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1.	García, Maria C, et al. (författare) Mature-onset obesity in interleukin-1 receptor I knockout mice. 2006 Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 55:5, s. 1205-13 Tidskriftsartikel (refereegranskat)abstract Interleukin-1 (IL-1) is a major mediator of inflammation that exerts its biological activities through the IL-1 type I receptor (IL-1RI). The body weights of IL-1RI(-/-) mice of both sexes started to deviate from those of wild-type mice at 5-6 months of age and were 20% higher at 9 months of age. Visceral and subcutaneous fat mass, measured by dual-energy X-ray absorptiometry and magnetic resonance imaging, was markedly (1.5- to 2.5-fold) increased. Lean body mass and crown-rump length were also slightly (11 and 5%, respectively) increased, as was serum IGF-I. Obese IL-1RI(-/-) mice were insulin resistant, as evidenced by hyperinsulinemia, decreased glucose tolerance, and insulin sensitivity. To elucidate the mechanisms for the development of obesity, young pre-obese IL-1RI(-/-) mice were investigated. They showed decreased suppression of body weight and food intake in response to systemic leptin treatment. The decreased leptin responsiveness was even more pronounced in older obese animals. Moreover, spontaneous locomotor activity and fat utilization, as measured by respiratory quotient, were decreased in pre-obese IL-1RI(-/-) mice. In conclusion, lack of IL-1RI-mediated biological activity causes mature-onset obesity. This obese phenotype is preceded by decreased leptin sensitivity, fat utilization, and locomotor activity.
2.	Sjögren, Klara, 1970, et al. (författare) Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. 1999 Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424. ; 96:12, s. 7088-92 Tidskriftsartikel (refereegranskat)abstract The body growth of animals is regulated by growth hormone and IGF-I. The classical theory of this regulation is that most IGF-I in the blood originates in the liver and that body growth is controlled by the concentration of IGF-I in the blood. We have abolished IGF-I production in the livers of mice by using the Cre/loxP recombination system. These mice demonstrated complete inactivation of the IGF-I gene in the hepatocytes. Although the liver accounts for less than 5% of body mass, the concentration of IGF-I in the serum was reduced by 75%. This finding confirms that the liver is the principal source of IGF-I in the blood. However, the reduction in serum IGF-I concentration had no discernible effect on postnatal body growth. We conclude that postnatal body growth is preserved despite complete absence of IGF-I production by the hepatocytes.
3.	Wallenius, Kristina, 1973, et al. (författare) Liver-derived IGF-I regulates GH secretion at the pituitary level in mice. 2001 Ingår i: Endocrinology. - 0013-7227. ; 142:11, s. 4762-70 Tidskriftsartikel (refereegranskat)abstract We have reported that liver-specific deletion of IGF-I in mice (LI-IGF-I-/-) results in decreased circulating IGF-I and increased GH levels. In the present study, we determined how elimination of hepatic IGF-I modifies the hypothalamic-pituitary GH axis to enhance GH secretion. The pituitary mRNA levels of GH releasing factor (GHRF) receptor and GH secretagogue (GHS) receptor were increased in LI-IGF-I-/- mice, and in line with this, their GH response to ip injections of GHRF and GHS was increased. Expression of mRNA for pituitary somatostatin receptors, hypothalamic GHRF, somatostatin, and neuropeptide Y was not altered in LI-IGF-I-/- mice, whereas hypothalamic IGF-I expression was increased. Changes in hepatic expression of major urinary protein and the PRL receptor in male LI-IGF-I-/- mice indicated an altered GH release pattern most consistent with enhanced GH trough levels. Liver weight was enhanced in LI-IGF-I-/- mice of both genders. In conclusion, loss of liver-derived IGF-I enhances GH release by increasing expression of pituitary GHRF and GHS receptors. The enhanced GH release in turn affects several liver parameters, in line with the existence of a pituitary-liver axis.
4.	Bratlie, Svein-Olav, et al. (författare) Proteomic Approach to the Potential Role of Angiotensin II in Barrett Dysplasia 2019 Ingår i: Proteomics - Clinical Applications. - : Wiley. - 1862-8346 .- 1862-8354. ; 13:4 Tidskriftsartikel (refereegranskat)abstract Background and Aim: Dysplasia in Barrett's esophagus (BE) is regarded as a preneoplastic lesion. The renin–angiotensin system (RAS), known for its role in electrolyte homeostasis and hemodynamics, has also been shown to have tissue-based features linked to proliferation, inflammation, and cancer. RAS is associated with BE dysplasia. The aim of this study is to investigate possible effects of the RAS in BE dysplasia by using RAS-interfering pharmaceutical agents and by assessment of global protein expression in esophageal mucosal biopsies. Methods: Endoscopic biopsies are taken from 18 BE in patients with low-grade dysplasia before and after 3 weeks of treatment with either angiotensin-converting enzyme inhibitors (enalapril 5 mg; n = 6) or angiotensin II receptor type 1 blockers (candesartan 8 mg; n = 6), or no treatment (n = 6). A global proteomics analysis by 2D gel electrophoresis and mass spectrometry (MS) is then performed to identify proteins that are regulated after interference with RAS. Results: Three proteins are identified to show significant modulation of expression 60 kDa heat shock protein (downregulated), protein disulfide isomerase A3 (downregulated), and inorganic pyrophosphatase (upregulated). Conclusion: Three proteins with no previously known links to esophageal RAS, but with possible relevance for the development of esophageal adenocarcinoma (EAC) are detected. Altered expression by interference with the RAS suggests an involvement of angiotensin II in the development of EAC in BE. © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
5.	Casselbrant, Anna, 1970, et al. (författare) Angiotensin II exerts dual actions on sodium-glucose transporter 1-mediated transport in the human jejunal mucosa 2015 Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 50:9, s. 1068-1075 Tidskriftsartikel (refereegranskat)abstract Objectives. Intestinal glucose absorption is mainly mediated via the sodium-glucose transporter 1 (SGLT1) at the apex of the enterocytes, whereas the glucose transporter 2 (GLUT2) provides a basolateral exit. It has been shown in rats that Angiotensin II (AngII), the principal mediator of renin-angiotensin system (RAS), inhibits jejunal SGLT1-mediated glucose absorption. The aim of the present study was to investigate if a similar mechanism exists also in the human jejunal mucosa. Material and methods. Enteroscopy with mucosal biopsy sampling was performed in 28 healthy volunteers. Functional assessments were performed in Ussing chambers using a pharmacological approach. Western blotting and immunohistochemistry were used to assess the presence of the AngII type 1 (AT1R) and type 2 receptor (AT2R), as well as the glucose transporters SGLT1 and GLUT2. Results. Exposure of the mucosa to 10 mM glucose elicited a »50% increase in the epithelium-generated current (Iep). This glucose-induced electrogenic response was sensitive to the competitive SGLT1 inhibitor phlorizin, but not to AngII when given alone. AngII combined with the AT2R blocker PD123319 markedly inhibited the response. AngII in combination with the AT1R antagonist losartan tended to increase the electrogenic response, whereas direct activation of AT2R using the agonist C21 significantly enhanced the mucosal response to glucose. The AT1R and AT2R as well as SGLT1 and GLUT2 were detected inside the human enterocytes. Conclusions. The pharmacological analysis indicated that activation of AT1R inhibits, whereas activation of AT2R enhances SGLT1-mediated glucose transport in the human jejunal mucosa.
6.	Casselbrant, Anna, 1970, et al. (författare) Expression of tight-junction proteins in human proximal small intestinal mucosa before and after Roux-en-Y gastric bypass surgery 2015 Ingår i: Surgery for Obesity and Related Diseases. - : Elsevier BV. - 1550-7289. ; 11:1, s. 45-53 Tidskriftsartikel (refereegranskat)abstract Background Increased permeability and uptake of proinflammatory bacterial endotoxins from gut microbiota has been suggested as a mechanism for obesity-associated chronic inflammation that causes obesity-associated insulin resistance. We hypothesized that intestinal barrier function may be restored after Roux-en-Y gastric bypass (RYGB) surgery and thereby contribute to decreased inflammation. The objective of this study was to investigate levels of the permeability-regulating tight-junction proteins in human small intestinal mucosa before and after RYGB surgery. Methods Paired intraindividual jejunal mucosa samples were retrieved at the time of surgery and 6 to 8 months after surgery. Mucosal cell surface area was calculated by histomorphometry. Mucosal samples were analyzed by proteomics to find patterns of protein regulations. Based on these findings further analyses were performed by Western blotting. Ussing chambers were used to analyze permeability in the retrieved mucosal samples. Results Mucosal surface area was significantly decreased after surgery. Global protein expression analysis showed a significant increase in the cytokeratin-8 (Ck8), which was confirmed by Western blotting. Further analyses showed a significant increase in claudin-3 and -4 expression after surgery, whereas occludin and zonula occludens-1 levels were decreased. Expressions of claudin-1, -2, -5 and vinculin were unchanged. Ussing chamber experiments revealed a linear correlation between the epithelial electrical resistance and claudin-3 protein expression. Conclusion Several alterations were found in the rerouted small intestine after surgery, indicating a decreased jejunal mucosal surface area and decreased paracellular permeability. These changes could contribute to decreased uptake of luminal microbiota-derived inflammatory mediators such as endotoxins after RYGB.
