| 41. |
- Baird, Denis A., et al.
(författare)
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Identification of Novel Loci Associated With Hip Shape : A Meta-Analysis of Genomewide Association Studies.
- 2019
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Ingår i: Journal of Bone and Mineral Research. - : Wiley-Blackwell. - 0884-0431 .- 1523-4681. ; 34:2, s. 241-251
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Tidskriftsartikel (refereegranskat)abstract
- We aimed to report the first genomewide association study (GWAS) meta-analysis of dual-energy X-ray absorptiometry (DXA)-derived hip shape, which is thought to be related to the risk of both hip osteoarthritis and hip fracture. Ten hip shape modes (HSMs) were derived by statistical shape modeling using SHAPE software, from hip DXA scans in the Avon Longitudinal Study of Parents and Children (ALSPAC; adult females), TwinsUK (mixed sex), Framingham Osteoporosis Study (FOS; mixed), Osteoporotic Fractures in Men study (MrOS), and Study of Osteoporotic Fractures (SOF; females) (total N = 15,934). Associations were adjusted for age, sex, and ancestry. Five genomewide significant (p < 5 × 10-9 , adjusted for 10 independent outcomes) single-nucleotide polymorphisms (SNPs) were associated with HSM1, and three SNPs with HSM2. One SNP, in high linkage disequilibrium with rs2158915 associated with HSM1, was associated with HSM5 at genomewide significance. In a look-up of previous GWASs, three of the identified SNPs were associated with hip osteoarthritis, one with hip fracture, and five with height. Seven SNPs were within 200 kb of genes involved in endochondral bone formation, namely SOX9, PTHrP, RUNX1, NKX3-2, FGFR4, DICER1, and HHIP. The SNP adjacent to DICER1 also showed osteoblast cis-regulatory activity of GSC, in which mutations have previously been reported to cause hip dysplasia. For three of the lead SNPs, SNPs in high LD (r2 > 0.5) were identified, which intersected with open chromatin sites as detected by ATAC-seq performed on embryonic mouse proximal femora. In conclusion, we identified eight SNPs independently associated with hip shape, most of which were associated with height and/or mapped close to endochondral bone formation genes, consistent with a contribution of processes involved in limb growth to hip shape and pathological sequelae. These findings raise the possibility that genetic studies of hip shape might help in understanding potential pathways involved in hip osteoarthritis and hip fracture. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
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| 42. |
- Bake, Tina, et al.
(författare)
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The gravitostat protects diet-induced obese rats against fat accumulation and weight gain
- 2021
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Ingår i: Journal of Neuroendocrinology. - : Wiley. - 0953-8194 .- 1365-2826. ; 33:8
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Tidskriftsartikel (refereegranskat)abstract
- The gravitostat is a novel homeostatic body weight-regulating mechanism, mostly studied in mice, and recently confirmed in obese humans. In the present study, we explored the effect of weight loading on metabolic outcomes, meal patterns and parameters linked to energy expenditure in both obese and lean rats. Diet-induced obese (DIO) and lean rats were implanted with capsules weighing either 15% of biological body weight (load) or empty capsules (1.3% of body weight; controls). Loading protected against fat accumulation more markedly in the DIO group. In line with this, the obesity-related impairment in insulin sensitivity was notably ameliorated in DIO rats upon loading, as revealed by the reduction in serum insulin levels and homeostatic model assessment for insulin resistance index scores. Although 24-hour caloric intake was reduced in both groups, this effect was greater in loaded DIO rats than in loaded lean peers. During days 10-16, after recovery from surgery, loading: (i) decreased meal size in both groups (only during the light phase in DIO rats) but this was compensated in lean rats by an increase in meal frequency; (ii) reduced dark phase locomotor activity only in lean rats; and (iii) reduced mean caloric efficiency in DIO rats. Muscle weight was unaffected by loading in either group. Dietary-obese rats are therefore more responsive than lean rats to loading.
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| 43. |
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| 44. |
- Barroso, A., et al.
