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P Flachs,
R Rühl,
M Hensler,
P Janovska,
P Zouhar,
V Kus,
Z Macek Jilkova,
E Papp,
O Kuda,
M Svobodova,
M Rossmeisl,
G Tsenov, V Mohamed-Ali,
J Kopecky
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ABSTRACT: Calorie restriction is an essential component in the treatment of obesity and associated diseases. Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) act as natural hypolipidaemics, reduce the risk of cardiovascular disease and could prevent the development of obesity and insulin resistance. We aimed to characterise the effectiveness and underlying mechanisms of the combination treatment with LC n-3 PUFA and 10% calorie restriction in the prevention of obesity and associated disorders in mice.
Male mice (C57BL/6J) were habituated to a corn-oil-based high-fat diet (cHF) for 2 weeks and then randomly assigned to various dietary treatments for 5 weeks or 15 weeks: (1) cHF, ad libitum; (2) cHF with LC n-3 PUFA concentrate replacing 15% (wt/wt) of dietary lipids (cHF + F), ad libitum; (3) cHF with calorie restriction (CR; cHF + CR); and (4) cHF + F + CR. Mice fed a chow diet were also studied.
We show that white adipose tissue plays an active role in the amelioration of obesity and the improvement of glucose homeostasis by combining LC n-3 PUFA intake and calorie restriction in cHF-fed mice. Specifically in the epididymal fat in the abdomen, but not in other fat depots, synergistic induction of mitochondrial oxidative capacity and lipid catabolism was observed, resulting in increased oxidation of metabolic fuels in the absence of mitochondrial uncoupling, while low-grade inflammation was suppressed, reflecting changes in tissue levels of anti-inflammatory lipid mediators, namely 15-deoxy-Δ(12,15)-prostaglandin J(2) and protectin D1.
White adipose tissue metabolism linked to its inflammatory status in obesity could be modulated by combination treatment using calorie restriction and dietary LC n-3 PUFA to improve therapeutic strategies for metabolic syndrome.
Diabetologia 07/2011; 54(10):2626-38. · 6.81 Impact Factor
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O Kuda,
T Jelenik,
Z Jilkova,
P Flachs,
M Rossmeisl,
M Hensler,
L Kazdova,
N Ogston,
M Baranowski,
J Gorski,
P Janovska,
V Kus,
J Polak, V Mohamed-Ali,
R Burcelin,
S Cinti,
M Bryhn,
J Kopecky
Diabetologia 06/2009; · 6.81 Impact Factor
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N C Ogston,
K Karastergiou,
M J Hosseinzadeh-Attar,
R Bhome,
R Madani,
M Stables,
D Gilroy,
P Flachs,
M Hensler,
J Kopecky, V Mohamed-Ali
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ABSTRACT: Chronically elevated interleukin-6 (IL-6) is implicated in obesity-associated pathologies, where a proportion of this cytokine is derived from adipose tissue. Proinflammatory prostaglandins, which regulate this cytokine elsewhere, are also produced by this tissue.
To investigate whether constitutively active cyclooxygenase (COX)/prostaglandin (PG) pathway in white adipose tissue (WAT) is responsible for basal IL-6 production.
The effect of acetylsalicylic acid (ASA), an inhibitor of COX, on IL-6 was assessed in human subjects and mice. COX, downstream PG synthase (PGS) activity and PG receptor signalling were determined in subcutaneous (SC), gonadal (GN) WAT and adipocytes.
In obese humans, low-dose ASA (150 mg day(-1) for 10 days) inhibited systemic IL-6 and reduced IL-6 release from SC WAT ex vivo (0.2 mM). Similarly, in mice, ASA (0.2 and 2.0 mg kg(-1)) suppressed SC WAT 6-keto-PGF(1alpha) (a stable metabolite of prostacyclin) and IL-6 release. Although both COX isoforms are comparably expressed, prostacyclin synthase expression is higher in GN WAT, with levels of activity correlating directly with IL-6. Both ASA (5 mM) and NS-398 (COX-2 selective inhibitor <or=1 microM), but not SC-560 (COX-1 selective inhibitor <or=1 microM), attenuated IL-6 release from murine WAT in vitro and abolished its depot differences. Prostacyclin receptor (IP) and, to a lesser extent, PGE(2) (EP2 and EP4) receptor agonists elevated the release of IL-6 from adipocytes.