7.	Casselbrant, Anna, 1970, et al. (författare) Glycocholic acid and butyrate synergistically increase vitamin D-induced calcium uptake in Caco-2 intestinal epithelial cell monolayers 2020 Ingår i: Bone Reports. - : Elsevier BV. - 2352-1872. ; 13 Tidskriftsartikel (refereegranskat)abstract Background: Roux-en-Y gastric bypass (RYGB) substantially decreases intestinal calcium absorption and may eventually lead to bone resorption. This is likely a consequence of bile diversion from the alimentary limb, as the presence of bile seems necessary for vitamin D-mediated calcium uptake. We recently suggested that the mediating mechanism may be a down-regulation of the vitamin D co-activator heat-shock protein (Hsp)90β. Recent evidence suggests that vitamin D may have effects on both active and passive calcium absorption. Aim: To identify mechanisms in vitro that may be responsible for the decreased calcium absorption after RYGB. We hypothesized that bile, alone or in concert with nutritional compounds, could be of importance. Material & methods: Caco-2 cells were grown confluent on semi-permeable membranes in a double-chamber setup to mimic small intestinal mucosa. The effect of bile acids chenodeoxycholic, lithocholic, glycocholic and taurocholic acid, with and without the addition of the fatty-acid butyrate, were tested for their effects on Hsp90β expression and active and passive calcium-flux monitored using radioactive 45Ca. Results: We initially found that whole human bile, but only together with the fatty acid butyrate, potently induced Hsp90β expression. In line with this, a single bile acid, e.g. glycocholic acid (GCA), in combination with butyrate, increased Hsp90β expression (40 ± 13% vs. GCA, butyrate or vehicle alone; p < 0,001; n = 14–25). Further, this combination together with vitamin D increased the passive gradient-driven flux of calcium, compared to stimulation with vitamin D alone or in combination with either GCA or butyrate (880 ± 217% vs. vitamin D and GCA or butyrate, or vitamin D only; p = 0,01–0.006; n = 5–11). Surprisingly, this combination had no effect on active calcium transport in the absence of calcium gradient. Conclusion: The combination of GCA and butyrate increased gradient-driven calcium uptake up to 9-fold in Caco-2 intestinal epithelial cells, but had no effect on active calcium absorption. This effect was mediated via the vitamin D receptor co-activator Hsp90β. © 2020 The Authors
8.	Casselbrant, Anna, 1970, et al. (författare) Intestinal Ketogenesis and Permeability 2024 Ingår i: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - 1661-6596 .- 1422-0067. ; 25:12 Tidskriftsartikel (refereegranskat)abstract Consumption of a high-fat diet (HFD) has been suggested as a contributing factor behind increased intestinal permeability in obesity, leading to increased plasma levels of microbial endotoxins and, thereby, increased systemic inflammation. We and others have shown that HFD can induce jejunal expression of the ketogenic rate-limiting enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS). HMGCS is activated via the free fatty acid binding nuclear receptor PPAR-alpha, and it is a key enzyme in ketone body synthesis that was earlier believed to be expressed exclusively in the liver. The function of intestinal ketogenesis is unknown but has been described in suckling rats and mice pups, possibly in order to allow large molecules, such as immunoglobulins, to pass over the intestinal barrier. Therefore, we hypothesized that ketone bodies could regulate intestinal barrier function, e.g., via regulation of tight junction proteins. The primary aim was to compare the effects of HFD that can induce intestinal ketogenesis to an equicaloric carbohydrate diet on inflammatory responses, nutrition sensing, and intestinal permeability in human jejunal mucosa. Fifteen healthy volunteers receiving a 2-week HFD diet compared to a high-carbohydrate diet were compared. Blood samples and mixed meal tests were performed at the end of each dietary period to examine inflammation markers and postprandial endotoxemia. Jejunal biopsies were assessed for protein expression using Western blotting, immunohistochemistry, and morphometric characteristics of tight junctions by electron microscopy. Functional analyses of permeability and ketogenesis were performed in Caco-2 cells, mice, and human enteroids. Ussing chambers were used to analyze permeability. CRP and ALP values were within normal ranges and postprandial endotoxemia levels were low and did not differ between the two diets. The PPAR alpha receptor was ketone body-dependently reduced after HFD. None of the tight junction proteins studied, nor the basal electrical parameters, were different between the two diets. However, the ketone body inhibitor hymeglusin increased resistance in mucosal biopsies. In addition, the tight junction protein claudin-3 was increased by ketone inhibition in human enteroids. The ketone body beta-Hydroxybutyrate (beta HB) did not, however, change the mucosal transition of the large-size molecular FD4-probe or LPS in Caco-2 and mouse experiments. We found that PPAR alpha expression was inhibited by the ketone body beta HB. As PPAR alpha regulates HMGCS expression, the ketone bodies thus exert negative feedback signaling on their own production. Furthermore, ketone bodies were involved in the regulation of permeability on intestinal mucosal cells in vitro and ex vivo. We were not, however, able to reproduce these effects on intestinal permeability in vivo in humans when comparing two weeks of high-fat with high-carbohydrate diet in healthy volunteers. Further, neither the expression of inflammation markers nor the aggregate tight junction proteins were changed. Thus, it seems that not only HFD but also other factors are needed to permit increased intestinal permeability in vivo. This indicates that the healthy gut can adapt to extremes of macro-nutrients and increased levels of intestinally produced ketone bodies, at least during a shorter dietary challenge.
9.	Casselbrant, Anna, 1970, et al. (författare) Morphological Adaptation in the Jejunal Mucosa after Iso-Caloric High-Fat versus High-Carbohydrate Diets in Healthy Volunteers: Data from a Randomized Crossover Study 2022 Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 14:19 Tidskriftsartikel (refereegranskat)abstract Background and aims: The conditions for jejunal glucose absorption in healthy subjects have not been thoroughly studied. In this study we investigated differences in the jejunal villi enlargement factor, as well as ultrastructural aspects of the surface enterocytes and mitochondria, comparing 2 weeks of high-carbohydrate (HCD) versus high-fat diets (HFD). We also measured the ketogenesis rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) in relation to jejunal mitochondria. Methods: A single-centre, randomized, unblinded crossover study in 15 healthy volunteers ingesting strictly controlled equicaloric diets (either HCD or HFD), with 60% energy from the respective source. An enteroscopy was carried out after 2 weeks of each diet and jejunal mucosal biopsies were acquired. Conventional histology, immunofluorescent staining, transmission electron microscopy and confocal microscopy were used. Results: The villi did not demonstrate any change in the epithelial enlargement factor. Despite an increased mitosis, there were no changes in apoptotic indices. However, the ultrastructural analysis demonstrated a significant increase in the enlargement factor at the bases of the villi. The mitochondria demonstrated increased amounts of cristae after the HFD. The confocal microscopy revealed increased HMGCS2 per mitochondrial marker at the top of the villi after the HFD compared to the HCD. Conclusion: There is a morphometric adaption in the jejunal mucosa following the 2-week diets, not only on a histological level, but rather on the ultrastructural level. This study supports the notion that mitochondrial HMGCS2 is regulated by the fat content of the diet and is involved in the expression of monosaccharide transporters.
10.	Cervin, Jakob, et al. (författare) GM1 ganglioside-independent intoxication by Cholera toxin 2018 Ingår i: PLoS Pathogens. - : Public Library of Science (PLoS). - 1553-7366 .- 1553-7374. ; 14:2 Tidskriftsartikel (refereegranskat)abstract Cholera toxin (CT) enters and intoxicates host cells after binding cell surface receptors via its B subunit (CTB). We have recently shown that in addition to the previously described binding partner ganglioside GM1, CTB binds to fucosylated proteins. Using flow cytometric analysis of primary human jejunal epithelial cells and granulocytes, we now show that CTB binding correlates with expression of the fucosylated Lewis X (LeX) glycan. This binding is competitively blocked by fucosylated oligosaccharides and fucose-binding lectins. CTB binds the LeX glycan in vitro when this moiety is linked to proteins but not to ceramides, and this binding can be blocked by mAb to LeX. Inhibition of glycosphingolipid synthesis or sialylation in GM1-deficient C6 rat glioma cells results in sensitization to CT-mediated intoxication. Finally, CT gavage produces an intact diarrheal response in knockout mice lacking GM1 even after additional reduction of glycosphingolipids. Hence our results show that CT can induce toxicity in the absence of GM1 and support a role for host glycoproteins in CT intoxication. These findings open up new avenues for therapies to block CT action and for design of detoxified enterotoxin-based adjuvants.
11.	Colldén, Hannah, et al. (författare) The gut microbiota is a major regulator of androgen metabolism in intestinal contents. 2019 Ingår i: American journal of physiology. Endocrinology and metabolism. - 1522-1555. ; 317:6 Tidskriftsartikel (refereegranskat)abstract Androgens exert important effects both in androgen-responsive tissues and in the intestinal tract. To determine the impact of the gut microbiota (GM) on intestinal androgen metabolism, we measured unconjugated (free) and glucuronidated androgen levels in intestinal contents from the small intestine, with a low bacterial density, and from cecum and colon, with a high bacterial density. Using a specific, sensitive gas chromatography-tandem mass spectrometry method, we detected high levels of glucuronidated testosterone (T) and dihydrotestosterone (DHT) in small intestinal content of mice of both sexes, whereas in the distal intestine we observed remarkably high levels of free DHT, exceeding serum levels by >20-fold. Similarly, in young adult men high levels of unconjugated DHT, >70-fold higher than in serum, were detected in feces. In contrast to mice with a normal GM composition, germ-free mice had high levels of glucuronidated T and DHT, but very low free DHT levels, in the distal intestine. These findings demonstrate that the GM is involved in intestinal metabolism and deglucuronidation of DHT and T, resulting in extremely high free levels of the most potent androgen, DHT, in the colonic content of young and healthy mice and men.
12.	Elebring, Erik, 1990, et al. (författare) A Fatty Diet Induces a Jejunal Ketogenesis Which Inhibits Local SGLT1-Based Glucose Transport via an Acetylation Mechanism-Results from a Randomized Cross-Over Study between Iso-Caloric High-Fat versus High-Carbohydrate Diets in Healthy Volunteers 2022 Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 14:9 Tidskriftsartikel (refereegranskat)abstract Background and aims: Insights into the nature of gut adaptation after different diets enhance the understanding of how food modifications can be used to treat type 2 diabetes and obesity. The aim was to understand how diets, enriched in fat or carbohydrates, affect glucose absorption in the human healthy jejunum, and what mechanisms are involved. Methods: Fifteen healthy subjects received, in randomised order and a crossover study design, two weeks of iso-caloric high-fat diet (HFD) and high-carbohydrate diet (HCD). Following each dietary period, jejunal mucosa samples were retrieved and assessed for protein expression using immunofluorescence and western blotting. Functional characterisation of epithelial glucose transport was assessed ex vivo using Ussing chambers. Regulation of SGLT1 through histone acetylation was studied in vitro in Caco-2 and human jejunal enteroid monolayer cultures. Results: HFD, compared to HCD, decreased jejunal Ussing chamber epithelial glucose transport and the expression of apical transporters for glucose (SGLT1) and fructose (GLUT5), while expression of the basolateral glucose transporter GLUT2 was increased. HFD also increased protein expression of the ketogenesis rate-limiting enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) and decreased the acetylation of histone 3 at lysine 9 (H3K9ac). Studies in Caco-2 and human jejunal enteroid monolayer cultures indicated a ketogenesis-induced activation of sirtuins, in turn decreasing SGLT1 expression. Conclusion: Jejunal glucose absorption is decreased by a fat-enriched diet, via a ketogenesis-induced alteration of histone acetylation responsible for the silencing of SGLT1 transcription. The work relates to a secondary outcome in ClinicalTrials.gov (NCT02088853).
