Bodil Bjørndal

Different Adipose Depots: Their Role in the Development of Metabolic Syndrome and Mitochondrial Response to Hypolipidemic Agents

Adipose tissue metabolism is closely linked to insulin resistance, and differential fat distributions are associated with disorders like hypertension, diabetes, and cardiovascular disease. Adipose tissues vary in their impact on metabolic risk due to diverse gene expression profiles, leading to differences in lipolysis and in the production and release of adipokines and cytokines, thereby affecting the function of other tissues. In this paper, the roles of the various adipose tissues in obesity are summarized, with particular focus on mitochondrial function. In addition, we discuss how a functionally mitochondrial-targeted compound, the modified fatty acid tetradecylthioacetic acid (TTA), can influence mitochondrial function and decrease the size of specific fat depots.

Microbiota‐dependent metabolite trimethylamine‐N‐oxide is associated with disease severity and survival of patients with chronic heart failure

Recent metabolomic, experimental and clinical studies have demonstrated that trimethylamine‐N‐oxide (TMAO), a microbiota‐dependent metabolite from dietary phosphatidylcholine and carnitine, is a strong predictor of coronary artery disease (CAD). This finding suggests a link between the gut microbiota and atherosclerosis. The potential impact of TMAO in chronic heart failure (HF) is unknown. We hypothesized that TMAO levels would provide prognostic information about adverse outcomes in chronic HF.

Dietary supplementation of krill oil attenuates inflammation and oxidative stress in experimental ulcerative colitis in rats

Abstract Objective. To evaluate the effects of krill oil (KO) on inflammation and redox status in dextran sulfate sodium (DSS)-induced colitis in rats. Materials and methods . Thirty male Wistar rats were divided into three groups: Control, DSS, and DSS + KO 5% in a 4-week diet study. Colitis was induced by 5% DSS in the drinking water the last week of the experiment. Weight and disease activity index (DAI), colon length, histological combined score (HCS), colon levels of selected cytokines and prostaglandins, markers of protein oxidative damage, fatty acid profile, and expression of selected genes were measured. Results. Rats in the DSS group increased their DAI and HCS compared with healthy controls. The colon length was significantly preserved after KO diet. Tumor necrosis factor (TNF)-α and interleukin (IL)-1β were elevated in the DSS group compared with controls. Cytokines and HCS were nonsignificantly lower in the KO versus the DSS group. Prostaglandin (PG)E3 increased significantly in the KO versus the other groups. Peroxisome proliferator-activated receptor (PPAR)-γ expression was nonsignificantly increased while PPAR-γ coactivator 1α (Pparg1α) expression increased significantly after KO. The levels of protein oxidation markers decreased significantly. Conclusions . KO showed protective potential against DSS colitis based on the preservation of colon length, reduction of oxidative markers and the consistent beneficial changes of HCS, cytokine, and (PG)E3 levels, as well as PPAR-γ and Pparg1α expression compared with DSS alone. These findings indicate an anti-inflammatory and a protein antioxidant effect of KO.

Fish oil and krill oil supplementations differentially regulate lipid catabolic and synthetic pathways in mice.

BackgroundMarine derived oils are rich in long-chain polyunsaturated omega-3 fatty acids, in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which have long been associated with health promoting effects such as reduced plasma lipid levels and anti-inflammatory effects. Krill oil (KO) is a novel marine oil on the market and is also rich in EPA and DHA, but the fatty acids are incorporated mainly into phospholipids (PLs) rather than triacylglycerols (TAG). This study compares the effects of fish oil (FO) and KO on gene regulation that influences plasma and liver lipids in a high fat diet mouse model.MethodsMale C57BL/6J mice were fed either a high-fat diet (HF) containing 24% (wt/wt) fat (21.3% lard and 2.3% soy oil), or the HF diet supplemented with FO (15.7% lard, 2.3% soy oil and 5.8% FO) or KO (15.6% lard, 2.3% soy oil and 5.7% KO) for 6 weeks. Total levels of cholesterol, TAG, PLs, and fatty acid composition were measured in plasma and liver. Gene regulation was investigated using quantitative PCR in liver and intestinal epithelium.ResultsPlasma cholesterol (esterified and unesterified), TAG and PLs were significantly decreased with FO. Analysis of the plasma lipoprotein particles indicated that the lipid lowering effect by FO is at least in part due to decreased very low density lipoprotein (VLDL) content in plasma with subsequent liver lipid accumulation. KO lowered plasma non-esterified fatty acids (NEFA) with a minor effect on fatty acid accumulation in the liver. In spite of a lower omega-3 fatty acid content in the KO supplemented diet, plasma and liver PLs omega-3 levels were similar in the two groups, indicating a higher bioavailability of omega-3 fatty acids from KO. KO more efficiently decreased arachidonic acid and its elongation/desaturation products in plasma and liver. FO mainly increased the expression of several genes involved in fatty acid metabolism, while KO specifically decreased the expression of genes involved in the early steps of isoprenoid/cholesterol and lipid synthesis.ConclusionsThe data show that both FO and KO promote lowering of plasma lipids and regulate lipid homeostasis, but with different efficiency and partially via different mechanisms.

