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| 2. |
- Andersson, DP, et al.
(författare)
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Relationship Between a Sedentary Lifestyle and Adipose Insulin Resistance
- 2023
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 72:3, s. 316-325
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Tidskriftsartikel (refereegranskat)abstract
- Sedentary people have insulin resistance in their skeletal muscle, but whether this also occurs in fat cells was unknown. Insulin inhibition of hydrolysis of triglycerides (antilipolysis) and stimulation of triglyceride formation (lipogenesis) were investigated in subcutaneous fat cells from 204 sedentary and 336 physically active subjects. Insulin responsiveness (maximum hormone effect) and sensitivity (half-maximal effective concentration) were determined. In 69 women, hyperinsulinemia-induced circulating fatty acid levels were measured. In 128 women, adipose gene expression was analyzed. Responsiveness of insulin for antilipolysis (60% inhibition) and lipogenesis (twofold stimulation) were similar between sedentary and active subjects. Sensitivity for both measures decreased ˜10-fold in sedentary subjects (P < 0.01). However, upon multiple regression analysis, only the association between antilipolysis sensitivity and physical activity remained significant when adjusting for BMI, age, sex, waist-to-hip ratio, fat-cell size, and cardiometabolic disorders. Fatty acid levels decreased following hyperinsulinemia but remained higher in sedentary compared with active women (P = 0.01). mRNA expression of insulin receptor and its substrates 1 and 2 was decreased in sedentary subjects. In conclusion, while the maximum effect is preserved, sensitivity to insulin’s antilipolytic effect in subcutaneous fat cells is selectively lower in sedentary subjects.
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| 3. |
- Andersson, DP, et al.
(författare)
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Relationship Between a Sedentary Lifestyle and Adipose Insulin Resistance
- 2023
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 72:3, s. 316-325
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Tidskriftsartikel (refereegranskat)abstract
- Sedentary people have insulin resistance in their skeletal muscle, but whether this also occurs in fat cells was unknown. Insulin inhibition of hydrolysis of triglycerides (antilipolysis) and stimulation of triglyceride formation (lipogenesis) were investigated in subcutaneous fat cells from 204 sedentary and 336 physically active subjects. Insulin responsiveness (maximum hormone effect) and sensitivity (half-maximal effective concentration) were determined. In 69 women, hyperinsulinemia-induced circulating fatty acid levels were measured. In 128 women, adipose gene expression was analyzed. Responsiveness of insulin for antilipolysis (60% inhibition) and lipogenesis (twofold stimulation) were similar between sedentary and active subjects. Sensitivity for both measures decreased ˜10-fold in sedentary subjects (P < 0.01). However, upon multiple regression analysis, only the association between antilipolysis sensitivity and physical activity remained significant when adjusting for BMI, age, sex, waist-to-hip ratio, fat-cell size, and cardiometabolic disorders. Fatty acid levels decreased following hyperinsulinemia but remained higher in sedentary compared with active women (P = 0.01). mRNA expression of insulin receptor and its substrates 1 and 2 was decreased in sedentary subjects. In conclusion, while the maximum effect is preserved, sensitivity to insulin’s antilipolytic effect in subcutaneous fat cells is selectively lower in sedentary subjects.
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| 11. |
- Kerr, A. G., et al.
(författare)
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The long noncoding RNA ADIPINT regulates human adipocyte metabolism via pyruvate carboxylase
- 2022
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- The pleiotropic function of long noncoding RNAs is well recognized, but their direct role in governing metabolic homeostasis is less understood. Here, we describe a human adipocyte-specific lncRNA, ADIPINT, that regulates pyruvate carboxylase, a pivotal enzyme in energy metabolism. We developed an approach, Targeted RNA-protein identification using Orthogonal Organic Phase Separation, which identifies that ADIPINT binds to pyruvate carboxylase and validated the interaction with electron microscopy. ADIPINT knockdown alters the interactome and decreases the abundance and enzymatic activity of pyruvate carboxylase in the mitochondria. Reduced ADIPINT or pyruvate carboxylase expression lowers adipocyte lipid synthesis, breakdown, and lipid content. In human white adipose tissue, ADIPINT expression is increased in obesity and linked to fat cell size, adipose insulin resistance, and pyruvate carboxylase activity. Thus, we identify ADIPINT as a regulator of lipid metabolism in human white adipocytes, which at least in part is mediated through its interaction with pyruvate carboxylase.