13.	Elebring, Erik, 1990, et al. (författare) βHB inhibits glucose-induced GLP-1 secretion in GLUTag and human jejunal enteroids 2023 Ingår i: Journal of molecular endocrinology. - 1479-6813. ; 70:4 Tidskriftsartikel (refereegranskat)abstract Ingestion of nutrients stimulates incretin secretion from enteroendocrine cells (EECs) of the epithelial layer of the gut. Glucagon-like peptide-1 (GLP-1) is one of these incretins that stimulate postprandial insulin release and signal satiety to the brain. Understanding the regulation of incretin secretion might open up new therapeutic options for obesity and type-2 diabetes mellitus. To investigate the inhibitory effect of the ketone body β-hydroxybutyrate (βHB) on glucose-induced GLP-1 secretion from EECs, in vitro cultures of murine GLUTag cells and differentiated human jejunal enteroid monolayers were stimulated with glucose to induce GLP-1 secretion. The effect of βHB on GLP-1 secretion was studied using ELISA and ECLIA methods. GLUTag cells stimulated with glucose and βHB were analysed using global proteomics focusing on cellular signalling pathways and the results were verified by Western blot. Results demonstrated βHB had a significant inhibitory effect on glucose-induced GLP-1 secretion at a dose of 100 mM in GLUTag cells. In differentiated human jejunal enteroid monolayers, glucose-induced secretion of GLP-1 was inhibited at a much lower dose of 10 mM βHB. The addition of βHB to GLUTag cells resulted in decreased phosphorylation of kinase AKT and transcription factor STAT3 and also influenced the expressions of signalling molecule IRS-2, kinase DGKε and receptor FFAR3. In conclusion, βHB displays an inhibitory effect on glucose-induced GLP-1 secretion in vitro in GLUTag cells and in differentiated human jejunal enteroid monolayers. This effect may be mediated through multiple downstream mediators of G-protein coupled receptor activation, such as PI3K signalling.
14.	Elias, Erik, 1979, et al. (författare) Bone mineral density and expression of vitamin D receptor-dependent calcium uptake mechanisms in the proximal small intestine after bariatric surgery 2014 Ingår i: British Journal of Surgery. - : Oxford University Press (OUP). - 0007-1323 .- 1365-2168. ; 101:12, s. 1566-1575 Tidskriftsartikel (refereegranskat)abstract Background Roux-en-Y gastric bypass may lead to impaired calcium uptake. Therefore, operation-specific effects of gastric bypass and vertical banded gastroplasty on bone mineral density (BMD) were examined in a randomized clinical trial. Bone resorption markers and mechanisms of decreased calcium uptake after gastric bypass were investigated using blood and endoscopic samples from two additional patient cohorts. Methods Total BMD and non-weight-bearing skull BMD were measured by dual-energy X-ray absorptiometry at baseline, and 1 and 6years after gastric bypass or vertical banded gastroplasty in patients who were not receiving calcium supplements. Bone resorption markers in serum and calcium uptake mechanisms in jejunal mucosa biopsies were analysed after gastric bypass by proteomics including radioimmunoassay, gel electrophoresis and mass spectrometry. Results One year after surgery, weight loss was similar after gastric bypass and vertical banded gastroplasty. There was a moderate decrease in skull BMD after gastric bypass, but not after vertical banded gastroplasty (P<0·001). Between 1 and 6years after gastric bypass, skull BMD and total BMD continued to decrease (P=0·001). C-terminal telopeptide levels in serum had increased twofold by 18months after gastric bypass. Proteomic analysis of the jejunal mucosa revealed decreased levels of heat-shock protein 90β, a co-activator of the vitamin D receptor, after gastric bypass. Despite increased vitamin D receptor levels, expression of the vitamin D receptor-regulated calcium transporter protein TRPV6 decreased. Conclusion BMD decreases independently of weight after gastric bypass. Bone loss might be attributed to impaired calcium absorption caused by decreased activation of vitamin D-dependent calcium absorption mechanisms mediated by heat-shock protein 90β and TRPV6.
15.	Jansson, John-Olov, 1954, et al. (författare) On the site and mechanism of action of the anti-obesity effects of interleukin-6. 2003 Ingår i: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. - 1096-6374. ; 13 Suppl A Tidskriftsartikel (refereegranskat)abstract We conducted an experimental study examining the site and mechanism of action of the anti-obesity effect of interleukin-6 (IL-6) in mice and rats. We used dual energy X-ray absorptiometry (DEXA) and computerized tomography to investigate the body composition of mice with knockout of the IL-6 gene and wild-type control mice. Rats were treated with IL-6 or vehicle through intracerebroventricular (ICV) cannulae. Energy expenditure was measured as oxygen consumption by indirect calorimetry in metabolic chambers. Results showed that the mice lacking IL-6 increased in body weight compared with wild-type mice from 6 months of age onward, although there was no marked difference in food intake between the pre-obese IL-6 knockout mice and the wild-type mice. IL-6 given as a single ICV injection to rats stimulated oxygen consumption; whereas, the same doses were ineffective when given peripherally. Chronic ICV IL-6 treatment decreased body weight and fat mass in rodents. Administration of IL-6 may decrease fat mass in mice and rats by stimulating energy expenditure at the CNS level, possibly in the hypothalamus.
16.	Malinauskas, Mantas, et al. (författare) Local expression of AP/AngIV/IRAP and effect of AngIV on glucose-induced epithelial transport in human jejunal mucosa 2015 Ingår i: Journal of the renin-angiotensin-aldosterone system. - : Hindawi Limited. - 1470-3203 .- 1752-8976. ; 16:4, s. 1101-8 Tidskriftsartikel (refereegranskat)
17.	Persson, Sara M.T., et al. (författare) Role of FFAR3 in ketone body regulated glucagon-like peptide 1 secretion 2024 Ingår i: BIOCHEMISTRY AND BIOPHYSICS REPORTS. - 2405-5808. ; 39 Tidskriftsartikel (refereegranskat)abstract Background: Roux-en-Y gastric bypass (RYGB) is an effective treatment for obesity, resulting in long-term weight loss and rapid remission of type 2 diabetes mellitus. Improved glucagon-like peptide 1 (GLP-1) levels is one factor that contributes to the positive effects. Prior to RYGB, GLP-1 response is blunted which can be attributed to intestinal ketogenesis. Intestinal produced ketone bodies inhibit GLP-1 secretion in enteroendocrine cells via an unidentified G-protein coupled receptors (GPCRs). A possible class of GPCRs through which ketone bodies may reach are the free fatty acid receptors (FFARs) located at the basolateral membrane of enteroendocrine cells. Aim: To evaluate FFAR3 expression in enteroendocrine cells of the small intestine under different circumstances, such as diet and bariatric surgery, as well as explore the link between ketone bodies and GLP-1 secretion. Materials and methods: FFAR3 and enteroendocrine cell expression was analyzed using Western blot and immunohistochemistry in biopsies from healthy volunteers, obese patients undergoing RYGB and mice. GLUTag cells were used to study GLP-1 secretion and FFAR3 signaling pathways. Results: The expression of FFAR3 is markedly influenced by diet, especially high fat diet, which increased FFAR3 protein expression. Lack of substrate such as free fatty acids in the alimentary limb after RYGB, downregulate FFAR3 expression. The number of enteroendocrine cells was affected by diet in the normal weight individuals but not in the subjects with obesity. In GLUTag cells, we show that the ketone bodies exert its blocking effect on GLP1 secretion via the FFAR3, and the G alpha i/o signaling pathway. Conclusion: Our findings that ketone bodies via FFAR3 inhibits GLP-1 secretion bring important insight into the pathophysiology of T2D. This highlights the role of FFAR3 as a possible target for future anti-diabetic drugs and treatments.
18.	Sotak, Matus, et al. (författare) Intestinal sodium/glucose cotransporter 3 expression is epithelial and downregulated in obesity. 2021 Ingår i: Life sciences. - : Elsevier BV. - 1879-0631 .- 0024-3205. ; 267 Tidskriftsartikel (refereegranskat)abstract We aimed to determine whether the sodium/glucose cotransporter family member SGLT3, a proposed glucose sensor, is expressed in the intestine and/or kidney, and if its expression is altered in mouse models of obesity and in humans before and after weight-loss surgery.We used in-situ hybridization and quantitative PCR to determine whether the Sglt3 isoforms 3a and 3b were expressed in the intestine and kidney of C57, leptin-deficient ob/ob, and diabetic BTBR ob/ob mice. Western blotting and immunohistochemistry were also used to assess SGLT3 protein levels in jejunal biopsies from obese patients before and after weight-loss Roux-en-Y gastric bypass surgery (RYGB), and in lean healthy controls.Sglt3a/3b mRNA was detected in the small intestine (duodenum, jejunum and ileum), but not in the large intestine or kidneys of mice. Both isoforms were detected in epithelial cells (confirmed using intestinal organoids). Expression of Sglt3a/3b mRNA in duodenum and jejunum was significantly lower in ob/ob and BTBR ob/ob mice than in normal-weight littermates. Jejunal SGLT3 protein levels in aged obese patients before Roux-en-Y gastric bypass (RYGB) were lower than in lean individuals, but substantially upregulated 6months post-RYGB.Our study shows that Sglt3a/3b is expressed primarily in epithelial cells of the small intestine in mice. Furthermore, we observed an association between intestinal mRNA Sglt3a/3b expression and obesity in mice, and between jejunal SGLT3 protein levels and obesity in humans. Further studies are required to determine the possible role of SGLT3 in obesity.