In adipose tissue, constitutive COX-2-coupled prostacyclin triggers the release of basal IL-6, which in obese subjects is significantly dampened by ASA ingestion, thus offering a novel, modifiable pathway to regulate the potentially pathological component of this cytokine.
International journal of obesity (2005) 11/2008; 32(12):1807-15. · 4.34 Impact Factor
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ABSTRACT: Diets rich in n-3 polyunsaturated fatty acids, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), protect against insulin resistance and obesity in rodents and increase insulin sensitivity in healthy humans. We tested whether the anti-diabetic effects of EPA and DHA involve enhanced production of the endogenous insulin sensitiser, adiponectin.
We studied the effects, in an obesity-promoting high-fat diet, of partial replacement of vegetable oils by EPA/DHA concentrate (6% EPA, 51% DHA) over a 5-week period in adult male C57BL/6J mice that either had free access to food or had their food intake restricted by 30%. At the end of the treatment, systemic markers of lipid and glucose metabolism and full-length adiponectin and leptin were measured. Adiponectin (Adipoq) and leptin (Lep) gene expression in dorsolumbar and epididymal white adipose tissue (WAT) and isolated adipocytes was quantified and adipokine production from WAT explants evaluated.
In mice with free access to food, plasma triacylglycerols, NEFA, and insulin levels were lower in the presence of EPA/DHA, while glucose and leptin levels were not significantly altered. Food restriction decreased plasma triacylglycerols, glucose, insulin and leptin, but not adiponectin. EPA/DHA increased plasma adiponectin levels, independent of food intake, reflecting the stimulation of Adipoq expression in adipocytes and the release of adiponectin from WAT, particularly from epididymal fat. Expression of Lep and the release of leptin from WAT, while being extremely sensitive to caloric restriction, was unaltered by EPA/DHA.
Intake of diets rich in EPA and DHA leads to elevated systemic concentrations of adiponectin, largely independent of food intake or adiposity and explain, to some extent, their anti-diabetic effects.
Diabetologia 03/2006; 49(2):394-7. · 6.81 Impact Factor
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ABSTRACT: Chronic periodontitis causes a low-grade systemic inflammatory response; its standard treatment, however, induces an acute inflammatory response. The aim of this study was to describe the systemic inflammatory reactions to an intensive periodontal treatment regimen.
Fourteen otherwise healthy subjects suffering from severe chronic periodontitis were enrolled in a 1 month pilot single-blind trial. Intensive periodontal treatment, consisting of full-mouth subgingival root debridement delivered within a 6-h period, was performed. Periodontal parameters were recorded before and 1 month after completion of treatment. Blood samples were taken at baseline and 1, 3, 5, 7 and 30 days after treatment. Interleukin-1 receptor antagonist (IL-1Ra), Interleukin-6 (IL-6) and C-reactive protein (CRP) serum concentrations were determined by enzyme-linked immunosorbent assay (ELISA). Complete blood counts were also performed.
One day after treatment, mild neutrophilia and monocytosis (p < 0.05) and lymphopenia (p < 0.01) were accompanied by a sharp increase in inflammatory markers (IL-1Ra, IL-6, p < 0.01). A 10-fold increase in CRP (p < 0.001) was detected on day 1 and its kinetics followed a pattern of a classical acute phase response (significantly raised concentrations up to 1 week, p < 0.01). At 3-7 days after treatment, subjects presented also with a mild tendency towards a normocytic anaemic state (p < 0.01) and a degree of lympho-thrombocytosis (p < 0.05). The observed changes were similar to those expected following the well-characterized endotoxin-challenge model of inflammation.
Intensive periodontal treatment produced an acute systemic inflammatory response of 1 week duration and might represent an alternative to classic endotoxin-challenge or drug-induced models to study acute inflammation in humans.