Disturbed carnitine regulation in chronic heart failure — Increased plasma levels of palmitoyl-carnitine are associated with poor prognosis

BACKGROUND/OBJECTIVES Heart failure is characterized by disturbed energy metabolism and impaired mitochondrial function. L-carnitine plays a critical role in fatty acid transport into the mitochondria and may thus influence inflammation and myocardial function. The aim of this study was to investigate carnitine metabolism in relation to progression of heart failure (HF). METHODS AND RESULTS We examined plasma levels of free L-carnitine as well as several of its precursors and derivates in HF patients (n=183) and matched healthy controls (n=111) as well as their relationship with cardiac dysfunction as assessed by echocardiographic measurements, inflammation (CRP) and neurohormonal activation (NT-proBNP) in addition to the prognostic value of carnitine derivates in relation to mortality in these patients. High levels of the carnitine derivates acetyl-carnitine and in particular palmitoyl-carnitine were associated with the degree of HF as evaluated by clinical (NYHA functional class) and neurohormonal assessments. Moreover, plasma levels of palmitoyl-carnitine were associated with serious adverse events (i.e., all-cause mortality and heart transplantation) during follow-up, independently of more established risk markers such as CRP and NT-proBNP, when analyzed by cox-regression and continous net reclassification improvement, but not c-statistics. CONCLUSIONS Our findings support a role for disturbed carnitine metabolism in the pathogenesis of HF, and suggest that some of its derivates could give prognostic information in these patients.

Fish oil and 3-thia fatty acid have additive effects on lipid metabolism but antagonistic effects on oxidative damage when fed to rats for 50 weeks

The 3-thia fatty acid tetradecylthioacetic acid (TTA) is a synthetic modified fatty acid, which, similar with dietary fish oil (FO), influences the regulation of lipid metabolism, the inflammatory response and redox status. This study was aimed to penetrate the difference in TTAs mode of action compared to FO in a long-term experiment (50 weeks of feeding). Male Wistar rats were fed a control, high-fat (25% w/v) diet or a high-fat diet supplemented with either TTA (0.375% w/v) or FO (10% w/v) or their combination. Plasma fatty acid composition, hepatic lipids and expression of relevant genes in the liver and biomarkers of oxidative damage to protein were assessed at the end point of the experiment. Both supplements given in combination demonstrated an additive effect on the decrease in plasma cholesterol levels. The FO diet alone led to removal of plasma cholesterol and a concurrent cholesterol accumulation in liver; however, with TTA cotreatment, the hepatic cholesterol level was significantly reduced. Dietary FO supplementation led to an increased oxidative damage, as seen by biomarkers of protein oxidation and lipoxidation. Tetradecylthioacetic acid administration reduced the levels of these biomarkers confirming its protective role against lipoxidation and protein oxidative damage. Our findings explore the lipid reducing effects of TTA and FO and demonstrate that these bioactive dietary compounds might act in a different manner. The experiment confirms the antioxidant capacity of TTA, showing an improvement in FO-induced oxidative stress.