19.	Stenlöf, Kaj, 1965, et al. (författare) Interleukin-6 levels in the central nervous system are negatively correlated with fat mass in overweight/obese subjects. 2003 Ingår i: The Journal of clinical endocrinology and metabolism. - 0021-972X. ; 88:9, s. 4379-83 Tidskriftsartikel (refereegranskat)abstract Recently, we demonstrated that intracerebroventricular injection of IL-6 increases energy expenditure and decreases body fat in rodents. Therefore, IL-6 may play a role in appetite and body weight control in the central nervous system. In the present study we evaluated cerebrospinal fluid (CSF) and serum IL-6 levels in humans in relation to body fat content and to CSF and serum levels of leptin. Thirty-two healthy overweight/obese male subjects with a body mass index range of 29.3-36.0 kg/m(2) were studied. Total and sc body fat were measured by dual energy x-ray absorptiometry and computed tomography, respectively. CSF IL-6 levels were in some individuals higher than serum IL-6 levels and correlated negatively with total body weight, sc and total body fat. In contrast, CSF leptin levels were 30-60 times lower than serum leptin levels and correlated positively with serum leptin, body weight, sc and total body fat. Furthermore, there was a negative correlation between CSF IL-6 and leptin. In conclusion, CSF IL-6 differs in many ways from CSF leptin. CSF IL-6 may be locally produced rather than serum derived, and body fat-regulating regions in the central nervous system may be exposed to insufficient IL-6 levels in more severe obesity.
20.	Strandberg, Louise, 1981, et al. (författare) Interleukin-1 system gene polymorphisms are associated with fat mass in young men. 2006 Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:7, s. 2749-54 Tidskriftsartikel (refereegranskat)abstract CONTEXT: There is growing evidence for interactions between the regulation of body fat and the immune system. Studies of knockout mice indicate that IL-1 has an antiobesity effect. OBJECTIVE: The objective of the study was to investigate our hypothesis that common polymorphisms of the IL-1 system, which are associated with IL-1 activity, also are associated with fat mass. DESIGN, SETTING, AND STUDY SUBJECTS: The Gothenburg Osteoporosis and Obesity Determinants (GOOD) study is a population-based cross-sectional study of 18- to 20-yr-old men (n = 1068), mostly Caucasian, from the Gothenburg area (Sweden). Three different polymorphisms, IL-1beta +3953 C/T, IL-1beta-31 T/C, and IL-1 receptor antagonist (IL-1RN) variable number tandem repeat of 86 bp, were investigated in relation to body fat mass. MAIN OUTCOME MEASURE: The main outcome measures were genotype distributions and their association with body fat mass in different compartments, measured with dual-energy x-ray absorptiometry. RESULTS: Carriers of the T variant (CT and TT) of the +3953 C to T (F(T) = 0.25) IL-1beta gene polymorphism had significantly lower total fat mass (P = 0.013) and also significantly reduced arm, leg, and trunk fat, compared with CC individuals. IL-1RN*2 carriers with two repeats of the IL-1RN variable number tandem repeat polymorphism had increased total fat (P = 0.036), serum leptin, and fat of trunk and arm as well as serum levels of IL-1RN and IL-1RN production ex vivo. The IL-1beta-31 polymorphism did not correlate with the fat measurements. CONCLUSIONS: The IL-1 system, recently shown to affect fat mass in experimental animals, contains gene polymorphisms that are associated with fat mass in young men.
21.	Wallenius, Ville, 1970, et al. (författare) Glycemic Control and Metabolic Adaptation in Response to High-Fat versus High-Carbohydrate Diets-Data from a Randomized Cross-Over Study in Healthy Subjects. 2021 Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 13:10 Tidskriftsartikel (refereegranskat)abstract Granular study of metabolic responses to alterations in the ratio of dietary macro-nutrients can enhance our understanding of how dietary modifications influence patients with impaired glycemic control. In order to study the effect of diets enriched in fat or carbohydrates, fifteen healthy, normal-weight volunteers received, in a cross-over design, and in a randomized unblinded order, two weeks of an iso-caloric high-fat diet (HFD: 60E% from fat) and a high-carbohydrate diet (HCD: 60E% from carbohydrates). A mixed meal test (MMT) was performed at the end of each dietary period to examine glucose clearance kinetics and insulin and incretin hormone levels, as well as plasma metabolomic profiles. The MMT induced almost identical glycemia and insulinemia following the HFD or HCD. GLP-1 levels were higher after the HFD vs. HCD, whereas GIP did not differ. The HFD, compared to the HCD, increased the levels of several metabolomic markers of risk for the development of insulin resistance, e.g., branched-chain amino acid (valine and leucine), creatine and α-hydroxybutyric acid levels. In normal-weight, healthy volunteers, two weeks of the HFD vs. HCD showed similar profiles of meal-induced glycemia and insulinemia. Despite this, the HFD showed a metabolomic pattern implying a risk for a metabolic shift towards impaired insulin sensitivity in the long run.
22.	Wallenius, Ville, 1970, et al. (författare) Interleukin-6-deficient mice develop mature-onset obesity. 2002 Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 8:1, s. 75-9 Tidskriftsartikel (refereegranskat)abstract The immune-modulating cytokine interleukin-6 (IL-6) is expressed both in adipose tissue and centrally in hypothalamic nuclei that regulate body composition. We investigated the impact of loss of IL-6 on body composition in mice lacking the gene encoding IL-6 (Il6-/- mice) and found that they developed mature-onset obesity that was partly reversed by IL-6 replacement. The obese Il6-/- mice had disturbed carbohydrate and lipid metabolism, increased leptin levels and decreased responsiveness to leptin treatment. To investigate the possible mechanism and site of action of the anti-obesity effect of IL-6, we injected rats centrally and peripherally with IL-6 at low doses. Intracerebroventricular, but not intraperitoneal IL-6 treatment increased energy expenditure. In conclusion, centrally acting IL-6 exerts anti-obesity effects in rodents.
23.	Wallenius, Ville, 1970, et al. (författare) Suppression of enteroendocrine cell glucagon-like peptide (GLP)-1 release by fat-induced small intestinal ketogenesis: a mechanism targeted by Roux-en-Y gastric bypass surgery but not by preoperative very-low-calorie diet. 2020 Ingår i: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 69:8, s. 1423-1431 Tidskriftsartikel (refereegranskat)abstract Food intake normally stimulates release of satiety and insulin-stimulating intestinal hormones, such as glucagon-like peptide (GLP)-1. This response is blunted in obese insulin resistant subjects, but is rapidly restored following Roux-en-Y gastric bypass (RYGB) surgery. We hypothesised this to be a result of the metabolic changes taking place in the small intestinal mucosa following the anatomical rearrangement after RYGB surgery, and aimed at identifying such mechanisms.Jejunal mucosa biopsies from patients undergoing RYGB surgery were retrieved before and after very-low calorie diet, at time of surgery and 6 months postoperatively. Samples were analysed by global protein expression analysis and Western blotting. Biological functionality of these findings was explored in mice and enteroendocrine cells (EECs) primary mouse jejunal cell cultures.The most prominent change found after RYGB was decreased jejunal expression of the rate-limiting ketogenic enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHMGCS), corroborated by decreased ketone body levels. In mice, prolonged high-fat feeding induced the expression of mHMGCS and functional ketogenesis in jejunum. The effect of ketone bodies on gut peptide secretion in EECs showed a ∼40% inhibition of GLP-1 release compared with baseline.Intestinal ketogenesis is induced by high-fat diet and inhibited by RYGB surgery. In cell culture, ketone bodies inhibited GLP-1 release from EECs. Thus, we suggest that this may be a mechanism by which RYGB can remove the inhibitory effect of ketone bodies on EECs, thereby restituting the responsiveness of EECs resulting in increased meal-stimulated levels of GLP-1 after surgery.
24.	Wernstedt, Ingrid, 1978, et al. (författare) Increased levels of acylation-stimulating protein in interleukin-6-deficient (IL-6(-/-)) mice 2006 Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 147:6, s. 2690-5 Tidskriftsartikel (refereegranskat)abstract IL-6-deficient (IL-6(-/-)) mice develop obesity at 6-7 months of age. To elucidate the mechanisms of this mature-onset obesity, global gene expression profiles of 3-month-old preobese IL-6(-/-) were compared with those of IL-6(+/+) mice using DNA arrays. Genes that were up-regulated in IL-6(-/-) mice included the factors transthyretin and properdin in white adipose tissue and adipsin in muscle. These factors have been shown to influence the formation of acylation-stimulating protein (ASP), a cleavage product of complement C3. ASP stimulates the synthesis of triacylglycerol in adipocytes, and ASP-deficient mice are resistant to diet-induced obesity. In line with the increases in transthyretin, properdin, and adipsin, ASP levels in serum were increased by 31-54% in IL-6(-/-) compared with IL-6(+/+) mice. Furthermore, IL-6 replacement treatment in IL-6(-/-) mice decreased ASP levels significantly by 25-60%. In conclusion, ASP levels are increased in preobese IL-6(-/-) mice. This increase may result in increased triacylglycerol formation and uptake in IL-6(-/-) adipocytes and thereby contribute to the development of obesity in IL-6(-/-) mice.
25.	Agreus, L., et al. (författare) Significant over- and misuse of PPIs 2021 Ingår i: Lakartidningen. - 1652-7518. ; 118 Tidskriftsartikel (refereegranskat)abstract PPIs (Proton-pump inhibitors) offers the best treatment for acid related diseases. The predominant indications for PPI prescription are: GERD eradication of H. pylori-infection in combination with antibiotics H. pylori-negative peptic ulcer healing of and prophylaxis against NSAID/COXIB--induced gastroduodenal lesions acid hypersecretory states such as Zollinger-Ellisons syndrome. The market for PPIs continues to expand in most countries. A significant over- and misuse of PPIs prevails in hospital care as well as in general practice. The predominant reasons for and mechanisms behind the over- and misuse of PPIs are well recognised. The most important consequences of this overprescription of PPIs are increasing medical costs and risk for long-term adverse side effects. Continued education and dedicated information are key factors to guide physicians, medical personnel and patients to adopt to generally accepted principles for and balanced use of PPIs.