Journal of Periodontal Research 10/2004; 39(5):294-9. · 1.69 Impact Factor
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J S Yudkin,
I Juhan-Vague,
E Hawe,
S E Humphries,
G di Minno,
M Margaglione,
E Tremoli,
T Kooistra,
P E Morange,
P Lundman, V Mohamed-Ali,
A Hamsten
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ABSTRACT: Risk of coronary heart disease has been related to insulin resistance, but the mechanism for this is incompletely understood. Variables attributed to insulin resistance are associated with low-grade inflammation. A case-control study was performed of 469 male myocardial infarction (MI) survivors aged < 60 years and 575 control subjects recruited from centers in northern and southern Europe. Principal factor analysis was used to explore correlations between insulin resistance and inflammatory variables. Three factors resulted: (a) "Metabolic Syndrome" (insulin/proinsulin/ triglyceride/body mass index [BMI]); (b) "Inflammation" (fibrinogen/C-reactive protein [CRP]/interleukin-6 [IL-6]); and (c) "Blood Pressure" (systolic and diastolic blood pressure). The "Metabolic Syndrome" factor was related to the "Inflammation" factor (largely independently of obesity), the "Blood Pressure" factor, smoking, and south location (all P < or = .0002). There were significant relationships between all 3 factors and case status (P < or = .0002). Markers of low-grade inflammation are strongly related to metabolic syndrome variables independently of obesity. This raises the possibility that links between insulin resistance and cardiovascular disease could, in part, represent common consequences of low-grade inflammation.
Metabolism 07/2004; 53(7):852-7. · 2.66 Impact Factor
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ABSTRACT: Coronary artery disease (CAD) is more prevalent in people from a low socioeconomic background, and low socioeconomic status (SES) is associated with an increased exposure to psychological stress. The pro-inflammatory cytokine interleukin-6 (IL-6) plays a central role in CAD development. IL-6 is responsive to psychological stress and could potentially mediate the effect of psychosocial factors on CAD risk. Accordingly, we predicted that people of low SES would have greater and/or more sustained IL-6 responses to acute psychological stress. Based on previous findings, we also predicted that these people would have delayed post-stress cardiovascular recovery. Thirty-eight male civil servants were tested, with participants divided into high and low SES groups according to employment grade. There were no differences between the groups at baseline. However there were significant differences in IL-6 and heart rate responses to stress. Stress induced increases in plasma IL-6 in all participants. However, in the low SES group, IL-6 continued to increase between 75 min and 2h post-stress, whereas IL-6 levels stabilised at 75 min in the high SES group. Heart rate increased to the same extent following stress in both groups, however by 2h post-stress, it had returned to baseline in 75% of the high SES group compared with only 38.1% of the low SES group. These results suggest that low SES people are less able to adapt to stress than their high SES counterparts. Prolonged stress-induced increases in IL-6 in low SES groups represents a novel mechanism potentially linking socioeconomic position and heart disease.
Brain Behavior and Immunity 06/2004; 18(3):281-90. · 4.72 Impact Factor
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ABSTRACT: The cancer cachexia syndrome is characterized by anorexia, weight loss with muscle wasting and increased energy expenditure. It is associated with increased morbidity and mortality, but its aetiology is poorly understood and no effective therapeutic intervention is available. It may result from an imbalance between the activity or effect of anabolic and catabolic hormones, mediated by the inflammatory cytokines. IGF-I is a potent anabolic agent, with therapeutic potential. Our objective was to investigate the role and regulation of the IGF system in cancer cachexia.
We set up a prospective study of 30 patients with newly diagnosed unresectable non-small cell lung cancer, together with a cross-sectional comparison group of healthy volunteers.
We examined the relationship between aspects of the IGF system, including IGFBP-3 proteolysis (using Western ligand and immunoblotting and an in vitro IGFBP-3 protease assay); the inflammatory cytokines and their soluble receptors; and food intake and nutritional status (including biochemical and anthropometric assessments).
Although we did not observe a marked reduction in food intake in the cancer patients, the majority lost weight and functionally important lean body mass. We observed GH resistance in the cancer patients, and intermittent proteolysis of IGFBP-3, which correlated with the circulating interleukin-6 (IL-6) concentration. The pattern of IGFBP-3 proteolysis was unusual, with a prominent 17-kDa fragment. Less IGFBP-3 proteolysis was associated with more weight loss, suggesting that this could be a protective counter-regulatory mechanism, increasing IGF-I bioavailability to the tissues.
