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1.
Sci Rep ; 14(1): 14486, 2024 06 24.
Article in English | MEDLINE | ID: mdl-38914635

ABSTRACT

Obesity and systemic inflammation are associated with breast cancer (BC) outcomes. Systemic inflammation is increased in obesity. We examined the association between C-reactive protein (CRP) and disease-free survival (DFS) and overall survival (OS) overall, and according to body mass index (BMI). We assembled a cohort of women with BC (stage I-III) seen at Aarhus University Hospital between 2010 and 2020 who donated blood at BC diagnosis (N = 2673). CRP levels were measured and divided into quartiles. We followed patients from surgery to recurrence, contralateral BC, other malignancy, death, emigration, or end-of-follow-up. We used Cox regression to estimate hazard ratios (HRs) with 95% confidence intervals (95% CIs) to compare outcomes across CRP quartiles, overall and stratified by BMI (normal-weight (18.5 ≤ BMI < 25 kg/m2), overweight (25 ≤ BMI < 30 kg/m2), and obesity (BMI ≥ 30 kg/m2)). During follow-up, 368 events (212 recurrences, 38 contralateral BCs, and 118 deaths) occurred (median follow-up 5.55 years). For DFS, high CRP (CRP ≥ 3.19 mg/L) was associated with an increased risk of events (HRadj:1.62 [95% CI = 1.14-2.28]). In BMI-stratified analyses, high CRP was associated with elevated risk of events in normal-weight and overweight (HRadj:1.70 [95% CI = 1.09-2.66]; HRadj:1.75 [95% CI = 1.08-2.86]), but in obesity, the estimate was less precise (HRadj:1.73 [95% CI = 0.78-3.83]). For OS, high CRP was associated with increased risk of death (HRadj:2.47 [95% CI = 1.62-3.76]). The association was strong in normal-weight and overweight (HRadj:3.66 [95% CI = 1.95-6.87]; HRadj:1.92 [95% CI = 1.06-3.46]), but less clear in obesity (HRadj:1.40 [95% CI = 0.64-3.09]). To sum up, high CRP levels at BC diagnosis were associated with inferior prognosis in early BC irrespective of BMI, although less clear in patients with obesity.


Subject(s)
Biomarkers, Tumor , Body Mass Index , Breast Neoplasms , C-Reactive Protein , Obesity , Humans , C-Reactive Protein/metabolism , C-Reactive Protein/analysis , Female , Breast Neoplasms/blood , Breast Neoplasms/mortality , Breast Neoplasms/diagnosis , Middle Aged , Prognosis , Biomarkers, Tumor/blood , Obesity/complications , Obesity/blood , Aged , Adult , Disease-Free Survival , Neoplasm Recurrence, Local/blood , Inflammation/blood
2.
J Obes ; 2019: 4537274, 2019.
Article in English | MEDLINE | ID: mdl-31781387

ABSTRACT

Circulating BDNF is higher in women than in men and suggested to be affected by changes in food intake, body weight, and exercise. The purpose of this study was to compare BDNF concentrations in women and men during a 12-week weight loss intervention. Using a previously published 12-week randomized study, serum BDNF was assessed at baseline and after 12 weeks using an enzyme-linked immunosorbent assay method. Fifty overweight or obese but healthy individuals (26 women, mean age of 36.4 ± 7.9 years; 24 men, mean age of 38.0 ± 5.9 years) were included and allocated into three groups: exercise-only (EXO; 12 weeks of aerobic exercise and isocaloric diet), diet-only (DIO; 8 weeks of very low energy diet (VLED 600 kcal/day) followed by a 4-week weight maintenance diet), or diet and exercise (DEX; 12 weeks of aerobic exercise in parallel with 8 weeks of VLED (800 kcal/day) followed by a 4-week weight maintenance diet). At baseline, BDNF levels were 25% higher in women compared to men (p=0.006). Body weight was reduced in all intervention groups (p < 0.006). Exercise (EXO group) induced a 22% reduction in circulating BDNF in men (p=0.037) and women (p=0.080). In the DIO and DEX groups, a significant reduction in BDNF levels (29.9%; p=0.035 and 32.5%; p=0.003, respectively) was observed in women but not in men. In conclusion, circulating BDNF was significantly changed by diet alone or combined with exercise in women and only by exercise alone in men. This suggests that changes in circulating BDNF depend on weight loss methods (diet/exercise) as well as sex.


Subject(s)
Brain-Derived Neurotrophic Factor/blood , Diet, Reducing , Exercise , Obesity/blood , Overweight/blood , Weight Loss/physiology , Adult , Analysis of Variance , Female , Humans , Male , Middle Aged , Obesity/physiopathology , Obesity/prevention & control , Overweight/physiopathology , Overweight/prevention & control
3.
Data Brief ; 22: 241-244, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30591942

ABSTRACT

The data in this article describe the use of dietary supplements in Danish patients with type 1 diabetes (T1D) and type 2 diabetes (T2D). The data were collected from a web-based dietary survey on dietary habits in 774 patients with T1D (n = 426) and T2D (n = 348). The data demonstrate that 99% of the patients with diabetes use dietary supplements with no gender differences. In comparison, only 64% in the general population use dietary supplements [2]. A higher proportion of people in the general population use multivitamin/mineral supplementation as compared to patients with diabetes (48% vs. 34-37%) and a higher proportion of women than men with diabetes use multivitamin/mineral supplementation (T1D: 43% women vs. 26% men and T2D: 45% women vs. 34% men). More patients with diabetes than the general population use supplements such as calcium together with vitamin D, vitamin D, vitamin B, vitamin C, vitamin E, magnesium, calcium, Q10, ginger, garlic, and other herbal supplements.

