thermogenic signalings linked to energy expenditure.

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Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance.

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Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance.

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