Cancer cachexia in humans is a complex condition. Patients tend to be GH resistant. The significance of the intermittent increases in IGFBP-3 proteolysis, which may be regulated by IL-6, remains uncertain. A better understanding of the pathophysiology should enable the development of novel therapeutic approaches.
Clinical Endocrinology 07/2002; 56(6):723-33. · 3.17 Impact Factor
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ABSTRACT: Circulating IL-6 levels are elevated in obesity. Although IL-6 is expressed in adipose tissue, neither its regulation nor cell of origin is well characterized. Here we investigated the beta-adrenergic regulation of IL-6 release in a combination of studies on humans and animals in vivo and cultured adipocytes in vitro. Human in vivo study: Human volunteers were infused with isoproterenol, norepinephrine, or saline [4 M:4F; mean (SD) age 35.5 (5.8) yr; body mass index 24.6 (4.2) kg/m(-2)]. Plasma IL-6 levels increased during a 3-h infusion of isoproterenol (P = 0.01) and fell 2 h post infusion (P = 0.05). IL-6 levels did not change significantly with either norepinephrine or saline. Murine in vivo study: C57BL6/J male mice were injected ip with dobutamine (beta(1) agonist), clenbuterol (beta(2)), CL316243 (beta(3)), or saline placebo. Plasma IL-6 levels at 3 h were increased by clenbuterol (P = 0.02) and CL316243 (P = 0.02) but not dobutamine (P = 0.51), compared with placebo. In vitro studies: In human peripheral blood cells, lipopolysaccharide treatment enhanced secretion of IL-6 (vs. controls; P < 0.001), whereas isoproterenol inhibited IL-6 secretion (P = 0.012) and norepinephrine had no significant effect. In contrast, isolated human adipocytes and differentiated 3T3F442A adipocytes all rapidly secreted IL-6 in response to adrenergic agonists (P < 0.01, compared with untreated cells). We conclude that beta 2/beta 3 adrenoceptor stimulation on adipocytes, rather than macrophages, may be responsible for the increases in plasma IL-6 concentrations observed during sympathetic activation and in obesity.
Journal of Clinical Endocrinology & Metabolism 12/2001; 86(12):5864-9. · 6.50 Impact Factor
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ABSTRACT: To investigate the regulation of soluble adhesion molecules by tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and relationships with circulating cytokine receptors, in vivo, in type 1 diabetes.
Cross-sectional study.
University hospital diabetes clinic.
A total of 47 non-nephropathic, Caucasian type 1 diabetics and 39 nondiabetic controls.
Plasma levels of TNF-alpha, IL-6, their soluble receptors and adhesion molecules intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), sE-selectin and von Willebrand factor (vWF), and risk factors for cardiovascular disease.
Plasma concentrations of IL-6 were elevated in diabetic patients compared with controls [median (interquartiles) 1.28 (0.89-2.65) vs. 0.66 (0.45-1.73) pg mL(-1): P=0.016], and in these patients IL-6 and soluble IL-6 receptor (sIL-6R) levels correlated with concentrations of sICAM-1 (r = 0.41, P = 0.012 and r = 0.31, P = 0.04, respectively). Tumour necrosis factor-alpha soluble receptor-2 (sTN-FRII), but not TNF-alpha or tumour necrosis factor soluble receptor-1 (sTNFRI), was elevated in diabetic subjects (P = 0.027). Plasma TNF-alpha levels correlated with sVCAM-1 (r = 0.39, P = 0.008), triglycerides (r = 0.36, P = 0.02 1) and diastolic blood pressure (r = 0.35; P = 0.024). Both sTNFRI and sTNFRII correlated with blood pressure (r = 0.46, P = 0.002; r = 0.32, P = 0.034) and triglycerides (r = 0.33, P = 0.033; r = 0.29, P = 0.05). In contrast, HDL-cholesterol and triglyceride were related to sE-selectin (r = -0.45 and +0.45; both P < 0.001). Neither sE-selectin nor vWF were related to cytokine concentrations. Finally, both TNF-alpha and sIL-6R correlated sTNFRI and RII (r = 0.44-0.49, P < 0.001). None of these interactions were apparent in control subjects.