26.	Benrick, Anna, 1979, et al. (författare) Interleukin-6 mediates exercise-induced increase in insulin sensitivity in mice. 2012 Ingår i: Experimental physiology. - : Wiley. - 1469-445X .- 0958-0670. ; 97:11 SI, s. 1224-1235 Tidskriftsartikel (refereegranskat)abstract Interleukin-6 (IL-6) is released from working skeletal muscle during exercise. We investigated the acute and the long-term beneficial effects of IL-6 on exercise-induced glucose uptake in skeletal muscle and insulin sensitivity. The acute effect on exercise-induced glucose uptake was measured in IL-6 deficient (-/-) mice and wild type controls using a tracer technique. There was no difference in serum disappearance of 3H-2-deoxyglucose after a bolus dose of exercise between IL-6 -/- and wild type mice (13565 ± 426 vs. 14343 ± 1309 dpmmin/ml, p=0.5). The glucose uptake rate in the EDL muscle was however lower in IL-6 -/- compared to wildtype mice (398 ± 44 vs. 657 ± 41 nmol/g/min, p<0.01). In the long-term study, we monitored insulin sensitivity, serum retinol-binding protein-4 (RBP-4) levels, running activity, food intake, body weight and body composition in IL-6 -/- and wild type mice on a high-fat diet (HFD), with or without access to running wheels. In sedentary IL-6 -/- and wild type mice, HFD decreased insulin sensitivity (glucose AUC increased about 20% during an insulin tolerance test (ITT), p<0.05 for both genotypes vs. baseline) and led to a 30% increase in serum RBP-4 levels (p <0.01 for both genotypes vs. baseline). Wild type runners were protected against these effects of HFD and maintained their baseline insulin sensitivity and serum RBP-4 levels. In contrast, IL-6 -/- mice did not, to the same extent as wild types, benefit from running. IL-6 -/- runners had a similar decrease in insulin sensitivity as their sedentary littermates (glucose AUC during an ITT in runners vs. sedentary IL-6-/- HFD mice: 312 ± 14 vs. 340 ± 22 mmolmin/L, p=0.4) and displayed a 14% increase in serum RBP-4 as compared to baseline levels (p<0.01). Our results indicate that endogenous IL-6 contributes to the exercise-induced increase in insulin sensitivity, but only plays a minor role for glucose uptake into skeletal muscle during exercise.
27.	Börgeson, Emma, et al. (författare) AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin. 2017 Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 60:4, s. 729-739 Tidskriftsartikel (refereegranskat)abstract In this study, we aimed to evaluate the therapeutic potential of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-activated protein kinase, for ameliorating high-fat diet (HFD)-induced pathophysiology in mice. We also aimed to determine whether the beneficial effects of AICAR were dependent on adiponectin. Furthermore, human adipose tissue was used to examine the effect of AICAR ex vivo.Six-week-old male C57BL/6J wild-type and Adipoq (-/-) mice were fed a standard-fat diet (10% fat) or an HFD (60% fat) for 12weeks and given vehicle or AICAR (500μg/g) three times/week from weeks 4-12. Diet-induced pathophysiology was examined in mice after 11 weeks by IPGTT and after 12 weeks by flow cytometry and western blotting. Human adipose tissue biopsies from obese (BMI 35-50kg/m(2)) individuals were incubated with vehicle or AICAR (1mmol/l) for 6h at 37°C, after which inflammation was characterised by ELISA (TNF-α) and flow cytometry.AICAR attenuated adipose inflammation in mice fed an HFD, promoting an M1-to-M2 macrophage phenotype switch, while reducing infiltration of CD8(+) T cells. AICAR treatment of mice fed an HFD partially restored glucose tolerance and attenuated hepatic steatosis and kidney disease, as evidenced by reduced albuminuria (p<0.05), urinary H2O2 (p<0.05) and renal superoxide levels (p<0.01) in both wild-type and Adipoq (-/-) mice. AICAR-mediated protection occurred independently of adiponectin, as similar protection was observed in wild-type and Adipoq (-/-) mice. In addition, AICAR promoted an M1-to-M2 macrophage phenotype switch and reduced TNF-α production in tissue explants from obese human patients.AICAR may promote metabolic health and protect against obesity-induced systemic diseases in an adiponectin-independent manner. Furthermore, AICAR reduced inflammation in human adipose tissue explants, suggesting by proof-of-principle that the drug may reduce obesity-induced complications in humans.ClinicalTrials.gov NCT02322073.
28.	Cervin, Jakob, et al. (författare) Fucose-Galactose Polymers Inhibit Cholera Toxin Binding to Fucosylated Structures and Galactose-Dependent Intoxication of Human Enteroids. 2020 Ingår i: ACS infectious diseases. - : American Chemical Society (ACS). - 2373-8227. ; 6:5, s. 1192-1203 Tidskriftsartikel (refereegranskat)abstract A promising strategy to limit cholera severity involves blockers mimicking the canonical cholera toxin ligand (CT) ganglioside GM1. However, to date the efficacies of most of these blockers have been evaluated in noncellular systems that lack ligands other than GM1. Importantly, the CT B subunit (CTB) has a noncanonical site that binds fucosylated structures, which in contrast to GM1 are highly expressed in the human intestine. Here we evaluate the capacity of norbornene polymers displaying galactose and/or fucose to block CTB binding to immobilized protein-linked glycan structures and also to primary human and murine small intestine epithelial cells (SI ECs). We show that the binding of CTB to human SI ECs is largely dependent on the noncanonical binding site, and interference with the canonical site has a limited effect while the opposite is observed with murine SI ECs. The galactose-fucose polymer blocks binding to fucosylated glycans but not to GM1. However, the preincubation of CT with the galactose-fucose polymer only partially blocks toxic effects on cultured human enteroid cells, while preincubation with GM1 completely blocks CT-mediated secretion. Our results support a model whereby the binding of fucose to the noncanonical site places CT in close proximity to scarcely expressed galactose receptors such as GM1 to enable binding via the canonical site leading to CT internalization and intoxication. Our finding also highlights the importance of complementing CTB binding studies with functional intoxication studies when assessing the efficacy inhibitors of CT.
29.	Elias, Erik, 1979, et al. (författare) Central nervous system lipocalin-type prostaglandin D2-synthase is correlated with orexigenic neuropeptides, visceral adiposity and markers of the hypothalamic-pituitary-adrenal axis in obese humans. 2011 Ingår i: Journal of neuroendocrinology. - : Wiley. - 1365-2826 .- 0953-8194. ; 23:6, s. 501-7 Tidskriftsartikel (refereegranskat)abstract Lipocalin-type prostaglandin D2-synthase (L-PGDS) is the main producer of prostaglandin D2 (PGD2) in the central nervous system (CNS). Animal data suggest effects of central nervous L-PGDS in the regulation of food intake and obesity. No human data are available. We hypothesised that a role for CNS L-PGDS in metabolic function in humans would be reflected by correlations with known orexigenic neuropeptides. Cerebrospinal fluid (CSF) and serum samples were retrieved from 26 subjects in a weight loss study, comprising a 3-week dietary lead-in followed by 12-weeks of leptin or placebo treatment. At baseline, CSF L-PGDS was positively correlated with neuropeptide Y (NPY) (ρ=0.695, P<0.001, n=26) and galanin (ρ=0.651, P<0.001) as well as visceral adipose tissue (ρ=0.415, P=0.035). Furthermore, CSF L-PGDS was inversely correlated with CSF leptin (ρ=-0.529, P=0.005) and tended to correlate inversely with s.c. adipose tissue (ρ=-0.346, P=0.084). As reported earlier, leptin treatment had no effect on weight loss and did not affect CSF L-PGDS or NPY levels compared to placebo. After weight loss, the change of CSF L-PGDS was significantly correlated with the change of CSF NPY levels (ρ=0.604, P=0.004, n=21). Because of the correlation between baseline CSF L-PGDS levels and visceral adipose tissue, we examined associations with hypothalamic-pituitary-adrenal (HPA) axis components. Baseline CSF L-PGDS was correlated with corticotrophin-releasing hormone (ρ=0.764, P<0.001) and β-endorphin (ρ=0.491, P<0.001). By contrast, serum L-PGDS was not correlated with any of the measured variables either at baseline or after treatment. In summary, CSF L-PGDS was correlated with orexigenic neuropeptides, visceral fat distribution and central HPA axis mediators. The importance of these findings is unclear but could suggest a role for CSF L-PGDS in the regulation of visceral obesity by interaction with the neuroendocrine circuits regulating appetite and fat distribution. Further interventional studies will be needed to characterise these interactions in more detail.
30.	Elias, Erik, 1979, et al. (författare) Erythrocyte sodium-lithium countertransport activity is inversely correlated to adiponectin, retinol binding protein 4 and body height. 2010 Ingår i: Scandinavian journal of clinical and laboratory investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 70:7, s. 487-91 Tidskriftsartikel (refereegranskat)abstract We have previously described that the sodium/lithium countertransport (SLC) in the erythrocyte cell membrane is closely linked to obesity and insulin resistance. Adiponectin and retinol-binding protein 4 (RBP-4) are believed to affect obesity and insulin resistance. In the present study, we aimed to further characterize the relationship between SLC, inflammatory markers, adiponectin and RBP-4.
