| 1. |
- Castellanos-Jankiewicz, A., et al.
(författare)
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Short Article Hypothalamic bile acid-TGR5 signaling protects from obesity
- 2021
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131. ; 33:7
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Tidskriftsartikel (refereegranskat)abstract
- Bile acids (BAs) improve metabolism and exert anti-obesity effects through the activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic BA signaling is implicated in body weight control and obesity pathophysiology remains unknown. Here we show that hypothalamic BA content is reduced in diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist in these animals decreases body weight and fat mass by activating the sympathetic nervous system, thereby promoting negative energy balance. Conversely, genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus favors the development of obesity and worsens established obesity by blunting sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the anti-obesity action of dietary BA supplementation. Together, these findings identify hypothalamic TGR5 signaling as a key mediator of a top-down neural mechanism that counteracts diet induced obesity.
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| 2. |
- Henricsson, Fredrik, et al.
(författare)
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A biokinetic study of (209)Po in man.
- 2012
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Ingår i: Science of the Total Environment. - : Elsevier BV. - 1879-1026 .- 0048-9697. ; 437C, s. 384-389
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Tidskriftsartikel (refereegranskat)abstract
- Five adult volunteers participated in a biokinetic study of radioactive polonium. Portions of about 10Bq of (209)Po were orally administrated to four of the volunteers in a single ingestion. The fifth volunteer ingested a daily amount of 53mBq of 209Po for 243d to study the time to achieve equilibrium between intake and excretion for protracted intakes. For the subjects ingesting single intakes of (209)Po complete sampling of urine and feces was subsequently collected the first few days upon the ingestion. The samples were processed with radiochemical extraction and analyzed with alpha spectrometry. In the study, the maximum daily excretion rates in feces were 18-50% of the ingested activity, observed within 3d after intake. Regarding the urine excretion, the daily excretion peaked, on average, at 0.15-1% of the ingested activity within two days upon intake. These results indicate an average gastro-intestinal uptake fraction of 0.46±0.08, which agrees well with earlier biokinetic studies of polonium in man.
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| 3. |
- Henricsson, Fredrik, et al.
(författare)
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Aspects on the analysis of (210)Po.
- 2011
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Ingår i: Journal of Environmental Radioactivity. - : Elsevier BV. - 1879-1700 .- 0265-931X. ; 102:5, s. 415-419
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Tidskriftsartikel (refereegranskat)abstract
- There has been little development regarding analysis of polonium (Po) in environmental samples since the 1960ies. This is due to the straightforward spontaneous deposition of this element on silver (Ag), nickel (Ni) or copper (Cu) without any radiochemical separation. For many years, no radiochemical yield determinant was used and it was generally supposed that the yield was 100% after two depositions. Counting was often done using ZnS scintillation counter coupled to a photomultiplier tube. However, the use of the yield determinants (208)Po and (209)Po and the development of alpha spectrometry showed that the yield was lower. Furthermore, the tendency of Po to volatilize at low temperatures constrains the sample preparation techniques; dry-ashing cannot be used. But during the wet-ashing procedure, there are still some losses. The aim of this study was to evaluate the Po losses during wet-ashing by the use of a double-tracer technique. We have found that the losses were about 30% when open glass beakers were used and about 17% when the samples were digested in microwave oven. When long-necked bottles (Kjeldahl flasks) were used, a loss of about 20% was registered. It has also been observed that (210)Pb to some extent is plating out together with its daughter nuclide Po during the electrochemical deposition. This will result in a systematic error since an unknown amount of supported (210)Po will be produced from the (210)Pb decay depending on the fraction of (210)Pb being deposited on the disc and the waiting time between deposition and measurement of the sample. A further consequence of this is that in the assessment of the (210)Pb content in the sample, very often the remaining liquid is stored after deposition for build-up of (210)Po. Since some (210)Pb is lost on the disc, the result for (210)Pb will be too low. Both these systematic errors give rise to a too high (210)Po/(210)Pb ratio. The fraction of (210)Pb which is plating out has been assessed in this study for different matrices and is about 50-90%. During the measurement by solid state Si-detectors, some Po is evaporated in the vacuum conditions contaminating the detectors. Experiments have here been done by heating the discs after deposition which indicate that less Po is evaporated from Ag than from Ni. The losses from Ag are less than that from the other metals probably due to a deeper penetration into the surface of Po. We conclude that in most aspects, Ag is better to use than the other plating metals.
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| 4. |
- Henricsson, Fredrik, et al.