4.
Eur J Clin Nutr ; 69(8): 949-53, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26081486

ABSTRACT

BACKGROUND/OBJECTIVES: Sucrose-sweetened soft drinks (SSSDs) are associated with the development of metabolic disorders. Fructose is a major component of SSSDs and is demonstrated to induce uric acid (UA) production and stimulate fat accumulation independent of excess caloric intake. UA induce insulin resistance and low-grade inflammation, suggesting that UA may have a causal role in the development of metabolic complications. The objective of this study is to investigate the long-term effects of consuming SSSDs on circulating levels of UA in overweight and obese subjects. SUBJECTS/METHODS: Using a previously published study, circulating UA levels were assessed at baseline and after 6 months using chromogenic enzymatic absorptiometry. The study included 47 overweight and obese subjects without diabetes, randomised to consume 1 l daily of either SSSD (regular cola), isocaloric semi-skimmed milk, diet cola or water for 6 months. RESULTS: Circulating UA levels increased ~15% (P = 0.02) after the 6-month intervention in the SSSD group with no change in the other groups. In the SSSD group, circulating UA levels increased significantly after the intervention in both absolute (P = 0.005) and relative values (P = 0.004). The change in UA after the intervention correlated with changes in liver fat (P = 0.005), triglycerides (P = 0.02) and insulin (P = 0.002). CONCLUSIONS: In this secondary analysis daily intake of 1 l SSSD for 6 months was found to increase circulating UA levels compared with isocaloric milk, diet cola and water. Thus, a high daily intake of SSSDs in overweight and obese subjects without overt diabetes may increase the risk of developing metabolic complications through the elevation of UA. This trial is registered at ClinicalTrials.gov as NCT00777647.


Subject(s)
Carbonated Beverages/adverse effects , Dietary Sucrose/adverse effects , Obesity/blood , Sweetening Agents/adverse effects , Uric Acid/blood , Adult , Animals , Drinking Water/administration & dosage , Female , Humans , Insulin/blood , Liver/pathology , Male , Metabolic Diseases/etiology , Middle Aged , Milk/adverse effects , Obesity/complications , Overweight/blood , Overweight/complications , Risk Factors , Time Factors , Triglycerides/blood
5.
Mediators Inflamm ; 2013: 539156, 2013.
Article in English | MEDLINE | ID: mdl-24089589

ABSTRACT

BACKGROUND: The beneficial effects of testosterone treatment (TT) are debated. METHODS: Double-blinded, placebo-controlled study of six months TT (gel) in 54 men aged 60-78 with bioavailable testosterone (BioT) <7.3 nmol/L and waist >94 cm randomized to TT (50-100 mg/day, n = 20), placebo (n = 18), or strength training (ST) (n = 16) for 24 weeks. Moreover, the ST group was randomized to TT (n = 7) or placebo (n = 9) after 12 weeks. OUTCOMES: Chemokines (MIF, MCP-1, and MIP-1 α ) and lean body mass (LBM), total, central, extremity, visceral, and subcutaneous (SAT) fat mass established by DXA and MRI. Results. From 0 to 24 weeks, MIF and SAT decreased during ST + placebo versus placebo, whereas BioT and LBM were unchanged. TT decreased fat mass (total, central, extremity, and SAT) and increased BioT and LBM versus placebo. MIF levels increased during TT versus ST + placebo. ST + TT decreased fat mass (total, central, and extremity) and increased BioT and LBM versus placebo. From 12 to 24 weeks, MCP-1 levels increased during TT versus placebo and MCP-1 levels decreased during ST + placebo versus placebo. CONCLUSION: ST + placebo was associated with decreased MIF levels suggesting decreased inflammatory activity. TT may be associated with increased inflammatory activity.


Subject(s)
Aging , Chemokine CCL2/metabolism , Chemokine CCL3/metabolism , Intramolecular Oxidoreductases/metabolism , Macrophage Migration-Inhibitory Factors/metabolism , Resistance Training , Testosterone/therapeutic use , Absorptiometry, Photon , Aged , Body Composition , Chemokines/metabolism , Double-Blind Method , Gels , Humans , Inflammation/metabolism , Magnetic Resonance Imaging , Male , Middle Aged , Testosterone/metabolism , Time Factors , Treatment Outcome
6.
Obesity (Silver Spring) ; 21(3): 454-60, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23401397