Krill powder increases liver lipid catabolism and reduces glucose mobilization in tumor necrosis factor-alpha transgenic mice fed a high-fat diet

A promising approach to ameliorate obesity and obesity-associated diseases is the identification of new sources of dietary ingredients. The present study investigated the hepatic regulation of energy metabolism after feeding a powder isolated from Antarctic krill (Euphausia superba) in a transgenic mouse model of chronic inflammation (human tumor necrosis factor-alpha (hTNFα) mice) known to display unfavorable effects on lipid metabolism. Male hTNFα mice were fed high-fat diets (23.6%, w/w) with or without krill powder (6.4% lipids, 4.3% protein, w/w) for 6 weeks. Blood, liver lipid, and fatty acid composition, as well as hepatic enzyme activities and gene expressions, were determined. Krill powder fed mice displayed lowered hepatic and plasma triacylglycerol levels compared to mice on a high-fat casein diet. This was accompanied by down-regulated hepatic expression of genes involved in lipogenesis and glycerolipid synthesis, and increased β-oxidation activity. In addition, the krill powder diet lowered plasma levels of cholesterol, as well as hepatic gene expression of sterol regulatory element binding transcription factor 2 (SREBP2) and enzymes involved in cholesterol synthesis. Notably, genes involved in glycolysis and gluconeogenesis were significantly reduced in liver by the krill powder diet, while genes involved in oxidative phosphorylation and uncoupling were not affected. Krill powder also reduced endogenous TNFα in liver, indicating an anti-inflammatory effect. In a high-fat mouse model with disturbed lipid metabolism due to persistent hTNFα expression, krill powder showed significant effects on hepatic glucose- and lipid metabolism, resulting in an improved lipid status in liver and plasma.

A fish protein hydrolysate alters fatty acid composition in liver and adipose tissue and increases plasma carnitine levels in a mouse model of chronic inflammation

BackgroundThere is growing evidence that fish protein hydrolysate (FPH) diets affect mitochondrial fatty acid metabolism in animals. The aim of the study was to determine if FPH could influence fatty acid metabolism and inflammation in transgene mice expressing human tumor necrosis factor alpha (hTNFα).MethodshTNFα mice (C57BL/6 hTNFα) were given a high-fat (23%, w/w) diet containing 20% casein (control group) or 15% FPH and 5% casein (FPH group) for two weeks. After an overnight fast, blood, adipose tissue, and liver samples were collected. Gene expression and enzyme activity was analysed in liver, fatty acid composition was analyzed in liver and ovarian white adipose tissue, and inflammatory parameters, carnitine, and acylcarnitines were analyzed in plasma.ResultsThe n-3/n-6 fatty acid ratio was higher in mice fed the FPH diet than in mice fed the control diet in both adipose tissue and liver, and the FPH diet affected the gene expression of ∆6 and ∆9 desaturases. Mice fed this diet also demonstrated lower hepatic activity of fatty acid synthase. Concomitantly, a lower plasma INF-γ level was observed. Plasma carnitine and the carnitine precursor γ-butyrobetaine was higher in the FPH-group compared to control, as was plasma short-chained and medium-chained acylcarnitine esters. The higher level of plasma acetylcarnitine may reflect a stimulated mitochondrial and peroxisomal β-oxidation of fatty acids, as the hepatic activities of peroxisomal acyl-CoA oxidase 1 and mitochondrial carnitine palmitoyltransferase-II were higher in the FPH-fed mice.ConclusionsThe FPH diet was shown to influence hepatic fatty acid metabolism and fatty acid composition. This indicates that effects on fatty acid metabolism are important for the bioactivity of protein hydrolysates of marine origin.

Dietary intake of n-3 long-chain polyunsaturated fatty acids and risk of myocardial infarction in coronary artery disease patients with or without diabetes mellitus: a prospective cohort study

BackgroundA beneficial effect of a high n-3 long-chain polyunsaturated fatty acid (LCPUFA) intake has been observed in heart failure patients, who are frequently insulin resistant. We investigated the potential influence of impaired glucose metabolism on the relation between dietary intake of n-3 LCPUFAs and risk of acute myocardial infarction (AMI) in patients with coronary artery disease.MethodsThis prospective cohort study was based on the Western Norway B-Vitamin Intervention Trial and included 2,378 patients with coronary artery disease with available baseline glycosylated hemoglobin (HbA1c) and dietary data. Patients were sub-grouped as having no diabetes (HbA1c <5.7%), pre-diabetes (HbA1c ≥5.7%), or diabetes (previous diabetes, fasting baseline serum glucose ≥7.0, or non-fasting glucose ≥11.1 mmol/L). AMI risk was evaluated by Cox regression (age and sex adjusted), comparing the upper versus lower tertile of daily dietary n-3 LCPUFA intake.ResultsThe participants (80% males) had a mean age of 62 and follow-up of 4.8 years. A high n-3 LCPUFA intake was associated with reduced risk of AMI (hazard ratio 0.38, 95%CI 0.18, 0.80) in diabetes patients (median HbA1c = 7.2%), whereas no association was observed in pre-diabetes patients. In patients without diabetes a high intake tended to be associated with an increased risk (hazard ratio1.45, 95%CI 0.84, 2.53), which was significant for fatal AMI (hazard ratio 4.79, 95%CI 1.05, 21.90) and associated with lower HbA1c (mean ± standard deviation 4.55 ±0.68 versus 4.92 ±0.60, P = 0.02). No such differences in HbA1c were observed in those with pre-diabetes or diabetes.ConclusionsA high intake of n-3 LCPUFAs was associated with a reduced risk of AMI, independent of HbA1c, in diabetic patients, but with an increased risk of fatal AMI and lower HbA1c among patients without impaired glucose metabolism. Further studies should investigate whether patients with diabetes may benefit from having a high intake of n-3 LCPUFAs and whether patients with normal glucose tolerance should be careful with a very high intake of these fatty acids.Trial registrationThis trial is registered at clinicaltrials.gov as NCT00354081.