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| 15. |
- Kulyte, A, et al.
(författare)
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Shared genetic loci for body fat storage and adipocyte lipolysis in humans
- 2022
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1, s. 3666-
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Tidskriftsartikel (refereegranskat)abstract
- Total body fat and central fat distribution are heritable traits and well-established predictors of adverse metabolic outcomes. Lipolysis is the process responsible for the hydrolysis of triacylglycerols stored in adipocytes. To increase our understanding of the genetic regulation of body fat distribution and total body fat, we set out to determine if genetic variants associated with body mass index (BMI) or waist-hip-ratio adjusted for BMI (WHRadjBMI) in genome-wide association studies (GWAS) mediate their effect by influencing adipocyte lipolysis. We utilized data from the recent GWAS of spontaneous and isoprenaline-stimulated lipolysis in the unique GENetics of Adipocyte Lipolysis (GENiAL) cohort. GENiAL consists of 939 participants who have undergone abdominal subcutaneous adipose biopsy for the determination of spontaneous and isoprenaline-stimulated lipolysis in adipocytes. We report 11 BMI and 15 WHRadjBMI loci with SNPs displaying nominal association with lipolysis and allele-dependent gene expression in adipose tissue according to in silico analysis. Functional evaluation of candidate genes in these loci by small interfering RNAs (siRNA)-mediated knock-down in adipose-derived stem cells identified ZNF436 and NUP85 as intrinsic regulators of lipolysis consistent with the associations observed in the clinical cohorts. Furthermore, candidate genes in another BMI-locus (STX17) and two more WHRadjBMI loci (NID2, GGA3, GRB2) control lipolysis alone, or in conjunction with lipid storage, and may hereby be involved in genetic control of body fat. The findings expand our understanding of how genetic variants mediate their impact on the complex traits of fat storage and distribution.
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| 17. |
- Lundback, V, et al.
(författare)
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Genome-Wide Association Study of Diabetogenic Adipose Morphology in the GENetics of Adipocyte Lipolysis (GENiAL) Cohort
- 2020
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 9:5
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Tidskriftsartikel (refereegranskat)abstract
- An increased adipocyte size relative to the size of fat depots, also denoted hypertrophic adipose morphology, is a strong risk factor for the future development of insulin resistance and type 2 diabetes. The regulation of adipose morphology is poorly understood. We set out to identify genetic loci associated with adipose morphology and functionally evaluate candidate genes for impact on adipocyte development. We performed a genome-wide association study (GWAS) in the unique GENetics of Adipocyte Lipolysis (GENiAL) cohort comprising 948 participants who have undergone abdominal subcutaneous adipose biopsy with a determination of average adipose volume and morphology. The GWAS identified 31 genetic loci displaying suggestive association with adipose morphology. Functional evaluation of candidate genes by small interfering RNAs (siRNA)-mediated knockdown in adipose-derived precursor cells identified six genes controlling adipocyte renewal and differentiation, and thus of potential importance for adipose hypertrophy. In conclusion, genetic and functional studies implicate a regulatory role for ATL2, ARHGEF10, CYP1B1, TMEM200A, C17orf51, and L3MBTL3 in adipose morphology by their impact on adipogenesis.
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| 19. |
- Nasiri-Ansari, N, et al.