ABSTRACT

BACKGROUND: Vascular growth is a prerequisite for adipose tissue (AT) development and expansion. Some AT cytokines and hormones have effects on vascular development, like vascular endothelial growth factor (VEGF-A), angiopoietin (ANG-1), ANG-2 and angiopoietin-like protein-4 (ANGPTL-4). METHODS: In this study, the independent and combined effects of diet-induced weight loss and exercise on AT gene expression and proteins levels of those angiogenic factors were investigated. Seventy-nine obese males and females were randomized to: 1. Exercise-only (EXO; 12-weeks exercise without diet-restriction), 2. Hypocaloric diet (DIO; 8-weeks very low energy diet (VLED) + 4-weeks weight maintenance diet) and 3. Hypocaloric diet and exercise (DEX; 8-weeks VLED + 4-weeks weight maintenance diet combined with exercise throughout the 12 weeks). Blood samples and fat biopsies were taken before and after the intervention. RESULTS: Weight loss was 3.5 kg in the EXO group and 12.3 kg in the DIO and DEX groups. VEGF-A protein was non-significantly reduced in the weight loss groups. ANG-1 protein levels were significantly reduced 22-25% after all three interventions (P < 0.01). The ANG-1/ANG-2 ratio was also decreased in all three groups (P < 0.05) by 27-38%. ANGPTL-4 was increased in the EXO group (15%, P < 0.05) and 9% (P < 0.05) in the DIO group. VEGF-A, ANG-1, and ANGPTL-4 were all expressed in human AT, but only ANGPTL-4 was influenced by the interventions. CONCLUSIONS: Our data show that serum VEGF-A, ANG-1, ANG-2, and ANGPTL-4 levels are influenced by weight changes, indicating the involvement of these factors in the obese state. Moreover, it was found that weight loss generally was associated with a reduced angiogenic activity in the circulation.


Subject(s)
Adipose Tissue/metabolism , Angiogenesis Inducing Agents/blood , Angiogenesis Inducing Agents/metabolism , Exercise , Obesity/metabolism , Weight Loss , Adolescent , Adult , Angiopoietin-1/blood , Angiopoietin-2/blood , Angiopoietin-Like Protein 4 , Angiopoietins/blood , Angiopoietins/genetics , Anthropometry , Diet, Reducing , Energy Intake , Female , Humans , Linear Models , Male , Middle Aged , Vascular Endothelial Growth Factor A/blood , Young Adult
7.
Clin Dev Immunol ; 2012: 354894, 2012.
Article in English | MEDLINE | ID: mdl-23227084

ABSTRACT

BACKGROUND: Serum levels of the mannose-binding lectin (MBL), which is an activator of the complement system, have been considered as a pathogenic factor in a broad range of diseases, and means of modulating MBL are therefore being evaluated. In this study we examine the effects of weight loss on MBL levels, and in continuation of this if MBL is synthesized in human adipose tissue. METHODS: 36 nondiabetic obese subjects received a very low-calorie diet (VLCD) of 800 kcal/day for 8 weeks. Blood samples were collected at baseline and after VLCD. Furthermore, we measured MBL mRNA levels by the real-time RT-PCR on human adipose tissue compared to liver tissue. RESULTS: The mean body weight was reduced from 106.3 ± 2.6 kg to 92.8 ± 2.4 kg, P < 0.0001. Median MBL at baseline was 746 µg/L (IQR 316-1190) versus 892 µg/L (IQR 336-1511) after 8 weeks, P = 0.23. No correlations were found between weight loss and changes in MBL (r = -0.098, P = 0.57). MBL real-time RT-PCR showed no expression of mRNA in adipose tissue, but as expected a good expression in liver tissue was seen. CONCLUSIONS: MBL levels are not affected by weight loss and MBL is not synthesized in human adipose tissue.


Subject(s)
Mannose-Binding Lectin/blood , Weight Loss/physiology , Adipose Tissue/metabolism , Adult , Caloric Restriction/methods , Case-Control Studies , Female , Humans , Male , Mannose-Binding Lectin/genetics , Mannose-Binding Lectin/metabolism , Middle Aged , Obesity/blood , Obesity/genetics , Obesity/metabolism , RNA, Messenger/genetics , Young Adult
8.
Acta Physiol (Oxf) ; 201(3): 357-64, 2011 Mar.
Article in English | MEDLINE | ID: mdl-20726847

ABSTRACT

AIM: This study investigated the effect of a 15-week life style intervention (hypocaloric diet and regular exercise) on glucose tolerance, skeletal muscle lipids and muscle metabolic adaptations in 14 female and 9 male morbidly obese subjects (age: 32.5±2.3 years, body mass index: 46.1±1.9 kg m(-2) ). METHOD: Before and after the life style intervention, an oral glucose tolerance test was performed and a muscle biopsy was obtained in the fasted state. Maximal oxygen uptake was measured by an indirect test. RESULTS: After the intervention, body weight was decreased (P<0.05) by 11±1%, maximal oxygen uptake increased (P<0.05) by 18±5% and glucose tolerance increased (P<0.05) by 12±3%. Muscle glycogen was significantly increased by 47±14%, but muscle ceramide and triacylglycerol content remained completely unchanged. No sex difference was observed for any of these parameters, but during submaximal exercise a marked decrease (P<0.05) of 15±2% in respiratory exchange ratio was seen only in females indicating an enhanced fat oxidation. CONCLUSION: Despite a marked weight loss and an improved aerobic capacity muscle ceramide and triacylglycerol remained unchanged after intensive life style intervention, and muscle lipids hence do not seem to play a major role for the improved glucose tolerance in these morbidly obese subjects. Interestingly, only the females improved fat oxidation during submaximal exercise after the intervention implying the presence of a sex-dependent response to intensive life style adaptation.