Proteomics identifies molecular networks affected by tetradecylthioacetic acid and fish oil supplemented diets

UNLABELLED Fish oil (FO) and tetradecylthioacetic acid (TTA) - a synthetic modified fatty acid have beneficial effects in regulating lipid metabolism. In order to dissect the mechanisms underlying the molecular action of those two fatty acids we have investigated the changes in mitochondrial protein expression in a long-term study (50weeks) in male Wistar rats fed 5 different diets. The diets were as follows: low fat diet; high fat diet; and three diets that combined high fat diet with fish oil, TTA or combination of those two as food supplements. We used two different proteomics techniques: a protein centric based on 2D gel electrophoresis and mass spectrometry, and LC-MS(E) based peptide centric approach. As a result we provide evidence that fish oil and TTA modulate mitochondrial metabolism in a synergistic manner yet the effects of TTA are much more dramatic. We demonstrate that fatty acid metabolism; lipid oxidation, amino acid metabolism and oxidative phosphorylation pathways are involved in fish oil and TTA action. Evidence for the involvement of PPAR mediated signalling is provided. Additionally we postulate that down regulation of components of complexes I and II contributes to the strong antioxidant properties of TTA. BIOLOGICAL SIGNIFICANCE This study for the first time explores the effect of fish oil and TTA - tetradecyl-thioacetic acid and the combination of those two as diet supplements on mitochondria metabolism in a comprehensive and systematic manner. We show that fish oil and TTA modulate mitochondrial metabolism in a synergistic manner yet the effects of TTA are much more dramatic. We demonstrate in a large scale that fatty acid metabolism and lipid oxidation are affected by fish oil and TTA, a phenomenon already known from more directed molecular biology studies. Our approach, however, shows additionally that amino acid metabolism and oxidative phosphorylation pathways are also strongly affected by TTA and also to some extent by fish oil administration. Strong evidence for the involvement of PPAR mediated signalling is provided linking the different metabolic effects. The global and systematic viewpoint of this study compiles many of the known phenomena related to the effects of fish oil and fatty acids giving a solid foundation for further exploratory and more directed studies of the mechanisms behind the beneficial and detrimental effects of fish oil and TTA diet supplementation. This work is already a second article in a series of studies conducted using this model of dietary intervention. In the previous study (Vigerust et al., [21]) the effects of fish oil and TTA on the plasma lipids and cholesterol levels as well as key metabolic enzymes in the liver have been studied. In an ongoing study more work is being done to explore in detail for example the link between the down regulation of the components of the respiratory chain (observed in this study) and the strong antioxidant effects of TTA. The reference diet in this study has been designed to mimic an unhealthy - high fat diet that is thought to contribute to the development of metabolic syndrome - a condition that is strongly associated with diabetes, obesity and heart failure. Fish oil and TTA are known to have beneficial effects for the fatty acid metabolism and have been shown to alleviate some of the symptoms of the metabolic syndrome. To date very little is known about the molecular mechanisms behind these beneficial effects and the potential pitfalls of the consumption of those two compounds. Only studies of each compound separately and using only small scale molecular biology approaches have been carried out. The results of this work provide an excellent starting point for further studies that will help to understand the metabolic effects of fish oil and TTA and will hopefully help to design dietary programs directed towards reduction of the prevalence of metabolic syndrome and associated diseases.