(författare)
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Estrogen Receptor Subtypes Elicit a Distinct Gene Expression Profile of Endothelial-Derived Factors Implicated in Atherosclerotic Plaque Vulnerability
- 2022
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 23:18
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Tidskriftsartikel (refereegranskat)abstract
- In the presence of established atherosclerosis, estrogens are potentially harmful. MMP-2 and MMP-9, their inhibitors (TIMP-2 and TIMP-1), RANK, RANKL, OPG, MCP-1, lysyl oxidase (LOX), PDGF-β, and ADAMTS-4 play critical roles in plaque instability/rupture. We aimed to investigate (i) the effect of estradiol on the expression of the abovementioned molecules in endothelial cells, (ii) which type(s) of estrogen receptors mediate these effects, and (iii) the role of p21 in the estrogen-mediated regulation of the aforementioned factors. Human aortic endothelial cells (HAECs) were cultured with estradiol in the presence or absence of TNF-α. The expression of the aforementioned molecules was assessed by qRT-PCR and ELISA. Zymography was also performed. The experiments were repeated in either ERα- or ERβ-transfected HAECs and after silencing p21. HAECs expressed only the GPR-30 estrogen receptor. Estradiol, at low concentrations, decreased MMP-2 activity by 15-fold, increased LOX expression by 2-fold via GPR-30, and reduced MCP-1 expression by 3.5-fold via ERβ. The overexpression of ERα increased MCP-1 mRNA expression by 2.5-fold. In a low-grade inflammation state, lower concentrations of estradiol induced the mRNA expression of MCP-1 (3.4-fold) and MMP-9 (7.5-fold) and increased the activity of MMP-2 (1.7-fold) via GPR-30. Moreover, p21 silencing resulted in equivocal effects on the expression of the abovementioned molecules. Estradiol induced different effects regarding atherogenic plaque instability through different ERs. The balance of the expression of the various ER subtypes may play an important role in the paradoxical characterization of estrogens as both beneficial and harmful.
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| 20. |
- Nikolic, S, et al.
(författare)
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Exocrine and Endocrine Insufficiency in Autoimmune Pancreatitis: A Matter of Treatment or Time?
- 2022
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Ingår i: Journal of clinical medicine. - : MDPI AG. - 2077-0383. ; 11:13
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Tidskriftsartikel (refereegranskat)abstract
- Background: Autoimmune pancreatitis (AIP) is a specific form of chronic pancreatitis with a high relapse rate after treatment. AIP patients are burdened with an increased risk of long-term sequelae such as exocrine and endocrine insufficiency. Our objective was to investigate if pharmacological treatment affects both endocrine and exocrine pancreatic function in patients with AIP. Methods: We included 59 patients with definite AIP in the final analysis. Screening for diabetes mellitus (DM) and pancreatic exocrine insufficiency (PEI) was performed at the time of AIP diagnosis and during follow-up. Results: There were 40 (67.8%) males and 19 (32.2%) females; median age at diagnosis was 65 years. Median follow-up after the diagnosis of AIP was 62 months. PEI prevalence at diagnosis was 72.7% and was 63.5% at follow-up. The cumulative incidence of DM was 17.9%, with a prevalence of DM at diagnosis of 32.8%. No strong association was found between pharmacological treatment and occurrence of PEI and DM. Univariate analysis identified potential risk factors for PEI (other organ involvement and biliary stenting) and for DM (overweight, blue-collar profession, smoking, weight loss or obstructive jaundice as presenting symptoms, imaging showing diffuse pancreatic enlargement, smoking). In a multivariate analysis, only obstructive jaundice was identified as a risk factor for DM both at diagnosis and during follow-up. Conclusions: Our results suggest that the prevalence of endocrine and exocrine insufficiency in AIP is high at diagnosis with an additional risk of PEI and DM during follow-up despite pharmacological treatment.
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| 22. |
- Torén, Kjell, 1952, et al.