Subject(s)
Ceramides/metabolism , Glucose/metabolism , Muscle, Skeletal/metabolism , Obesity, Morbid/physiopathology , Obesity, Morbid/therapy , Triglycerides/metabolism , Adult , Diet Therapy , Exercise Therapy , Female , Glucose Tolerance Test , Humans , Life Style , Male , Treatment Outcome , Young Adult
9.
Nutr Metab Cardiovasc Dis ; 18(7): 497-502, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18502107

ABSTRACT

BACKGROUND AND AIM: Plant lignans are metabolised by the colonic micro-flora to the mammalian lignans enterodiol and enterolactone, which are hypothesized to be cardioprotective. The aim of this study was to investigate the effects of a plant lignan complex isolated from flaxseed, providing 500 mg/d of secoisolariciresinol diglucoside, on inflammatory markers. METHODS AND RESULTS: Healthy postmenopausal women (n=22) completed a randomised double-blind, placebo-controlled crossover study. Women consumed daily a low-fat muffin, with or without a lignan complex, for 6 weeks, separated by a 6-week washout period. A significant difference of approximately 15% (P=0.028) was observed for C-reactive protein (CRP) concentration between the lignan complex intervention period and placebo period. CRP concentrations (median; 25th, 75th percentiles) were 0.88 (0.63, 2.05) mg/L at baseline and 0.92 (0.59, 1.49) mg/L after the lignan complex intervention period compared with 0.80 (0.62, 1.62) mg/L at baseline and 1.10 (0.72, 1.62) mg/L after placebo. No significant differences in interleukin-6, tumor necrosis factor-alpha, soluble intracellular adhesion molecule-1, soluble vascular cell adhesion molecule-1, and monocyte chemoattractant protein-1 were found between the lignan complex intervention period and placebo period. CONCLUSION: Daily consumption for 6 week of a low-fat muffin enriched with a lignan complex may reduce CRP concentrations compared to a low-fat muffin with no lignans added.


Subject(s)
4-Butyrolactone/analogs & derivatives , C-Reactive Protein/metabolism , Flax/chemistry , Inflammation/drug therapy , Lignans/pharmacology , Phytoestrogens/pharmacology , Postmenopause/immunology , 4-Butyrolactone/blood , 4-Butyrolactone/pharmacology , 4-Butyrolactone/urine , Biomarkers/blood , C-Reactive Protein/immunology , Cross-Over Studies , Double-Blind Method , Female , Humans , Inflammation/blood , Inflammation/urine , Lignans/blood , Lignans/urine , Middle Aged , Phytoestrogens/blood , Phytoestrogens/urine , Postmenopause/blood , Postmenopause/physiology , Postmenopause/urine , Time Factors
10.
Eur Cell Mater ; 14: 45-54; discussion 54-5, 2007 Sep 11.
Article in English | MEDLINE | ID: mdl-17849370

ABSTRACT

Insertion of metal implants is associated with a possible change in the delicate balance between pro- and anti-inflammatory proteins, probably leading to an unfavourable predominantly pro-inflammatory milieu. The most likely cause is an inappropriate activation of macrophages in close relation to the metal implant and wear-products. The aim of the present study was to compare surfaces of as-cast and wrought Cobalt-Chrome-Molybdenum (CoCrMo) alloys and Titanium-Aluminium-Vanadium (TiAlV) alloy when incubated with mouse macrophage J774A.1 cell cultures. Changes in pro- and anti-inflammatory cytokines (TNF-alpha, IL-6, IL-alpha, IL-1beta, IL-10) and proteins known to induce proliferation (M-CSF), chemotaxis (MCP-1) and osteogenesis (TGF-beta, OPG) were determined by ELISA and Real Time reverse transcriptase - PCR (Real Time rt-PCR). Lactate dehydrogenase (LDH) was measured in the medium to asses the cell viability. Surface properties of the discs were characterised with a profilometer and with energy dispersive X-ray spectroscopy. We here report, for the first time, that the prosthetic material surface (non-phagocytable) of as-cast high carbon CoCrMo reduces the pro-inflammatory cytokine IL-6 transcription, the chemokine MCP-1 secretion, and M-CSF secretion by 77%, 36%, and 62%, respectively. Furthermore, we found that reducing surface roughness did not affect this reduction. The results suggest that as-cast CoCrMo alloy is more inert than wrought CoCrMo and wrought TiAlV alloys and could prove to be a superior implant material generating less inflammation which might result in less osteolysis.


Subject(s)
Alloys/pharmacology , Cytokines/genetics , Gene Expression Regulation/drug effects , Macrophages/metabolism , Prostheses and Implants , Proteins/metabolism , Tissue Engineering/methods , Aluminum/pharmacology , Animals , Cell Line , Chromium Alloys/pharmacology , Cobalt/pharmacology , Cytokines/drug effects , Macrophages/drug effects , Materials Testing , Mice , Molybdenum/pharmacology , Titanium/pharmacology , Vanadium/pharmacology
11.
Int J Obes (Lond) ; 29(1): 146-50, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15520826