(författare)
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Polonium-210 in the bio-sphere : Bio-kinetics and biological effects
- 2012
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Ingår i: Radionuclides : Sources, Properties and Hazards - Sources, Properties and Hazards. - 9781619427488 ; , s. 33-60
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Bokkapitel (refereegranskat)abstract
- Polonium-210 is an alpha particle emitting radioactive element with a half-life of 138 days. It appears at the end of the decay-chain of Uranium-238 where the long lived Lead-210 (22.3 a) decays to Bismuth-210, and finally Polonium-210. 210Po is introduced into the biosphere through various routes of terrestrial and marine radioecological pathways. The level of 210Po activity in drinking water (5 Bq.kg-1) and in most common food items of terrestrial origin are usually low (0.04-0.1 Bq.kg-1 wet mass) and considered to be without concerns for human health. In some terrestrial food items such as reindeer and caribou, high 210Po levels (10 Bq.kg-1 wet mass) are due to their habit of grazing lichens (250 Bq.kg-1 dry weight). The food chain lichen-reindeer and man in arctic and sub-arctic regions is a unique pathway of 210Po to man. The enhancement of 210Po concentrations is also very pronounced in marine organisms feeding upon phytoplankton at the base of the food chain. Fish and seafood therefore have high activity concentrations of 210Po (2-15 Bq.kg-1). The daily dietary intakes of 210Po vary widely around the world with an estimated average median of about 160mBq.day-1. That corresponds to annual effective doses of about 70μSv.a-1 for 210Po. Populations mainly living on reindeer meat or marine food have a 5-10 fold higher annual effective doses. High activity concentrations (13 ± 3 Bq.kg-1) of Po-210 and Pb-210 are found in tobacco and its products. The annual effective radiation dose from 210Po for the whole body of a smoker who smokes 20 cigarettes per day has been estimated to 400μSv.a-1. The concentrations of 210Po in the air-ways and the lung tissues caused by smoking of tobacco contributes to a high radiation adsorbed dose to the respiratory epithelium, which contribute to the increased incidence of lung cancer observed among smokers, In December of 2006, former Russian intelligence operative Alexander Litvinenko died by what proved to be ingestion of polonium-210. This incident brought with it an increased interest of the bio-kinetics and radio-toxicity of 210Po. Alpha particles have a greater relative biological effectiveness (RBE) than gamma and X-rays considering cancer induction. But there are still no significant proofs in terms of increased risk in humans of in vivo bystander effects of 210Po alpha particle radiation. More work has to been done in studying RBE and the mechanism of the bystander effect and its relevance to cancer induction in man.
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| 5. |
- Klinga-Levan, K, et al.
(författare)
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Integrated linkage maps in the rat
- 1998
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Ingår i: Transplantation Proceedings. - : Elsevier Inc.. ; , s. 1544-1545
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Konferensbidrag (refereegranskat)
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| 6. |
- Koopen, A., et al.
(författare)
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Duodenal Anaerobutyricum soehngenii infusion stimulates GLP-1 production, ameliorates glycaemic control and beneficially shapes the duodenal transcriptome in metabolic syndrome subjects: a randomised double-blind placebo-controlled cross-over study
- 2022
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 71:8, s. 1577-1587
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Tidskriftsartikel (refereegranskat)abstract
- Objective Although gut dysbiosis is increasingly recognised as a pathophysiological component of metabolic syndrome (MetS), the role and mode of action of specific gut microbes in metabolic health remain elusive. Previously, we identified the commensal butyrogenic Anaerobutyricum soehngenii to be associated with improved insulin sensitivity in subjects with MetS. In this proof-of-concept study, we investigated the potential therapeutic effects of A. soehngenii L2-7 on systemic metabolic responses and duodenal transcriptome profiles in individuals with MetS. Design In this randomised double-blind placebo-controlled cross-over study, 12 male subjects with MetS received duodenal infusions of A. soehngenii/ placebo and underwent duodenal biopsies, mixed meal tests (6 hours postinfusion) and 24-hour continuous glucose monitoring. Results A. soehngenii treatment provoked a markedly increased postprandial excursion of the insulinotropic hormone glucagon-like peptide 1 (GLP-1) and an elevation of plasma secondary bile acids, which were positively associated with GLP-1 levels. Moreover, A. soehngenii treatment robustly shaped the duodenal expression of 73 genes, with the highest fold induction in the expression of regenerating islet-protein 1B (REG1B)-encoding gene. Strikingly, duodenal REG1B expression positively correlated with GLP-1 levels and negatively correlated with peripheral glucose variability, which was significantly diminished in the 24 hours following A. soehngenii intake. Mechanistically, Reg1B expression is induced upon sensing butyrate or bacterial peptidoglycan. Importantly, A. soehngenii duodenal administration was safe and well tolerated. Conclusions A single dose of A. soehngenii improves peripheral glycaemic control within 24 hours; it specifically stimulates intestinal GLP-1 production and REG1B expression. Further studies are needed to delineate the specific pathways involved in REG1B induction and function in insulin sensitivity.
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| 7. |
- Makki, Kassem, et al.
