Bjørn Jostein Christensen

Switch from stress response to homeobox transcription factors in adipose tissue after profound fat loss.

Background In obesity, impaired adipose tissue function may promote secondary disease through ectopic lipid accumulation and excess release of adipokines, resulting in systemic low-grade inflammation, insulin resistance and organ dysfunction. However, several of the genes regulating adipose tissue function in obesity are yet to be identified. Methodology/Principal Findings In order to identify novel candidate genes that may regulate adipose tissue function, we analyzed global gene expression in abdominal subcutaneous adipose tissue before and one year after bariatric surgery (biliopancreatic diversion with duodenal switch, BPD/DS) (n = 16). Adipose tissue from lean healthy individuals was also analyzed (n = 13). Two different microarray platforms (AB 1700 and Illumina) were used to measure the differential gene expression, and the results were further validated by qPCR. Surgery reduced BMI from 53.3 to 33.1 kg/m2. The majority of differentially expressed genes were down-regulated after profound fat loss, including transcription factors involved in stress response, inflammation, and immune cell function (e.g., FOS, JUN, ETS, C/EBPB, C/EBPD). Interestingly, a distinct set of genes was up-regulated after fat loss, including homeobox transcription factors (IRX3, IRX5, HOXA5, HOXA9, HOXB5, HOXC6, EMX2, PRRX1) and extracellular matrix structural proteins (COL1A1, COL1A2, COL3A1, COL5A1, COL6A3). Conclusions/Significance The data demonstrate a marked switch of transcription factors in adipose tissue after profound fat loss, providing new molecular insight into a dichotomy between stress response and metabolically favorable tissue development. Our findings implicate homeobox transcription factors as important regulators of adipose tissue function.

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.

The nuclear receptors NUR77, NURR1 and NOR1 in obesity and during fat loss

Background:Adipose tissue is critical for systemic metabolic health. Identifying key factors regulating adipose tissue function is a research priority. The NR4A subfamily of nuclear receptors (NRs) (NR4A1/NUR77, NR4A2/NURR1 and NR4A3/NOR1) has emerged as important proteins in different disease states and in the regulation of metabolic tissues, particularly in liver and muscle. However, the expression of the NR4A members in human adipose tissue has not previously been described, and their target genes are largely unknown.Objective:To determine whether the NR4As are differentially expressed in human adipose tissue in obesity, and identify potential NR4A target genes.Design:Prospective analysis of s.c. adipose tissue before and 1 year after fat loss, and during in vitro differentiation of primary human preadipocytes. Case-control comparison of omental (OM) adipose tissue.Subjects:A total of 13 extremely obese patients undergoing biliopancreatic diversion with duodenal switch for fat loss, 12 extremely obese patients undergoing laparoscopic sleeve gastrectomy and 37 lean individuals undergoing hernia repair or laparotomy were included in the study. Measurements were done by quantitative PCR gene expression analysis of the NR4A members and in silico promoter analysis based on microarray data.Results:There was a strong upregulation of the NR4As in extreme obesity and normalization after fat loss. The NR4As were expressed at the highest level in stromal–vascular fraction compared with adipocytes, but were downregulated in both fractions after fat loss. Their expression levels were also significantly higher in OM compared with s.c. adipocytes in obesity. The NR4As were downregulated during differentiation of primary human preadipocytes. Moreover, the NR4As were strongly induced within 30 min of tissue incubation. Finally, promoter analysis revealed potential NR4A target genes involved in stress response, immune response, development and other functions. Our data show altered adipose tissue expression of the NR4As in obesity, suggesting that these stress responsive nuclear receptors may modulate pathogenic potential in humans.

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.

Long-term treatment with the pan-PPAR agonist tetradecylthioacetic acid or fish oil is associated with increased cardiac content of n-3 fatty acids in rat

BackgroundExcess peroxisome proliferator-activated receptor (PPAR) stimulation has been associated with detrimental health effects including impaired myocardial function. Recently, supplementation with n-3 polyunsaturated fatty acids (PUFA) has been associated with improved left ventricular function and functional capacity in patients with dilated cardiomyopathy. We investigated the long-term effects of the pan-PPAR agonist tetradecylthioacetic acid (TTA) and/or high-dose fish oil (FO) on cardiac fatty acid (FA) composition and lipid metabolism. Male Wistar rats were given one out of four different 25% (w/v) fat diets: control diet; TTA diet; FO diet; or diet containing both TTA and FO.ResultsAfter 50 weeks n-3 PUFA levels were increased by TTA and FO in the heart, whereas liver levels were reduced following TTA administration. TTA was associated with a decrease in arachidonic acid, increased activities of carnitine palmitoyltransferase II, fatty acyl-CoA oxidase, glycerol-3-phosphate acyltransferase, and fatty acid synthase in the heart. Furthermore, cardiac Ucp3 and Cact mRNA was upregulated.ConclusionsLong-term treatment with the pan-PPAR agonist TTA or high-dose FO induced marked changes in PUFA composition and enzymatic activity involved in FA metabolism in the heart, different from liver. Changes included increased FA oxidation and a selective increase in cardiac n-3 PUFA.