(i) IL-6, through effects on sICAM-1, and TNF-alpha via effects on sVCAM-1, may promote vascular adhesion; (ii) plasma levels of TNF-alpha are associated with dyslipidaemia and increased blood pressure, adding to vascular disease risk; (iii) the actions of both cytokines are probably modified by altered production of soluble receptors in diabetic subjects.
Journal of Internal Medicine 11/2001; 250(5):415-21. · 5.48 Impact Factor
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ABSTRACT: The influence of acute mental stress on cardiovascular responses and concentrations of inflammatory cytokines up to 2 h later was assessed in 12 subjects exposed to stress and in eight control subjects. Beat-by-beat recordings of finger blood pressure and heart rate were made at rest and during two behavioural tasks (colour-word interference and mirror tracing). Blood was drawn after adaptation and at 45 min and 2 h after the tasks, and assayed for interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), interleukin-1 receptor antagonist (IL-1Ra), C-reactive protein (CRP) and haematocrit. Saliva was sampled periodically and assayed for free cortisol. The tasks were rated as stressful by the participants. The stress group showed significant increases in systolic and diastolic blood pressure (mean rises of 16.4+/-12.3 and 12.6+/-6.9 mmHg respectively) and heart rate (5.39+/-5.3 beats/min); these values returned to baseline during the recovery period. The IL-6 concentration was increased by 56% at 2 h after the tasks (P<0.05), while IL-1Ra was increased by 12.3% (P<0.01). No changes in cardiovascular variables or cytokine concentrations were observed in the control subjects, and haematocrit did not change. The magnitude of blood pressure responses during tasks was correlated positively with the IL-6 concentration after 45 min (r=0.70, P<0.05), and with the IL-1Ra concentration after 2 h (r=0.63, P<0.05). Increases in TNF-alpha after 2 h were correlated with heart rate responses to tasks (r=0.66, P<0.05). Associations between IL-6 and IL-1Ra concentrations were also recorded. This study indicates that inflammatory cytokines respond to acute mental stress in humans with delayed increases, and suggest that individual differences in cytokine responses are associated with sympathetic reactivity.
Clinical Science 09/2001; 101(2):185-92. · 4.61 Impact Factor
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ABSTRACT: Detected levels of IL-6, TNF-alpha and leptin may be affected by methods of storage, anticoagulant or repeated freezing-thawing. Blood samples from 22 healthy subjects were: (i) allowed to stand for 1, 2, 4 or 6 h prior to, or after separation, before freezing at -70 degrees C; (ii) taken into tubes with lithium heparin, sodium citrate, EDTA or no anticoagulant, separated and frozen; and (iii) separated, and plasma repeatedly freeze-thawed for up to six cycles prior to assay. Leptin was assayed by RIA, and IL-6 and TNF-alpha by high-sensitivity ELISA. (i) IL-6 and TNF-alpha levels were not altered significantly in separated samples but IL-6 declined by mean (SEM) 14.3% (3.7%) and TNF-alphaincreased by 9.6% (2.3%) in samples left unseparated for 4 h (P=0.003 and 0.002, respectively). Leptin remained unchanged. (ii) Serum and EDTA-plasma samples gave comparable results for all three cytokines, but levels in the other anticoagulant samples were highly variable. (iii) IL-6 and leptin levels were not altered by up to 6 cycles of freeze-thawing, but TNF-alpha increased by 17.0% (3.7%) after 3 cycles. Concentrations of these molecules are significantly altered by storage conditions, therefore they need to be standardized for epidemiological and clinical studies, and between-study comparisons of levels may not be reliable.
Cytokine 12/2000; 12(11):1712-6. · 3.02 Impact Factor
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ABSTRACT: Improved glycaemic control might reduce both microvascular and macrovascular complications of Type II diabetes (non-insulin-dependent) mellitus. To explore such possible mechanisms, we investigated the effects of intensive treatment on markers of endothelial dysfunction and of acute phase activation, using both sulphonylureas and insulin.