ABSTRACT

BACKGROUND: Obesity is associated with insulin resistance and premature atherosclerosis. The human adipose tissue produce several adipokines including monocyte chemoattractant protein (MCP)-1, associated with cardiovascular disease and found to be involved in the pathogenesis of atherosclerosis in vitro. OBJECTIVE: (1) To compare mRNA levels of MCP-1, leptin and a macrophage-specific marker (CD68) in isolated adipocytes vs stromal-vascular (SV) cells, (2) to compare mRNA levels of MCP-1 in human adipose tissue to circulating MCP-1 and adiposity (eg BMI: kg/m2) and (3) investigate the effect of weight loss in obese subjects on circulating MCP-1 and leptin. RESULTS: (1) MCP-1 and CD68 mRNA levels in isolated adipocytes vs SV cells were 17% (P<0.01) and approximately 2% (P<0.001), respectively. Leptin mRNA levels in SV cells were approximately 1% of that in isolated adipocytes (P<0.01). (2) MCP-1 mRNA levels correlated with circulating MCP-1 (P<0.05) and BMI (P<0.05). (3) A 12% weight loss (P<0.001) was associated with a 25% decrease in insulin levels (P<0.01). Circulating MCP-1 and leptin decreased by 20% (P<0.001) and by 24% (P<0.001), respectively. DISCUSSION: The findings demonstrate that MCP-1 is produced in isolated human adipocytes. In addition, the findings suggest that MCP-1 may be involved in obesity-related health complications and support the hypothesis that weight loss is beneficial by improving the low-grade inflammation observed in obesity.


Subject(s)
Adipocytes/metabolism , Chemokine CCL2/biosynthesis , Obesity, Morbid/metabolism , Adipocytes/chemistry , Adult , Antigens, CD/analysis , Antigens, Differentiation, Myelomonocytic/analysis , Biomarkers/analysis , Body Constitution , Cells, Cultured , Chemokine CCL2/blood , Chemokine CCL2/genetics , Female , Humans , Leptin/blood , Leptin/genetics , Male , Obesity, Morbid/immunology , Obesity, Morbid/therapy , RNA, Messenger/analysis , Weight Loss
12.
Biochem Biophys Res Commun ; 310(3): 878-83, 2003 Oct 24.
Article in English | MEDLINE | ID: mdl-14550286

ABSTRACT

Adipokines such as Plasminogen activator inhibitor-1 (PAI-1), interleukin (IL)-8, and tumor necrosis factor (TNF)-alpha are elevated in patients with obesity, insulin resistance, and type 2 diabetes. In the present study, we investigated whether glucose affected the production of these adipokines in human adipose tissue in vitro. Glucose (up to 35mM) increased secretion of PAI-1 (p<0.01) and IL-8 (p<0.01), but not TNF-alpha, in a dose- and time-dependent manner. Half-maximal stimulatory concentration of glucose was about 1mM. Glucosamine (5mM) decreased production of PAI-1 (p<0.05) and IL-8 (p<0.05), indicating that the hexosamine biosynthesis pathway is not involved in the glucose-induced increment in adipokine secretion. The present data demonstrate that glucose increases PAI-1 and IL-8 secretion. However, glucose concentrations above 5mM had no additional effects on adipokine secretion, suggesting that mechanisms other than diabetes/insulin resistance-related hyperglycemia may be involved in the observed elevation of these adipokines.


Subject(s)
Adipose Tissue/metabolism , Chemokines/metabolism , Glucose/metabolism , Plasminogen Activator Inhibitor 1/metabolism , Adult , Dose-Response Relationship, Drug , Female , Glucosamine/metabolism , Glucose/pharmacology , Humans , Hyperglycemia/metabolism , In Vitro Techniques , Insulin/metabolism , Interleukin-8/biosynthesis , RNA, Messenger/metabolism , Time Factors , Tumor Necrosis Factor-alpha/biosynthesis
13.
Horm Metab Res ; 35(3): 142-6, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12734773

ABSTRACT

Obesity is associated with an increased risk of developing insulin resistance, Type 2 diabetes, and cardiovascular disease. Reports have suggested that adipose tissue-derived cytokines such as tumor necrosis factor-alpha, interleukin-6 and interleukin-8 could be involved in the development of these health complications. Since estrogen has been suggested to attenuate the development of atherosclerosis and cardiovascular disease, we investigated whether ovariectomy affected the production and release of these three adipose tissue-derived cytokines with and without estrogen replacement in vivo and in vitro. Female Wistar rats were submitted to either a) ovariectomy, b) ovariectomy and estrogen replacement, or c) sham operation. After five months, animals were sacrificed and parametrial adipose tissue was removed and incubated for up to 24 hours with either interleukin-1beta (IL-1beta) (5 micro g/l), dexamethasone (50 nM) or estrogen (50 nM). Ovariectomy significantly increased interleukin-6 gene expression (p < 0.05) as well as interleukin-8 protein levels (p < 0.05) and gene expression (p < 0.05) in the adipose tissue, and estrogen replacement significantly reversed this increase (p < 0.05). However, no direct effects of estrogen were found in in vitro adipose tissue incubations. Neither ovariectomy nor estrogen replacement had any effects on tumor necrosis factor-alpha protein levels or gene expression. In conclusion, estrogen-deficient rats were found to have increased production of interleukin-6 and interleukin-8, which could be attenuated by estrogen-replacement. Since estrogen is suggested to be anti-atherosclerotic, this effect might be caused by a reduction in cytokine production from the adipose tissue.