31.	Fändriks, Lars, 1956, et al. (författare) Bariatric surgery for diabetes mellitus type 2 control in adults with BMI<35 kg/m2 2016 Rapport (övrigt vetenskapligt/konstnärligt)abstract Background: Obesity is strongly linked to diabetes and premature mortality, mainly from cardiovascular causes. In 2013, the prevalence of obesity (BMI ≥ 30 kg/m2) in adults in Sweden was 14 %. The prevalence of diabetes mellitus in Sweden is approximately 5 % with a slow increase due to an ageing population. In 2015, 73,225 patients in VGR had a diagnosis of diabetes mellitus. The treatment of overweight and obesity in adults is based on three principles: lifestyle changes, pharmacological treatment and surgery. Today, weight reducing (bariatric) surgery can be offered to individuals with BMI ≥40 kg/m2, and patients with BMI ≥35 kg/m2 with an obesity associated disease, in particular diabetes mellitus type 2 (T2D). Bariatric surgery in persons with BMI < 35 kg/m2 is currently not endorsed in Swedish national guidelines (National Board of Health and Welfare, 2015). Glycaemic stabilisation is reported to occur very early after surgery, before any significant weight loss. In a recent joint statement by several international diabetes organizations, it was proposed that bariatric surgery should be considered to be an option to treat T2D in patients with BMI 30.0–34.99 kg/m2 and inadequately controlled hyperglycaemia despite optimal medical treatment. Objective: To study if bariatric surgery in patients with T2D and a BMI <35 kg/m2 is superior to standard treatment with regard to diabetes control. Search methods and study selection criteria: During January 2016 two authors performed systematic searches in PubMed, Embase, the Cochrane Library and a number of HTA-databases for systematic reviews, randomized (RCT) and non-randomised controlled studies. Due to the small number of original articles fulfilling the inclusion criteria we chose to only include and critically appraise original articles. Main results: The literature search resulted in four RCTs and six cohort studies (two reporting on the same population) comparing results of bariatric surgery with medical treatment in T2D patients with BMI <35 kg/m2. The studies had limitations mainly related to, e.g., short follow-up, some inconsistency, indirectness due to different interventions or unclear patient selection, and imprecision. Mortality was reported in two studies with only one reported death. Remission of T2D was studied in three RCTs and four cohort studies. The frequency of T2D remission during 1–3 years follow-up may be higher after bariatric surgery compared with non-surgical standard care (GRADE ⊕⊕ ). Diabetes related and cardiovascular complications were not studied. Health related quality of life (SF-36) was reported in one RCT and physical wellbeing may improve after bariatric surgery compared with medical treatment (GRADE ⊕⊕ ). Regarding glycaemic control, bariatric surgery compared with non-surgical standard care probably reduces HbA1c (GRADE ⊕⊕⊕ ), may reduce fasting plasma glucose (GRADE ⊕⊕ ) but the effect on the number of glucose-lowering medications is uncertain (GRADE ⊕ ). Bariatric surgery compared with non-surgical standard care probably reduces BMI (GRADE ⊕⊕⊕ ) but the effects on other metabolic risk factors are uncertain (GRADE ⊕ ). Risks and complications: The rate of surgical complications was reported from four to 17% ranging from mild to more severe complications requiring surgical intervention. Concluding remarks: This systematic review shows that bariatric surgery compared with medical treatment may increase the frequency of diabetes remission and probably results in improved glycaemic control in adults with overweight or obesity (BMI< 35 kg/m2, mainly 30 – 34.99 kg/m2) during 1–3 years follow-up. The bariatric surgical procedures mainly performed in Sweden today (Roux-en-Y gastric bypass, vertical sleeve gastrectomy) were investigated in only half of the current studies. Data on long term efficacy and safety are lacking and there are no results indicating reduced risk of cardiovascular disease, cancer or death. No relevant health economic analyses are available.
32.	Hallersund, Peter, 1975, et al. (författare) Correction: Gastric Bypass Surgery Is Followed by Lowered Blood Pressure and Increased Diuresis - Long Term Results from the Swedish Obese Subjects (SOS) Study. 2013 Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:5 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract [This corrects the article on p. e49696 in vol. 7.].
33.	Hallersund, Peter, 1975, et al. (författare) Gastric Bypass Surgery Is Followed by Lowered Blood Pressure and Increased Diuresis - Long Term Results from the Swedish Obese Subjects (SOS) Study. 2012 Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 7:11 Tidskriftsartikel (refereegranskat)abstract To compare two bariatric surgical principles with regard to effects on blood pressure and salt intake.
34.	Hernandez-Carretero, A., et al. (författare) Obesity-induced changes in lipid mediators persist after weight loss 2018 Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 42:4, s. 728-736 Tidskriftsartikel (refereegranskat)abstract Background:Obesity induces significant changes in lipid mediators, however, the extent to which these changes persist after weight loss has not been investigated.Subjects/Methods:We fed C57BL6 mice a high-fat diet to generate obesity and then switched the diet to a lower-fat diet to induce weight loss. We performed a comprehensive metabolic profiling of lipid mediators including oxylipins, endocannabinoids, sphingosines and ceramides in key metabolic tissues (including adipose, liver, muscle and hypothalamus) and plasma.Results:We found that changes induced by obesity were largely reversible in most metabolic tissues but the adipose tissue retained a persistent obese metabolic signature. Prostaglandin signaling was perturbed in the obese state and lasting increases in PGD 2, and downstream metabolites 15-deoxy PGJ 2 and delta-12-PGJ 2 were observed after weight loss. Furthermore expression of the enzyme responsible for PGD 2 synthesis (hematopoietic prostaglandin D synthase, HPGDS) was increased in obese adipose tissues and remained high after weight loss. We found that inhibition of HPGDS over the course of 5 days resulted in decreased food intake in mice. Increased HPGDS expression was also observed in human adipose tissues obtained from obese compared with lean individuals. We then measured circulating levels of PGD 2 in obese patients before and after weight loss and found that while elevated relative to lean subjects, levels of this metabolite did not decrease after significant weight loss.Conclusions:These results suggest that lasting changes in lipid mediators induced by obesity, still present after weight loss, may play a role in the biological drive to regain weight. © 2018 Macmillan Publishers Limited.
35.	Höskuldsdóttir, Gudrun, et al. (författare) Comparing effects of obesity treatment with very low energy diet and bariatric surgery after 2 years: a prospective cohort study 2022 Ingår i: Bmj Open. - : BMJ. - 2044-6055. ; 12:4 Tidskriftsartikel (refereegranskat)abstract Objectives To compare long-term effects and complications of medical treatment (MT) of obesity including very low energy diet with bariatric surgery. Design and setting This prospective study conducted in a clinical setting recruited individuals with body mass index (BMI) >= 35 kg/m(2) referred for obesity treatment. Demographic and anthropometric data, laboratory samples, and questionnaire replies were collected at baseline and 2 years. Participants and interventions 971 individuals were recruited 2015-2017. 382 received MT, 388 Roux-en-Y gastric bypass (RYGB) and 201 sleeve gastrectomy (SG). Main outcome measures Primary outcomes included changes in anthropometric measures, metabolic variables and safety. These were analysed using a linear regression model. A logistic regression model was used to analyse composite variables for treatment success (secondary outcomes). A random forest (RF) model was used to examine the importance of 15 clinical domains as predictors for successful treatment. Results Two-year data were available for 667 individuals (68.7%). Regarding primary outcomes, the decrease in excess BMI was 27.5%, 82.5% and 70.3% and proportion achieving a weight of >10% was 45.3%, 99.6% and 95.6% for MT, RYGB and SG, respectively (p<0.001). The groups were comparable regarding levels of vitamins, minerals and haemoglobin or safety measures. Likelihood for success (secondary outcome) was higher in the surgical groups (RYGB: OR 5.3 (95% CI 3.9 to 7.2) vs SG: OR 4.3 ((95% CI 3.0 to 6.2)) in reference to MT. Baseline anthropometry had the strongest predictive value for treatment success, according to the RF model. Conclusions In clinical practice, bariatric surgery by RYGB or SG is most effective, but meaningful weight loss is achievable by MT with strict caloric restriction and stepwise introduction of a normal diet. All treatments showed positive effects on well-being, cardiovascular risk factors, and levels of vitamins and minerals at 2-year follow-up and groups were similar regarding safety measures.
36.	Höskuldsdóttir, Gudrun, et al. (författare) Design and baseline data in the BAriatic surgery SUbstitution and Nutrition study (BASUN): a 10-year prospective cohort study 2020 Ingår i: BMC Endocrine Disorders. - : Springer Science and Business Media LLC. - 1472-6823. ; 20:1 Tidskriftsartikel (refereegranskat)abstract Background There is still a lack of knowledge on long-term effects of surgical and non-surgical weight-lowering treatments. BASUN is a prospective study with 10 years of follow-up that will observe the effects and consequences of surgical and medical treatment of obesity. The aims are to cover areas where data on long-term outcomes are lacking, e.g., nutritional deficiencies, substance abuse, psychiatric health, as well as patient-reported outcomes. Methods BASUN is a cohort study that recruited study persons with obesity (BMI >= 35 kg/m(2)) referred to the Regional Obesity Centre of Region Vastra Gotaland. The interventions were Roux-en-Y gastric bypass (RYGB) or Sleeve gastrectomy (SG), or 12 months of structured, multi-professional medical treatment (MT), including very low energy diet, followed by diet and pharmaceutical treatment. The study is not randomized, but based on patients preferences and multidisciplinary assessments. The study persons are examined at baseline, 2, 5, and 10 years with blood tests, measurements and questionnaires. The recruitment period lasted from May 2015 to November 2017. Results One thousand one hundred twenty-seven patients were included (74% female). Three hundred eighty-two patients were accepted for medical treatment, 589 for surgical treatment (388 RYGB and 201 SG) and 156 patients left the study without treatment, leaving a final study population of 971 patients. There were slight differences between the treatment groups with regards to age and BMI. Pharmaceutical treatments, level of education, smoking and marital status were not significantly different between the groups. Conclusion This study will follow 971 obese subjects in clinical practice treated with the best surgical or medical methods currently available. It has the potential to evaluate outcomes usually not reported in short-term studies, and to assist in identifying factors that are of importance for the choices of treatment. The main limitations are non-randomization and differences in baseline characteristics. The large number of participants and the length of the prospective follow-up are major strengths of the study. BASUN is designed to identify both early and late benefits and adverse events of treatment of obesity.