(författare)
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Neonatal exposure to androgens dynamically alters gut microbiota architecture
- 2020
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Ingår i: Journal of Endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 247:1, s. 69-85
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Tidskriftsartikel (refereegranskat)abstract
- Gonadal steroids strongly contribute to the metabolic programming that shapes the susceptibility to the manifestation of diseases later in life, and the effect is often sexually dimorphic. Microbiome signatures, together with metabolic traits and sex steroid levels, were analyzed at adulthood in neonatally androgenized female rats, and compared with those of control male and female rats. Exposure of female rats to high doses of androgens on early postnatal life resulted in persistent alterations of the sex steroid profile later on life, namely lower progesterone and higher estr adiol and estrone levels, with no effect on endogenous androgens. Neonatally androgenized females were heavier (10% at early adulthood and 26% at adulthood) than controls and had impaired glucose homeostasis observed by higher AUC of glucose in GTT and ITT when subjected to obesogenic manipulations. Androgenized female displayed overt alterations in gut microbiota, indicated especially by higher Bacteroidetes and lower Firmicutes abundance at early adulthood, which disappeared when animals were concurrently overfed at adulthood. Notably, these changes in gut microbiota were related with the intestinal expression of several miRNAs, such as miR-27a-3p, miR-29a-5p, and miR-100-3p. Our results suggest that nutritional and hormonal disruption at early developmental periods not only alters the metabolic programming of the individual later in life but also perturbs the architecture of gut microbiota, which may interact with the host by a cross-talk mediated by intestinal miRNAs; phenomena that may contribute to amplify the metabolic derangement caused by obesity, as seen in neonatally androgenized female rats.
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| 45. |
- Bellman, Jakob, et al.
(författare)
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Loading enhances glucose uptake in muscles, bones, and bone marrow of lower extremities in humans.
- 2024
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Ingår i: The Journal of clinical endocrinology and metabolism. - 1945-7197.
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Tidskriftsartikel (refereegranskat)abstract
- Increased standing time has been associated with improved health, but the underlying mechanism is unclear.We herein investigate if increased weight loading increases energy demand and thereby glucose uptake (GU) locally in bone and/or muscle in the lower extremities.In this single-center clinical trial with randomized crossover design (ClinicalTrials.gov ID, NCT05443620), we enrolled 10 men with body mass index (BMI) between 30 and 35kg/m2. Participants were treated with both high load (standing with weight vest weighing 11% of body weight) and no load (sitting) on the lower extremities. GU was measured using whole-body quantitative positron emission tomography/computed tomography (PET/CT) imaging. The primary endpoint was the change in GU ratio between loaded bones (i.e. femur and tibia) and non-loaded bones (i.e. humerus).High load increased the GU ratio between lower and upper extremities in cortical diaphyseal bone (e.g. femur/humerus ratio increased by 19%, p=0.029), muscles (e.g. m. quadriceps femoris/m. triceps brachii ratio increased by 28%, p=0.014) and in certain bone marrow regions (femur/humerus diaphyseal bone marrow region ratio increased by 17%, p=0.041). Unexpectedly, we observed the highest GU in the bone marrow region of vertebral bodies, but its GU was not affected by high load.Increased weight-bearing loading enhances GU in muscles, cortical bone, and bone marrow of the exposed lower extremities. This could be interpreted as increased local energy demand in bone and muscle caused by increased loading. The physiological importance of the increased local GU by static loading remains to be determined.
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| 46. |
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| 47. |
- Ben-Avraham, Dan, et al.
(författare)
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The complex genetics of gait speed : Genome-wide meta-analysis approach
- 2017
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Ingår i: Aging. - : Impact Journals, LLC. - 1945-4589. ; 9:1, s. 209-246
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Tidskriftsartikel (refereegranskat)abstract
- Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.
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| 48. |
- Benrick, Anna, 1979, et al.
(författare)
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A non-conservative polymorphism in the IL-6 signal transducer (IL6ST)/gp130 is associated with myocardial infarction in a hypertensive population.
- 2008
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Ingår i: Regulatory peptides. - : Elsevier BV. - 0167-0115. ; 146:1-3, s. 189-96
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Tidskriftsartikel (refereegranskat)abstract
- Inflammation is a key component in the development of atherosclerosis, and myocardial infarction (MI); therefore we investigated the association between an interleukin-6 signal transducer (IL6ST)/gp130 polymorphism, gp130 function and risk of MI. Structural modeling suggested that a non-conservative single nucleotide polymorphism in the gp130, Gly148Arg, can change the stability and functional properties of the molecule. In vitro studies were done with BAF/3 cells lacking endogenous gp130. Cells stably transfected with the gp130 148Arg variant proliferated less and showed slightly lower STAT-3 phosphorylation in response to gp130 stimulation as compared to cells transfected with gp130 148Gly. In a prospectively followed hypertensive cohort we identified 167 patients who suffered a MI during the study and compared them to matched controls (mean age 57 years, 73% males, n=482). Carriers of the 148Arg variant (f(Arg)=0.12) of the gp130 receptor had decreased odds ratio for MI in univariate analysis (0.56, 95% CI 0.34-0.91, p=0.02). In conclusion, a genetically determined structural variant of the IL-6 receptor subunit gp130 is, independently of other known risk factors, associated with decreased risk of MI. The variant is also associated with decreased IL-6 responsiveness and could lead to a configuration change in the gp130 receptor.