(författare)
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6 alpha-hydroxylated bile acids mediate TGR5 signalling to improve glucose metabolism upon dietary fiber supplementation in mice
- 2023
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Ingår i: Gut. - : BMJ. - 0017-5749 .- 1468-3288. ; 72:2, s. 314-324
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Tidskriftsartikel (refereegranskat)abstract
- Objective Dietary fibres are essential for maintaining microbial diversity and the gut microbiota can modulate host physiology by metabolising the fibres. Here, we investigated whether the soluble dietary fibre oligofructose improves host metabolism by modulating bacterial transformation of secondary bile acids in mice fed western-style diet. Design To assess the impact of dietary fibre supplementation on bile acid transformation by gut bacteria, we fed conventional wild-type and TGR5 knockout mice western-style diet enriched or not with cellulose or oligofructose. In addition, we used germ-free mice and in vitro cultures to evaluate the activity of bacteria to transform bile acids in the caecal content of mice fed with western-style diet enriched with oligofructose. Finally, we treated wild-type and TGR5 knockout mice orally with hyodeoxycholic acid to assess its antidiabetic effects. Results We show that oligofructose sustains the production of 6 alpha-hydroxylated bile acids from primary bile acids by gut bacteria when fed western-style diet. Mechanistically, we demonstrated that the effects of oligofructose on 6 alpha-hydroxylated bile acids were microbiota dependent and specifically required functional TGR5 signalling to reduce body weight gain and improve glucose metabolism. Furthermore, we show that the 6 alpha-hydroxylated bile acid hyodeoxycholic acid stimulates TGR5 signalling, in vitro and in vivo, and increases GLP-1R activity to improve host glucose metabolism. Conclusion Modulation of the gut microbiota with oligofructose enriches bacteria involved in 6 alpha-hydroxylated bile acid production and leads to TGR5-GLP1R axis activation to improve body weight and metabolism under western-style diet feeding in mice.
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| 8. |
- Molinaro, Antonio, et al.
(författare)
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Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism.
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| 9. |
- Molinaro, Antonio, et al.
(författare)
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Microbially Produced Imidazole Propionate Is Associated With Heart Failure and Mortality
- 2023
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Ingår i: JACC: Heart Failure. - 2213-1779 .- 2213-1787. ; 11:7, s. 810-821
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Tidskriftsartikel (refereegranskat)abstract
- Background: Over the past years, it has become clear that the microbial ecosystem in the gut has a profound capacity to interact with the host through the production of a wide range of bioactive metabolites. The microbially produced metabolite imidazole propionate (ImP) is clinically and mechanistically linked with insulin resistance and type 2 diabetes, but it is unclear how ImP is associated with heart failure. Objectives: The authors aimed to explore whether ImP is associated with heart failure and mortality. Methods: ImP serum measurements in 2 large and independent clinical cohorts of patients (European [n = 1,985] and North American [n = 2,155]) with a range of severity of cardiovascular disease including heart failure. Univariate and multivariate Cox regression analyses were performed to delineate the impact of ImP on 5-year mortality in the North American cohort, independent of other covariates. Results: ImP is independently associated with reduced ejection fraction and heart failure in both cohorts, even after adjusting for traditional risk factors. Elevated ImP was a significant independent predictor of 5-year mortality (for the highest quartile, adjusted HR: 1.85 [95% CI: 1.20-2.88]; P < 0.01). Conclusions: The gut microbial metabolite ImP is increased in individuals with heart failure and is a predictor of overall survival.
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| 10. |
- Schröder, Björn O., et al.
(författare)
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Obesity-associated microbiota contributes to mucus layer defects in genetically obese mice
- 2020
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 295:46, s. 15712-15726
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Tidskriftsartikel (refereegranskat)abstract
- The intestinal mucus layer is a physical barrier separating the tremendous number of gut bacteria from the host epithelium. Defects in the mucus layer have been linked to metabolic diseases, but previous studies predominantly investigated mucus function during high-caloric/low-fiber dietary interventions, thus making it difficult to separate effects mediated directly through diet quality from potential obesity-dependent effects. As such, we decided to examine mucus function in mouse models with metabolic disease to distinguish these factors. Here we show that, in contrast to their lean littermates, genetically obese (ob/ob) mice have a defective inner colonic mucus layer that is characterized by increased penetrability and a reduced mucus growth rate. Exploiting the coprophagic behavior of mice, we next co-housed ob/ob and lean mice to investigate if the gut microbiota contributed to these phenotypes. Co-housing rescued the defect of the mucus growth rate, whereas mucus penetrability displayed an intermediate phenotype in both mouse groups. Of note, non-obese diabetic mice with high blood glucose levels displayed a healthy colonic mucus barrier, indicating that the mucus defect is obesity- rather than glucose-mediated. Thus, our data suggest that the gut microbiota community of obesity-prone mice may regulate obesity-associated defects in the colonic mucosal barrier, even in the presence of dietary fiber. © 2020 Schroeder et al.
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