In a randomised cross-over study we gave sulphonylureas or insulin each for a period of 16 weeks to 22 poorly controlled Type II diabetic subjects who were being treated by diet. There was a 4 week washout period between each treatment. Subjects were studied at baseline and at the end of each treatment.
Treatment with sulphonylureas and insulin resulted in similar improvements in glycaemic control (glycated haemoglobin, baseline: 11.8 [(SD 2.2)%; after sulphonylureas: 8.6 (1.2)%,p < 0.001; after insulin: 8.6 (1.2)%, p < 0.001] and in insulin sensitivity ¿metabolic clearance rate of glucose, baseline: median 1.75 [interquartile (IQ) range 1.41, 2.27] ml x kg(-1) x min(-1); after sulphonylureas: 2.41 (1.82, 3.01) ml x kg(-1) x min(-1), p = 0.001; after insulin: 2.23 (1.92, 2.75) ml x kg(-1) min(-1), p = 0.027¿. There were no significant changes in concentrations of endothelial markers von Willebrand factor, cellular fibronectin, thrombomodulin, tissue plasminogen activator, soluble E-selectin or soluble intercellular adhesion molecule-1 or in urinary albumin excretion rate after either treatment period. Concentrations of C-reactive protein were not significantly influenced by sulphonylureas but fell after insulin [baseline: median 4.50 (IQ range 1.37, 6.44) microg x ml(-1); sulphonylureas: 2.69 (0.88, 9.65) microg x ml(-1) (p = 0.53); insulin: 2.07 (1.16, 5.24) microg x ml(-1) (p = 0.017)]. There were, however, no significant effects of either treatment on circulating concentrations of fibrinogen (p = 0.28-0.34) or of the proinflammatory cytokines interleukin-6 or tumour necrosis factor-alpha (p = 0.65-0.79).
Markers of endothelial dysfunction and concentrations of proinflammatory cytokines in Type II diabetes are not influenced by improved glycaemic control over 16 weeks. Improved metabolic control with insulin could, however, be associated with reduced concentrations of the acute phase marker C-reactive protein.
Diabetologia 10/2000; 43(9):1099-106. · 6.81 Impact Factor
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ABSTRACT: To determine the dependence of plasma leptin concentrations upon circulating noradrenaline (NA) and thyroid hormones (TH) in humans.
Cross-sectional study in 40 newly diagnosed untreated patients with primary thyroid disease, and 69 lean and obese euthyroid control subjects.
Plasma leptin, NA, free T3 (fT3) and TSH in the fasting state. Anthropometry and % body fat (electrical bioimpedance).
Leptin levels were highest in 37 obese euthyroid and 22 hypothyroid (median [interquartiles]31.5 [19.0- 48.0], 19.2 [11.5-31.5] ng ml(-1)), and lowest in 32 lean euthyroid and 18 hyperthyroid subjects (6.6 [3.9-14.4], 8.9 [5.5-11.1]; ANOVA, P< 0.0001). Plasma NA was similar in all groups (P= n.s.). In obese controls, TSH correlated with % body fat and leptin (r= 0.67, r= 0.61; P< 0.001). Treatment of hypothyroidism (n= 10) with T4 reduced leptin from 20.8 [11.8-31.6] to 12.9[4.6-21.2] (P= 0.005) with no change in BMI.
Thyroid status modifies leptin secretion independently of adiposity and NA. The data suggest leptin-thyroid interactions at hypothalamic and adipocyte level.
International Journal of Obesity 07/2000; 24 Suppl 2:S165-6. · 4.69 Impact Factor
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ABSTRACT: To investigate the effects of beta-adrenergic stimulation on IL-6 secretion in humans, and to determine the potential contribution to this response of adipocytes and peripheral blood cells (PBC).
Experimental study in 8 human volunteers, and in vitro studies on murine adipocyte cell-line, 3T3.L1 and 3T3.F442A, and human PBC.