Implementation of a trauma system in Norway: a national survey.

Trauma systems have improved outcomes for injured patients, but might be challenging to implement. We assessed the implementation of a trauma system in Norway after recommendations for a national trauma system were published in 2007, with a focus on elements in acute care hospitals.

Bile duct injuries following laparoscopic cholecystectomy

Introduction: Bile duct injuries occur rarely but are among the most dreadful complications following cholecystectomies. Methods: Prospective registration of bile duct injuries occurring in the period 1992–2013 at a tertiary referral hospital. Results: In total, 67 patients (47 women and 20 men) with a median age of 55 (range 14–86) years had a leak or a lesion of the bile ducts during the study period. Total incidence of postoperative bile leaks or bile duct injuries was 0.9% and for bile duct injuries separately, 0.4%. Median delay from injury to repair was 5 days (range 0–68 days). In 12 patients (18%), the injury was discovered intraoperatively. Bile leak was the major symptom in 59%, and 52% had a leak from the cystic duct or from assumed aberrant ducts in the liver bed of the gall bladder. Following the Clavien–Dindo classification, 39% and 45% were classified as IIIa and IIIb, respectively, 10% as IV, and 6% as V. In all, 31 patients had injuries to the common bile duct or hepatic ducts, and in these patients, 71% were treated with a hepaticojejunostomy. Of patients treated with a hepaticojejunostomy, 56% had an uncomplicated event, whereas 14% later on developed a stricture. Out of 36 patients with injuries to the cystic duct/aberrant ducts, 30 could be treated with stents or sphincterotomies and percutaneous drainage. Conclusion: Half of injuries following cholecystectomies are related to the cystic duct, and most of these can be treated with endoscopic or percutaneous procedures. A considerable number of patients following hepaticojejunostomy will later on develop a stricture.

Changes in adipose glucocorticoid metabolism before and after bariatric surgery assessed by direct hormone measurements

Increased intra‐adipose cortisol is thought to promote obesity, but few human studies have investigated intra‐adipose glucocorticoid hormones and none have demonstrated prospective changes with fat loss.

Effective Hemostasis in Severe Mesenteric Vein Laceration with Tachosil ® , using a Low- or Non-thrombogenic Patch to Prevent Tachosil ® -induced Thrombosis

Fibrinogen- and thrombin-coated collagen fleece (FTCC) facilitates surgical hemostasis, and is of particular value during resection of parenchymatous organs. Since thrombosis may ensue if the preparation is unintentionally applied intravascularly, it has not been recommended for treating lacerations of large veins, and no previous reports describe its use in vein repair. Our observations in two patients suggest, however, that FTCC might be indicated for hemostasis in vein injury where vascular suture is difficult or not possible, provided a low- or non-thrombogenic patch is interposed to prevent FTCC-induced vein thrombosis. Our two patients had severe lacerations of the proximal superior mesenteric vein (SMV) not amenable to conventional vein repair. Rapid hemostasis was obtained without suturing using Tachosil®, an FTCC preparation, covered with omentum. In the first patient hemostasis was obtained at the expense of vein thrombosis, apparently due to contact between the coagulant-containing side of Tachosil® and the inside of the vein wall. In our second patient we therefore put a small patch of parietal peritoneum on the section of the Tachosil® targeted to cover the vein tear to avoid direct contact between Tachosil® and the vein lumen. Ultrasound examination 3 days postoperatively, and autopsy 11.5 months later showed that the vein was widely patent with no stenosis or thrombus. Our observations in these two patients were that an FTCC-omentum pack alone secured rapid hemostasis in severe SMV laceration, and when a peritoneal patch was interposed between FTCC and a lacerated SMV, FTCC-induced vein thrombosis did not occur.

Treatment of splenic trauma in Norway: a retrospective cohort study

BackgroundNon-operative management of splenic injuries has become the treatment of choice in hemodynamically stable patients over the last decades. The aim of the study is to describe the incidence, initial treatment and early outcome of patients with splenic injuries on a national level.MethodsAll hospitals in Norway admitting trauma patients were invited to participate in the study. The study period was January through December 2013. The hospitals delivered anonymous data on primarily admitted patients with splenic injury.ResultsThree of the four regional trauma centers and 26 of the remaining 33 acute care hospitals delivered data on a total of 151 patients with splenic injury indicating an incidence of 4 splenic injuries per 100,000 inhabitants/year, and a median of 4 splenic injuries per hospital per year. A total of 128 (85%) patients were successfully treated non-operatively including 20 patients who underwent an angiographic procedure. The remaining 23 (15%) patients underwent open splenectomy or spleen-preserving surgery.ConclusionMost patients with splenic injuries are managed non-operatively. Despite the low number of splenic injuries per hospital, the results indicate satisfactory outcome on a national level.