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| 49. |
- Benrick, Anna, 1979, et al.
(författare)
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Resveratrol Is Not as Effective as Physical Exercise for Improving Reproductive and Metabolic Functions in Rats with Dihydrotestosterone-Induced Polycystic Ovary Syndrome
- 2013
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Ingår i: Evidence-Based Complementary and Alternative Medicine. - : Hindawi Limited. - 1741-427X .- 1741-4288.
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Tidskriftsartikel (refereegranskat)abstract
- Polycystic ovary syndrome (PCOS) is a reproductive and metabolic disorder associated with obesity and insulin resistance that often precedes the development of type-2 diabetes. Rats continuously exposed to dihydrotestosterone from prepuberty display typical reproductive and metabolic PCOS characteristics including anovulation, polycystic ovaries, insulin resistance, and obesity. Our aim was to investigate if resveratrol improves reproductive and metabolic functions in PCOS rats. The effect was compared to exercise. Control and PCOS rats were treated with vehicle or resveratrol (400mg·kg−1·day−1) for 5-6 weeks. Another group of PCOS rats received vehicle treatment and exercised for 5-6 weeks. Insulin sensitivity was determined by euglycemic-hyperinsulinemic clamp. The glucose infusion rate was lower in the PCOS-vehicle group compared to control-vehicle rats (). Exercise increased insulin sensitivity compared with PCOS-vehicle rats (), but resveratrol did not. Resveratrol treatment and exercise resulted in smaller adipocytes, upregulated estrogen-related receptor α gene expression in subcutaneous fat, and improved estrus cyclicity in the previously acyclic PCOS rats. Although resveratrol had positive effects on adiposity and cyclicity in a similar manner to exercise, resveratrol does not seem to be a good candidate for treating insulin resistance associated with PCOS because no improvement in insulin sensitivity was observed in PCOS rats on normal chow.
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| 50. |
- Bentham, J, et al.
(författare)
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A double-staining technique for detection of growth hormone and insulin-like growth factor-I binding to rat tibial epiphyseal chondrocytes.
- 1993
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Ingår i: The Journal of endocrinology. - 0022-0795. ; 137:3, s. 361-7
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Tidskriftsartikel (refereegranskat)abstract
- In the present study a double-staining technique was developed to investigate simultaneous GH and insulin-like growth factor-I (IGF-I) binding to chondrocytes in a monolayer cell culture. Rat tibial epiphyseal chondrocytes were isolated by enzymatic digestion and cultured in monolayer. GH and IGF-I were labelled with biotin. The affinity of the biotin-labelled ligands was compared with unlabelled ligands in a radioreceptor assay. To study the distribution of GH and IGF-I binding in the monolayer, chondrocytes were incubated with biotinylated ligands with or without an excess of unlabelled ligands, followed by incubation with Vectastain ABC complex, which was then reacted with diaminobenzidine (DAB). Double staining was accomplished by carrying out the first reaction with DAB in the presence of nickel ammonium sulphate to give a black precipitate, followed by incubation with the second ligand, then ABC complex and finally DAB in the absence of nickel ammonium sulphate to give a brown stain. The presence of type-II collagen was demonstrated by immunohistochemistry and used as a marker for differentiated chondrocytes. Biotin-labelled GH and biotin-labelled IGF-I exhibited dose-dependent displacements of 125I-labelled GH and 125I-labelled IGF-I respectively from the chondrocytes in a radioreceptor assay. The displacement curves were identical to those of unlabelled ligands indicating that the affinity was unaltered. Binding of biotinylated GH to cells was seen throughout the culture in regions where there was little or no type-II collagen staining. IGF-I binding was predominantly localized to cells at high density; areas which also showed a high degree of staining for type-II collagen.(ABSTRACT TRUNCATED AT 250 WORDS)
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