Subject(s)
Adipose Tissue/chemistry , Adipose Tissue/drug effects , Cytokines/analysis , Estradiol/pharmacology , Animals , Dexamethasone/pharmacology , Estrogen Replacement Therapy , Female , Gene Expression/drug effects , Interleukin-1/pharmacology , Interleukin-6/genetics , Interleukin-8/analysis , Interleukin-8/genetics , Ovariectomy , RNA, Messenger/analysis , Rats , Rats, Wistar , Tumor Necrosis Factor-alpha/analysis
14.
Horm Metab Res ; 35(3): 178-82, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12734779

ABSTRACT

Human adipose tissue can produce plasminogen activator inhibitor-1 (PAI-1). It has been suggested that high levels of PAI-1 are of importance in enhanced cardiovascular disease observed among obese subjects, especially abdominally obese individuals. In the present study, we investigated the level of mRNA and production of PAI-1 in adipose tissue from two adipose tissue depots (omental vs. subcutaneous). Adipose tissue from both depots was obtained from obese (mean BMI, 46.9 kg/m 2) and non-obese (mean BMI, 23.9 kg/m 2) women. PAI-1 mRNA was measured both in fresh adipose tissue obtained immediately after surgery and after the adipose tissue (fragments) had been incubated for up to 72 h. In immediately frozen adipose tissue, PAI-1 mRNA expression was similar in omental and subcutaneous adipose tissue. No differences between obese and non-obese women were found. However, when adipose tissue fragments were cultured, PAI-1 mRNA and PAI-1 production were significantly higher in omental than in subcutaneous adipose tissue (p < 0.05). In the culture system, the production of PAI-1 in obese subjects was higher than in non-obese subjects in both subcutaneous (p < 0.05) and in omental adipose tissue (p = 0.19). In order to test whether these regional differences observed after incubation of the adipose tissue were due to differences in local accumulation of cytokines that may stimulate PAI-1 by a paracrine or autocrine manner, we investigated the expression of transforming growth factor beta1 (TGF-beta1) mRNA and tumor necrosis factor alpha (TNF-alpha) mRNA and protein. No differences between the two fat depots were found. In conclusion, no differences in PAI-1 expression between omental and subcutaneous adipose tissue were observed in biopsies frozen immediately after removal, but after incubation of adipose tissue (which somehow stimulates PAI-1 production), higher levels of PAI-1 were found in omental adipose tissue than in subcutaneous adipose tissue. Finally, PAI-1 production in adipose tissue from obese women was higher in non-obese women after incubation for 72 h.


Subject(s)
Adipose Tissue/chemistry , Obesity/metabolism , Omentum , Plasminogen Activator Inhibitor 1/analysis , Subcutaneous Tissue , Adult , Body Mass Index , Body Weight , Culture Techniques , Female , Gene Expression/drug effects , Humans , Interleukin-1/pharmacology , Middle Aged , Plasminogen Activator Inhibitor 1/genetics , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta1 , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/genetics
15.
Horm Metab Res ; 35(1): 18-23, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12669266

ABSTRACT

Biguanides and thiazolidinediones (TZDs), which are primarily used as anti-diabetic drugs, are also associated with other beneficial effects on cardiovascular risk factors such as reduced plasma plasminogen activator inhibitor-1 (PAI-1) concentration in both diabetic and non-diabetic obese subjects. Since human adipose tissue is of importance for the production of PAI-1, the aim of the present study was to investigate the possible direct effects of these anti-diabetic agents on PAI-1 mRNA and secretion by human adipose tissue. Adipose tissue was obtained from biopsies taken from the subcutaneous abdominal depot. Adipose tissue fragments, isolated mature adipocytes, and preadipocytes were incubated in vitro with metformin and various TZDs. Metformin (0.1 - 10 mM) dose-dependently decreased PAI-1 production (and PAI-1 mRNA) under both basal (43 % inhibition at 10 mM, p < 0.05) and interleukin-1beta (IL-1beta)-stimulated conditions where the levels were inhibited by 47.8 % at 1 mM metformin (p < 0.05) and by 100 % at 10 mM (p < 0.01). None of the TZDs tested (PPAR-gamma agonists: troglitazone, pioglitazone, or ciglitazone) had any effects on PAI-1 production. Moreover, no effects on PAI-1 production were observed using various PPAR-alpha agonists such as 5, 8, 11, 14-eicosatetraynoic acid (ETYA), Wy14643 and fenofibrate. Our findings indicate no direct effects of TZDs on PAI-1 secretion, whereas metformin was able to directly inhibit PAI-1 production in human adipose tissue.


Subject(s)
Adipose Tissue/metabolism , Chromans/pharmacology , Hypoglycemic Agents/pharmacology , Metformin/pharmacology , Plasminogen Activator Inhibitor 1/biosynthesis , Thiazolidinediones/pharmacology , Adipocytes/drug effects , Adipocytes/metabolism , Adipose Tissue/drug effects , Adult , Cells, Cultured , Culture Techniques , Dose-Response Relationship, Drug , Female , Humans , Kinetics , Pioglitazone , Receptors, Cytoplasmic and Nuclear/agonists , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors/agonists , Troglitazone
16.
Biochem Biophys Res Commun ; 288(1): 191-7, 2001 Oct 19.
Article in English | MEDLINE | ID: mdl-11594772