37.	Höskuldsdóttir, Gudrun, et al. (författare) Potential Benefits and Harms of Gastric Bypass Surgery in Obese Individuals With Type 1 Diabetes : A Nationwide, Matched, Observational Cohort Study 2020 Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 43:12, s. 3079-3085 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: To study the potential long-term benefits and possible complications of bariatric surgery in patients with type 1 diabetes (T1D).RESEARCH DESIGN AND METHODS: In this register-based nationwide cohort study, we compared individuals with T1D and obesity who underwent Roux-en-Y gastric bypass (RYGB) surgery with patients with T1D and obesity matched for age, sex, BMI, and calendar time that did not undergo surgery. By linking the Swedish National Diabetes Register and Scandinavian Obesity Surgery Registry study individuals were included between 2007 and 2013. Outcomes examined included all-cause mortality, cardiovascular disease, stroke, heart failure, and hospitalization for serious hypo- or hyperglycemic events, amputation, psychiatric disorders, changes in kidney function, and substance abuse.RESULTS: We identified 387 individuals who had undergone RYGB and 387 control patients. Follow-up for hospitalization was up to 9 years. Analysis showed lower risk for cardiovascular disease (hazard ratio [HR] 0.43; 95% CI 0.20-0.9), cardiovascular death (HR 0.15; 95% CI 0.03-0.68), hospitalization for heart failure (HR 0.32; 95% CI 0.15-0.67) and stroke (HR 0.18; 95% CI 0.04-0.82) for the RYGB group. There was a higher risk for serious hyperglycemic events (HR 1.99; 95% CI 1.07-3.72) and substance abuse (HR 3.71; 95% CI 1.03-3.29) after surgery.CONCLUSIONS: This observational study suggests bariatric surgery may yield similar benefits on risk for cardiovascular outcomes and mortality in patients with T1D and obesity as for patients with type 2 diabetes. However, some potential serious adverse effects suggest need for careful monitoring of such patients after surgery.
38.	Höskuldsdóttir, Gudrun, et al. (författare) The BAriatic surgery SUbstitution and nutrition (BASUN) population: a data-driven exploration of predictors for obesity 2021 Ingår i: Bmc Endocrine Disorders. - : Springer Science and Business Media LLC. - 1472-6823. ; 21:1 Tidskriftsartikel (refereegranskat)abstract Background: The development of obesity is most likely due to a combination of biological and environmental factors some of which might still be unidentified. We used a machine learning technique to examine the relative importance of more than 100 clinical variables as predictors for BMI. Methods: BASUN is a prospective non-randomized cohort study of 971 individuals that received medical or surgical treatment (treatment choice was based on patient's preferences and clinical criteria, not randomization) for obesity in the Vastra Gotaland county in Sweden between 2015 and 2017 with planned follow-up for 10 years. This study includes demographic data, BMI, blood tests, and questionnaires before obesity treatment that cover three main areas: gastrointestinal symptoms and eating habits, physical activity and quality of life, and psychological health. We used random forest, with conditional variable importance, to study the relative importance of roughly 100 predictors of BMI, covering 15 domains. We quantified the predictive value of each individual predictor, as well as each domain. Results: The participants received medical (n = 382) or surgical treatment for obesity (Roux-en-Y gastric bypass, n = 388; sleeve gastrectomy, n = 201). There were minor differences between these groups before treatment with regard to anthropometrics, laboratory measures and results from questionnaires. The 10 individual variables with the strongest predictive value, in order of decreasing strength, were country of birth, marital status, sex, calcium levels, age, levels of TSH and HbA1c, AUDIT score, BE tendencies according to QEWPR, and TG levels. The strongest domains predicting BMI were: Socioeconomic status, Demographics, Biomarkers (notably TSH), Lifestyle/habits, Biomarkers for cardiovascular disease and diabetes, and Potential anxiety and depression. Conclusions: Lifestyle, habits, age, sex and socioeconomic status are some of the strongest predictors for BMI levels. Potential anxiety and / or depression and other characteristics captured using questionnaires have strong predictive value. These results confirm previously suggested associations and advocate prospective studies to examine the value of better characterization of patients eligible for obesity treatment, and consequently to evaluate the treatment effects in groups of patients.
39.	Jansson, John-Olov, 1954, et al. (författare) Point-counterpoint: Interleukin-6 does/does not have a beneficial role in insulin sensitivity and glucose homeostasis. 2007 Ingår i: Journal of applied physiology (Bethesda, Md. : 1985). - 8750-7587. ; 102:2 Tidskriftsartikel (refereegranskat)
40.	Laurenius, Anna, et al. (författare) Resolution of diabetes, gastrointestinal symptoms, and self-reported dietary intake after gastric bypass versus sleeve gastrectomy: a randomized study 2023 Ingår i: Surgery for Obesity and Related Diseases. - : Elsevier BV. - 1550-7289 .- 1878-7533. ; 19:5, s. 440-448 Tidskriftsartikel (refereegranskat)abstract Background: There is a lack of randomized studies examining diabetes remission and dietary intake between patients undergoing Roux-en-Y gastric bypass (RYGB) versus sleeve gastrectomy (SG). Objective: To examine longitudinal differences in diabetes resolution, dietary intake, and gastrointestinal (GI) symptoms in patients with obesity and type 2 diabetes (T2D) randomized to either RYGB or SG and according to remission of T2D. Setting: Four hospitals in Sweden, 2 of which are university hospitals. Methods: Dietary intake and GI symptoms were calculated from questionnaires and morphometric differences between surgical methods and T2D remission were compared using the Student t test, effect size (ES) for parametric parameters, and Mann-Whitney U test for nonparametric parameters. Results: Five years after RYGB or SG there was no significant difference in the rate of remission of T2D between RYGB and SG (43% versus 20%, P = .176). RYGB (n = 19) patients had greater weight loss than SG patients (n = 14) (26.4 [9.5] versus 13.1 [9.6] kg, P < .001), despite reporting higher daily caloric intake (Δ 669 kcal, P = .059, ES .67) and food weight (Δ 1029 g/d, P = .003, ES 1.11). RYGB patients, compared with SG patients, also ate 1 more fruit per day (P = .023). Pooled data showed no differences between patients with and without T2D remission regarding weight loss, but those in remission drank more nonalcoholic drinks and milk. Conclusions: Five years postoperatively, patients randomized to RYGB reported considerably higher food intake compared with SG despite lower body weight. The reason and importance of the higher food intake after RYGB compared with SG needs to be further studied.
41.	Maleckas, Almantas, et al. (författare) Surgery in the treatment of type 2 diabetes mellitus. 2015 Ingår i: Scandinavian journal of surgery : SJS : official organ for the Finnish Surgical Society and the Scandinavian Surgical Society. - : SAGE Publications. - 1799-7267. ; 104:1, s. 40-47 Tidskriftsartikel (refereegranskat)abstract The prevalence of diabetes is increasing worldwide, and most of the cases are type 2 diabetes mellitus. The relationship between type 2 diabetes mellitus and obesity is well established, and surgical treatment is widely used for obese patients with type 2 diabetes mellitus. The aim was to present current knowledge about the possible mechanisms responsible for glucose control after surgical procedures and to review the surgical treatment results.
42.	Mejaddam, Ala, et al. (författare) Effects of medical and surgical treatment on vitamin D levels in obesity 2023 Ingår i: PLoS ONE. - 1932-6203. ; 18:12 December Tidskriftsartikel (refereegranskat)abstract Introduction Persons living with obesity treated with bariatric surgery are at a high risk of developing nutritional deficiencies. The primary aim of this observational cohort study was to compare vitamin D levels in patients two years after bariatric surgery (Roux-en-Y gastric bypass/ RYGB and sleeve gastrectomy/SG) with a very low-energy diet (VLED). The same subjects were also compared with a population sample from the same region at baseline. The primary hypothesis was that surgery, especially RYGB, would lead to an increased prevalence of vitamin D deficiency compared to subjects treated with VLED. 971 individuals eligible for surgical, RYGB (n = 388), SG (n = 201), and medical treatment (n = 382), in routine care, were included consecutively between 2015 and 2017. A random population sample from the WHO-MONICA project was used as a reference, (n = 414). S-calcium, S-25(OH)D (vitamin D), and S-PTH (parathyroid hormone) were measured in all persons with obesity at baseline and two years after treatment (n = 713). Self-reported use of vitamin D and calcium supplementation was registered. Results Vitamin D deficiency (S-25(OH)D <25mmol/l) was found in 5.2% of the persons with obesity at baseline versus 1.7% of the general population (SMD>0.1). S-25(OH)D increased for all treatment groups but was higher in RYGB and SG (SMD>0.1, standardized mean difference). Thirteen subjects (1.8%) had vitamin D deficiency after obesity treatment. Conclusion Surgical intervention for obesity followed by vitamin D supplementation was not associated with a higher risk for vitamin D deficiency, irrespective of surgery type, compared to individuals on medical treatment. However, persons living with obesity seeking weight loss treatment are more likely to have deficient vitamin D levels compared to the general population.
43.	Persson, Linda, 1971, et al. (författare) Lack of complement factor C3, but not factor B, increases hyperlipidemia and atherosclerosis in apolipoprotein E-/- low-density lipoprotein receptor-/- mice 2004 Ingår i: Arterioscler Thromb Vasc Biol. - 1079-5642. ; 24:6, s. 1062-1067 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: To investigate the effect of complement deficiency on atherogenesis and lipidemia, we used mice deficient in the third complement component (C3-/-) or factor B (FB-/-). METHODS AND RESULTS: Complement-deficient mice were crossed with mice deficient in both apolipoprotein E and the low-density lipoprotein receptor (Apoe-/- LDLR-/-). The percent lesion area in the aorta at 16 weeks, determined by en face analysis, was 84% higher in C3-/- mice than in controls (11.8%+/-0.4% versus 6.4%+/-0.8%, mean+/-SEM, P<0.00005). The C3-/- mice also had 58% higher serum triglyceride levels (P<0.05) and a more proatherogenic lipoprotein profile, with significantly more low-density lipoprotein cholesterol and very-low-density lipoprotein triglycerides than control mice. The C3-/- mice weighed 13% less (P<0.01) and had a lower body fat content (3.5%+/-1.0% versus 13.1%+/-3.0%, P<0.01). There were no differences between FB-/- mice and controls. CONCLUSIONS: Complement activation by the classical or lectin pathway exerts atheroprotective effects, possibly through the regulation of lipid metabolism.