(författare)
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Occupational exposure to dust and to fumes, work as a welder and invasive pneumococcal disease risk
- 2020
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Ingår i: Occupational and Environmental Medicine. - : BMJ. - 1351-0711 .- 1470-7926. ; 77:2, s. 57-63
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Tidskriftsartikel (refereegranskat)abstract
- Objectives Occupational exposures to metal fumes have been associated with increased pneumonia risk, but the risk of invasive pneumococcal disease (IPD) has not been characterised previously. Methods We studied 4438 cases aged 20-65 from a Swedish registry of invasive infection caused by Streptococcus pneumoniae. The case index date was the date the infection was diagnosed. Six controls for each case, matched for gender, age and region of residency, were selected from the Swedish population registry. Each control was assigned the index date of their corresponding case to define the study observation period. We linked cases and controls to the Swedish registries for socioeconomic status (SES), occupational history and hospital discharge. We applied a job-exposure matrix to characterise occupational exposures. We used conditional logistic analyses, adjusted for comorbidities and SES, to estimate the OR of IPD and the subgroup pneumonia-IPD, associated with selected occupations and exposures in the year preceding the index date. Results Welders manifested increased risk of IPD (OR 2.99, 95% CI 2.09 to 4.30). Occupational exposures to fumes and silica dust were associated with elevated odds of IPD (OR 1.11, 95%CI 1.01 to 1.21 and OR 1.33, 95%CI 1.11 to 1.58, respectively). Risk associated with IPD with pneumonia followed a similar pattern with the highest occupational odds observed among welders and among silica dust exposed. Conclusion Work specifically as a welder, but also occupational exposures more broadly, increase the odds for IPD. Welders, and potentially others with relevant exposures, should be offered pneumococcal vaccination.
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| 23. |
- Vujasinovic, M, et al.
(författare)
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Low Bone Mineral Density and Risk for Osteoporotic Fractures in Patients with Chronic Pancreatitis
- 2021
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 13:7
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Chronic pancreatitis (CP) can lead to malnutrition, an established risk factor for low bone mineral density (BMD) and fractures. This study aims to determine the prevalence of low BMD, assess fracture incidence and explore risk factors for fractures in patients with CP. Patients and methods: We performed a retrospective analysis of all patients treated for CP at Karolinska University Hospital between January 1999 and December 2020. Electronic medical records were retrieved to assess demographic, laboratory and clinical data. Patients subjected to dual-energy X-ray absorptiometry (DXA) were categorised as either low BMD or normal BMD. We investigated whether the rate of fractures, defined by chart review, differed between these groups using Cox regression, adjusting the model for age, sex and body mass index (BMI). Additional within-group survival analysis was conducted to identify potential risk factors. Results: DXA was performed in 23% of patients with definite CP. Some 118 patients were included in the final analysis. Low BMD was present in 63 (53.4%) patients. Mean age at CP diagnosis in the total cohort was 53.1 years and was significantly lower in patients with normal BMD than in patients with low BMD (45.5 vs. 59.8, p < 0.001). Significant differences were observed in smoking status and disease aetiology, i.e., a higher proportion of patients with low BMD were current or former smokers, with nicotine or alcohol being a more common cause of CP (p < 0.05). Total follow-up time was 898 person-years. Fractures were found in 33 (28.0%) patients: in 5 of 55 patients (16.7%) with normal DXA and in 28 of 63 patients (44.4%) with low BMD (adjusted hazard ratio = 3.4, 95% confidence interval (CI) = 1.2–9.6). Patients with at least 3 months of consecutive pancreatic enzyme replacement therapy (PERT) or vitamin D treatment had a longer median time to fracture after CP diagnosis. Conclusion: DXA was only performed in 23% of patients with definite CP in this study, indicating a low adherence to current European guidelines. A low BMD was found in 53.4% of patients with CP, and 44% of the patients with a low BMD experienced a fracture during follow-up. Moreover, the fracture rate in patients with low BMD increased compared to those with normal BMD.
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