ABSTRACT

The effects of ovariectomy (OVX) and estrogen substitution on body weight, body composition, food intake, weight gain, and expression of uncoupling proteins (UCPs) in brown adipose tissue (BAT), white adipose tissue (WAT), and skeletal muscle were studied in four groups of rats: (1) Sham-operated rats (N = 8), (2) ovariectomized rats (OVX - E) (N = 8), (3) estrogen-treated OVX rats (OVX + E) (N = 8), and (4) OVX rats on energy restriction (OVX - E + D) (N = 8). OVX was associated with an increase in food intake and body weight gain during a 5-week study period compared to sham-operated rats. The estrogen-substituted rats had a significantly lower food intake and weight gain during the 5 weeks compared to the sham-operated group. However, we also included a nontreated OVX group that was allowed to eat only enough chow to match the weight gain of the sham-operated group. To match the weight gain in the two groups, the OVX group had to consume 16% less chow than the sham-operated group. In BAT, the UCP1 expression was significantly lower in estrogen-deficient rats compared to either intact rats or estrogen-substituted rats, whereas UCP2 and UCP3 mRNA expression was similar in BAT from all four groups. In WAT, both estrogen-deficient groups had significantly lower UCP2 mRNA expression compared to the control rats and estrogen-treated rats; In contrast, the UCP3 mRNA expression in WAT was similar in all four groups. Finally, in skeletal muscle the OVX group on mild energy restriction had reduced UCP3 mRNA expression compared to control, OVX, and estrogen-treated rats. In contrast, the UCP2 mRNA expression in skeletal muscle was similar in all four groups. Thus, the findings that estrogen deficiency is followed by reduced UCP1 expression in BAT and reduced UCP2 expression in WAT in association with weight gain probably caused by a decrease in energy expenditure might indicate that UCPs play a role for the estrogen-mediated changes in body weight and energy expenditure.


Subject(s)
Adipose Tissue/metabolism , Carrier Proteins/metabolism , Estrogens/pharmacology , Membrane Proteins/metabolism , Membrane Transport Proteins , Mitochondrial Proteins , Muscle, Skeletal/metabolism , Proteins/metabolism , Adipose Tissue, Brown/metabolism , Animals , Body Composition/drug effects , Body Weight/drug effects , Carrier Proteins/genetics , Down-Regulation , Eating/drug effects , Female , Ion Channels , Membrane Proteins/genetics , Ovariectomy , Proteins/genetics , RNA, Messenger/biosynthesis , Rats , Rats, Wistar , Transcription, Genetic , Uncoupling Protein 1 , Uncoupling Protein 2 , Uncoupling Protein 3 , Weight Gain/drug effects
17.
Mol Cell Endocrinol ; 182(1): 27-37, 2001 Aug 20.
Article in English | MEDLINE | ID: mdl-11500236

ABSTRACT

A novel ER-subtype, the ER-beta has recently been characterized in various tissues, furthermore five isoforms of the ER-beta are known (ER-beta1--ER-beta5). Using immunoblotting and real- time RT-PCR, ER-alpha and beta were studied in human adipose tissue. The expression of ER-alpha mRNA was equal in subcutaneous gluteal adipose tissue, subcutaneous abdominal and intra-abdominal adipose tissue, similar findings were obtained at the protein level. In contrast the amount of ER-beta1 (protein and mRNA) was significantly lower in intra-abdominal adipose tissue as compared with the subcutaneous adipose tissue (five-fold lower in women, P<0.005 and three-fold lower in men, P<0.005) whereas the expression of ER-beta4 and -beta5 mRNA isoforms were significantly higher in gluteal adipose tissue compared to subcutaneous abdominal adipose tissue. No significant gender differences in ER expression was detected in any of the fat depots investigated. During adipocyte differentiation the expression of ER-alpha, -beta4 and -beta5 mRNA declined, whereas, the expression of ER-beta1 mRNA was constant. In conclusion, the existence of ER-beta isoforms in human adipose tissue was demonstrated and the amount of these receptors was dependent upon fat depot localization, with much reduced expression of ER-beta1 in intra-abdominal adipose tissue compared to subcutaneous adipose tissue. These findings may indicate that estrogens could have differentiation and depot specific effects in human adipose tissue.


Subject(s)
Adipose Tissue/chemistry , Receptors, Estrogen/metabolism , Abdomen , Adipocytes/cytology , Adult , Cell Culture Techniques , Cell Differentiation , Estrogen Receptor alpha , Estrogen Receptor beta , Female , Humans , Male , Middle Aged , Protein Isoforms/genetics , Protein Isoforms/metabolism , RNA, Messenger/metabolism , Receptors, Estrogen/genetics , Sex Factors , Skin , Tissue Distribution
18.
Ugeskr Laeger ; 163(21): 2913-7, 2001 May 21.
Article in Danish | MEDLINE | ID: mdl-11402968

ABSTRACT

Adipose tissue is not only a passive storage organ for excessed energy intake, it is also able to produce and release several substances with local (autocrine) and systemic (endocrine) actions. An up-to-date review of our knowledge in this area is given here. Several of the compounds deriving from adipose tissue have been shown to play a role in obesity-related health complications. The production of cytokines (TNF-alpha, IL-6, IL-8) is implicated in the development of insulin resistance and atherosclerosis. All elements in the renin-angiotensin system are produced in adipose tissue, which is thus related to hypertension. The production of PAI-1 could be related to enhanced thrombogenesis. The release of the compounds described is generally higher from adipocytes in the visceral depot, which could explain the close association between this depot and health complications.