44.	Picarda, Elodie, et al. (författare) The immune checkpoint B7-H3 (CD276) regulates adipocyte progenitor metabolism and obesity development. 2022 Ingår i: Science advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 8:17 Tidskriftsartikel (refereegranskat)abstract The immune checkpoint B7-H3 (CD276) is a member of the B7 family that has been studied in the tumor microenvironment and immunotherapy, but its potential role in metabolism remains largely unknown. Here, we show that B7-H3 is highly expressed in mouse and human adipose tissue at steady state, with the highest levels in adipocyte progenitor cells. B7-H3 is rapidly down-regulated upon the initiation of adipocyte differentiation. Combined RNA sequencing and metabolic studies reveal that B7-H3 stimulates glycolytic and mitochondrial activity of adipocyte progenitors. Loss of B7-H3 in progenitors results in impaired oxidative metabolism program and increased lipid accumulation in derived adipocytes. Consistent with these observations, mice knocked out for B7-H3 develop spontaneous obesity, metabolic dysfunction, and adipose tissue inflammation. Our results reveal an unexpected metabolic role for B7-H3 in adipose tissue and open potential new avenues for the treatment of metabolic diseases by targeting the B7-H3 pathway.
45.	Rohin Rajan, Meenu, et al. (författare) Comparative analysis of obesity-related cardiometabolic and renal biomarkers in human plasma and serum. 2019 Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1 Tidskriftsartikel (refereegranskat)abstract The search for biomarkers associated with obesity-related diseases is ongoing, but it is not clear whether plasma and serum can be used interchangeably in this process. Here we used high-throughput screening to analyze 358 proteins and 76 lipids, selected because of their relevance to obesity-associated diseases, in plasma and serum from age- and sex-matched lean and obese humans. Most of the proteins/lipids had similar concentrations in plasma and serum, but a subset showed significant differences. Notably, a key marker of cardiovascular disease PAI-1 showed a difference in concentration between the obese and lean groups only in plasma. Furthermore, some biomarkers showed poor correlations between plasma and serum, including PCSK9, an important regulator of cholesterol homeostasis. Collectively, our results show that the choice of biofluid may impact study outcome when screening for obesity-related biomarkers and we identify several markers where this will be the case.
46.	Sediqi, Ehsan, et al. (författare) Laparoscopic Heller myotomy or pneumatic dilatation in achalasia: results of a prospective, randomized study with at least a decade of follow-up 2021 Ingår i: Surgical Endoscopy. - : Springer Science and Business Media LLC. - 0930-2794 .- 1432-2218. ; 35, s. 1618-1625 Tidskriftsartikel (refereegranskat)abstract Background and objectives: The most efficient long-term treatment strategy for achalasia has yet to be established. This study compared the long-term results (≥ 10years) after either pneumatic dilatations or laparoscopic myotomy using treatment failure as the primary outcome. Secondary objectives were; the frequency and degree of dysphagia and effects on health-related quality of life (QoL). Patients and methods: Out of the 53 patients with achalasia who were initially randomized to either laparoscopic myotomy with a posterior partial fundoplication (LM) or repetitive pneumatic dilatation (PD), 43 remained for scrutiny after a median observation period of 170months (LM; n = 20 and PD; n = 23). Results: At the follow-up of 60months, 10 patients (36%) in the PD group and two patients (8%) in the LM group were classified as treatment failures (p = 0.016). At the latest follow-up time point (≥ 10years), the corresponding numbers were 13 (57%) and 4 (20%), respectively. The Kaplan–Meier analysis of the cumulative incidence of treatment failure revealed a significant advantage of LM over the dilatation strategy (p = 0.036)). QoL assessed by the generic instrument PGWB and the more disease-specific instrument GSRS revealed scores which were similar in the two study groups with no obvious changes over time. Reflux was better controlled in the LM group (p = 0.02 regarding PPI consumption). Conclusions: After more than a decade of follow-up, laparoscopic myotomy reinforces its superiority over repetitive pneumatic dilatation treatment strategy in the management of newly diagnosed achalasia. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.
47.	Sillén, Karin, et al. (författare) Rates and types of injuries during the three consecutive years 2016 to 2018 of the Vätternrundan - One of the world's largest and longest bicycle races 2019 Ingår i: Traffic Injury Prevention. - : Informa UK Limited. - 1538-9588 .- 1538-957X. ; 20:7, s. 749-752 Tidskriftsartikel (refereegranskat)abstract Objective: The present study was performed during 3 consecutive years of the Vatternrundan in Sweden, one of the world's longest and largest bicycle races. The aim was to examine the rates and types of injuries to participating cyclists in order to identify the reasons and mechanisms for injury, with the purpose of decreasing the risk of injury. Method: A retrospective observational interference study was performed over 3 consecutive years. Data were collected from medical records of cyclists who were treated at hospital for traumatic injuries at the Vatternrundan 2016. Injured cyclists were asked to fill out questionnaires about the accidents. During the 2 consecutive years 2017 to 2018, a follow-up was performed in order to evaluate whether the precautions taken, based on the data from the previous year, could decrease rate of injuries during the consecutive race. Results: Sixty-nine (0.35%) of the 19,663 participants in the Vatternrundan in 2016 were included in the study, due to their need for hospital care. The corresponding numbers for 2017 and 2018 were 52 (0.27%) and 44 (0.22%), respectively. The most common injury was fracture to the clavicle (18-30%). In total, 68-74% of all injuries were to the upper body (above the hip; P < .001 compared to lower body). A crash with another cyclist caused by crowding was the most frequent mechanism of injury. A few risky "hot spots" for injuries were identified along the race track, and the mechanisms for accidents were hypothesized based on the responses of injured cyclists and the geographic clustering of accidents. These reasons were systematically targeted during the planning of the race in 2017 and 2018. Conclusion: We found that the overwhelming majority of traumatic injuries were to the upper body, with the most common injury being clavicular fracture. The most common mechanism for injury was interference between cyclists in the first year's race, mainly due to crowding because of the track being too narrow at certain locations. The interventions performed, based on these findings, resulted in a substantial decrease in injuries during the next 2 consecutive Vatternrundan races. Thus, systematic identification and elimination of hazards contributed to a reduction of the rate of injury by 37% (P = .0013, chi(2)) during the 3 years of the study.
48.	Sjögren, Lovisa, et al. (författare) Impact of obesity on intensive care outcomes in patients with COVID-19 in Sweden—A cohort study 2021 Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 16:10 Tidskriftsartikel (refereegranskat)abstract Background Previous studies have shown that a high body mass index (BMI) is a risk factor for severe COVID-19. The aim of the present study was to assess whether a high BMI affects the risk of death or prolonged length of stay (LOS) in patients with COVID-19 during intensive care in Sweden. Methods and findings In this observational, register-based study, we included patients with COVID-19 from the Swedish Intensive Care Registry admitted to intensive care units (ICUs) in Sweden. Outcomes assessed were death during intensive care and ICU LOS 14 days. We used logistic regression models to evaluate the association (odds ratio [OR] and 95% confidence interval [CI]) between BMI and the outcomes. Valid weight and height information could be retrieved in 1,649 patients (1,227 (74.4%) males) with COVID-19. We found a significant association between BMI and the risk of the composite outcome death or LOS 14 days in survivors (OR per standard deviation [SD] increase 1.30, 95%CI 1.16–1.44, adjusted for sex, age and comorbidities), and this association remained after further adjustment for severity of illness (simplified acute physiology score; SAPS3) at ICU admission (OR 1.30 per SD, 95%CI 1.17–1.45). Individuals with a BMI 35 kg/m2 had a doubled risk of the composite outcome. A high BMI was also associated with death during intensive care and a prolonged LOS in survivors assessed as separate outcomes. The main limitations were the restriction to the first wave of the pandemic, and the lack of information on socioeconomic status as well as smoking. Conclusions In this large cohort of Swedish ICU patients with COVID-19, a high BMI was associated with increasing risk of death and prolonged length of stay in the ICU. Based on our findings, we suggest that individuals with obesity should be more closely monitored when hospitalized for COVID-19.
49.	Sotak, Matus, et al. (författare) Healthy Subcutaneous and Omental Adipose Tissue Is Associated with High Expression of Extracellular Matrix Components 2022 Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 23:1 Tidskriftsartikel (refereegranskat)abstract Obesity is associated with extensive expansion and remodeling of the adipose tissue architecture, including its microenvironment and extracellular matrix (ECM). Although obesity has been reported to induce adipose tissue fibrosis, the composition of the ECM under healthy physiological conditions has remained underexplored and debated. Here, we used a combination of three established techniques (picrosirius red staining, a colorimetric hydroxyproline assay, and sensitive gene expression measurements) to evaluate the status of the ECM in metabolically healthy lean (MHL) and metabolically unhealthy obese (MUO) subjects. We investigated ECM deposition in the two major human adipose tissues, namely the omental and subcutaneous depots. Biopsies were obtained from the same anatomic region of respective individuals. We found robust ECM deposition in MHL subjects, which correlated with high expression of collagens and enzymes involved in ECM remodeling. In contrast, MUO individuals showed lower expression of ECM components but elevated levels of ECM cross-linking and adhesion proteins, e.g., lysyl oxidase and thrombospondin. Our data suggests that subcutaneous fat is more prone to express proteins involved in ECM remodeling than omental adipose tissues. We conclude that a more dynamic ability to deposit and remodel ECM may be a key signature of healthy adipose tissue, and that subcutaneous fat may adapt more readily to changing metabolic conditions than omental fat.
50.	Sotak, Matus, et al. (författare) Lipoxins reduce obesity-induced adipose tissue inflammation in 3D-cultured human adipocytes and explant cultures 2022 Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:7 Tidskriftsartikel (refereegranskat)abstract Adipose tissue inflammation drives obesity-related cardiometabolic diseases. Enhancing endogenous resolution mechanisms through administration of lipoxin A4, a specialized pro-resolving lipid mediator, was shown to reduce adipose inflammation and subsequently protects againstobesity-inducedsystemic disease inmice. Here, we demonstrate that lipoxins reduce inflammation in 3D-cultured human adipocytes and adipose tissue explants from obese patients. Approximately 50% of patients responded particularlywell to lipoxins by reducing inflammatory cytokines and promoting an anti-inflammatory M2 macrophage phenotype. Responding patients were characterized by elevated systemic levels of C-reactive protein, which causes inflammation in cultured human adipocytes. Responders appeared more prone to producing anti-inflammatory oxylipins and displayed elevated prostaglandin D2 levels, which has been interlinked with transcription of lipoxin-generatingenzymes. Using explant cultures, this study provides the first proof-of-concept evidence supporting the therapeutic potential of lipoxins in reducing human adipose tissue inflammation. Our data further indicate that lipoxin treatment may require a tailored personalized-medicine approach.

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