Subject(s)
Adipocytes/metabolism , Adipose Tissue/metabolism , Cytokines/metabolism , Obesity/etiology , Adipose Tissue/immunology , Arteriosclerosis/etiology , Growth Substances/biosynthesis , Growth Substances/metabolism , Humans , Inflammation/etiology , Obesity/immunology , Obesity/metabolism , Plasminogen Activator Inhibitor 1/biosynthesis , Plasminogen Activator Inhibitor 1/metabolism , Protein Biosynthesis , Proteins/metabolism , Renin-Angiotensin System , Steroids/biosynthesis
19.
J Clin Endocrinol Metab ; 86(3): 1267-73, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11238519

ABSTRACT

A variety of cytokines and other compounds are produced in the human adipose tissue and may have autocrine functions in the adipose tissue as well as be involved in the complications seen in association with obesity. Because it recently has been reported that interleukin 8 (IL-8), through its effects on the macrophage and endothelial cell, may be involved in the pathogenesis of atherosclerosis, we found it of interest to investigate whether IL-8 is produced in human adipose tissue in vitro. Human sc adipose tissue was investigated both in incubations with whole adipose tissue fragments as well as with isolated mature adipocytes. In adipose tissue fragments, IL-1beta (3 nM) and tumor necrosis factor alpha (0.6 nM) were able to stimulate IL-8 production by 12-fold and 5-fold, respectively (P < 0.001), when incubated for 48 h. Incubations with isolated adipocytes were performed up to 6 h, and IL-1beta and tumor necrosis factor alpha significantly increased IL-8 production by 50-60% (P < 0.05). Dexamethasone (50 nM) decreased IL-8 production from adipose tissue fragments by 57% (P < 0.01) and from adipocytes by 37% (P < 0.05). IL-8 messenger RNA expression in adipocytes incubated with IL-1beta was increased already after 2 h (P < 0.05). Thus, the effect of proinflammatory cytokines and dexamethasone on IL-8 production in adipose tissue seems to be mediated at the transcriptional level. In conclusion, it is demonstrated for the first time that IL-8 is produced and released from human adipose tissue and from isolated adipocytes in vitro, which may indicate that IL-8 from adipose tissue could be involved in some of the obesity-related complications.


Subject(s)
Adipose Tissue/metabolism , Gene Expression Regulation , Interleukin-8/biosynthesis , Interleukin-8/genetics , Adult , Culture Techniques , Dexamethasone/pharmacology , Dose-Response Relationship, Drug , Female , Gene Expression Regulation/drug effects , Glucocorticoids/pharmacology , Humans , Interleukin-1/administration & dosage , Interleukin-1/pharmacology , Kinetics , Middle Aged , RNA, Messenger/analysis , Tumor Necrosis Factor-alpha/administration & dosage , Tumor Necrosis Factor-alpha/pharmacology
20.
Biochem Biophys Res Commun ; 279(3): 914-9, 2000 Dec 29.
Article in English | MEDLINE | ID: mdl-11162449

ABSTRACT

We have previously reported that systemic epidermal growth factor (EGF) treatment in rats reduces the amount of adipose tissue despite an unaltered food intake. The mitochondrial uncoupling proteins (UCP2 and UCP3) are thought to uncouple the respiratory chain and thus to increase energy expenditure. In order to find out whether the UCP system was involved in the EGF-induced weight loss, the effects of EGF on UCP2 and UCP3 in adipose tissue and skeletal muscle were investigated in the present study. Eight rats were treated with placebo or EGF (150 microg/kg/day) for seven days via mini-osmotic pumps. The EGF-treated rats gained significantly less body weight during the study period than the placebo-treated animals and had significantly less adipose tissue despite a similar food intake. The placebo group and the EGF group had similar UCP2 mRNA expression (in both adipose tissue and skeletal muscle), whereas the EGF-treated group compared to the placebo group had significantly higher UCP3 mRNA expression in both skeletal muscle (3.76 +/- 0.90 vs 8.41 +/- 0.87, P < 0.05) and in adipose tissue (6.38 +/- 0.71 vs 12.48 +/- 1.79, P < 0.05). In vitro studies with adipose tissue fragments indicated that the EGF effect probably is mediated indirectly as incubations with EGF (10 microM) were unable to affect adipose tissue UCP expression, whereas incubations with bromopalmitate stimulated both UCP2 and UCP3 mRNA expression twofold. Thus, EGF treatment in vivo was found to enhance UCP3 mRNA expression in both adipose tissue and skeletal muscle, which may indicate that the EGF effect on body composition might involve up-regulation of UCP3 in skeletal muscle and adipose tissue.


Subject(s)
Adipose Tissue/drug effects , Carrier Proteins/metabolism , Epidermal Growth Factor/pharmacology , Membrane Transport Proteins , Mitochondrial Proteins , Muscle, Skeletal/drug effects , Adipose Tissue/metabolism , Animals , Body Weight/drug effects , Carrier Proteins/genetics , Eating/drug effects , Epidermal Growth Factor/administration & dosage , Fat Body/drug effects , Ion Channels , Male , Muscle, Skeletal/metabolism , Proteins/genetics , Proteins/metabolism , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Rats , Rats, Wistar , Uncoupling Protein 2 , Uncoupling Protein 3
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