Plasma IL-6 and TNFalpha responses to isoprenaline infusion. Cytokine secretion from differentiated adipocyte cell-lines and PBC in response to isoprenaline.
Plasma IL-6 levels increased ninefold (median) by 180 min (baseline median 0.51 [interquartile range 0.47-1.4] vs 180 mins 4.53 [2.58-5.69] pg ml(-1), P=0.01). One hour after infusion, IL-6 levels (2.9 [1.27-3.98]) were lower than at 180 min (P=0.05), but higher than baseline (P=0.01). TNFalpha levels were unchanged. Differentiated adipocytes incubated in isoprenaline (0-0.1 microM) released significantly increased amounts of IL-6 whereas no response was elicited from PBC.
The induction of IL-6 observed in vivo may be attributed to the beta-adrenergic stimulation of IL-6 release specifically from adipocytes, as opposed to circulating blood cells.
International Journal of Obesity 07/2000; 24 Suppl 2:S154-5. · 4.69 Impact Factor
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ABSTRACT: The physiological significance of changes in uncoupling protein-2 (UCP-2) gene expression is controversial. In this study we investigated the biochemical and functional correlates of UCP-2 gene expression in sc abdominal adipose tissue in humans in vivo. UCP-2 messenger ribonucleic acid expression was quantified by nuclease protection in adipose tissue from lean and obese humans in both the fasting and postprandial states. Plasma fatty acids, insulin, and leptin were all determined in paired samples from the superficial epigastric vein and radial artery, and local production rates were calculated from 133Xe washout. In the fasting state UCP-2 expression correlated inversely with body mass index (r = -0.45; P = 0.026), percent body fat (r = -0.41; P = 0.05), plasma insulin (r = -0.47; P = 0.02), epigastric venous fatty acids (r = -0.45; P = 0.04), and leptin (r = -0.50; P = 0.018). UCP-2 expression remained inversely related with plasma leptin after controlling for percent body (r = -0.45; P = 0.038). At 2 or 4 h postprandially, there were no significant relationships between UCP-2 expression and biochemical parameters. In conclusion, 1) UCP-2 messenger ribonucleic acid expression in sc adipose tissue is inversely related to adiposity and independently linked to local plasma leptin levels; and 2) UCP-2 expression is not acutely regulated by food intake, insulin, or fatty acids. Reduced UCP-2 expression may be a maladaptive response to sustained energy surplus and could contribute to the pathogenesis and maintenance of obesity.
Journal of Clinical Endocrinology & Metabolism 07/2000; 85(6):2312-7. · 6.50 Impact Factor
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ABSTRACT: There is mounting evidence that inflammation plays a role in the development of coronary heart disease (CHD). Observations have been made linking the presence of infections in the vessel wall with atherosclerosis, and epidemiological data also implicate infection in remote sites in the aetiology of CHD. In this article we propose a key role for the proinflammatory cytokine interleukin-6 (IL-6) in several mechanisms that contribute to the development of CHD. IL-6 is a powerful inducer of the hepatic acute phase response. Elevated concentrations of acute phase reactants, such as C-reactive protein (CRP), are found in patients with acute coronary syndromes, and predict future risk in apparently healthy subjects. The acute phase reaction is associated with elevated levels of fibrinogen, a strong risk factor for CHD, with autocrine and paracrine activation of monocytes by IL-6 in the vessel wall contributing to the deposition of fibrinogen. The acute phase response is associated with increased blood viscosity, platelet number and activity. Furthermore, raised serum amyloid A lowers HDL-cholesterol levels. IL-6 decreases lipoprotein lipase (LPL) activity and monomeric LPL levels in plasma, which increases macrophage uptake of lipids. In fatty streaks and in the atheromatous 'cap' and 'shoulder' regions, macrophage foam cells and smooth muscle cells (SMC) express IL-6, suggesting a role for this cytokine along with interleukin-1 (IL-1) and tumour necrosis factor-alpha (TNF-alpha), in the progression of atherosclerosis. Both these cytokines induce the release of IL-6 from several cell types, including SMC. During vascular injury SMC are exposed to platelets or their products, and cytokine production by SMC further contributes to vascular damage. Furthermore, circulating IL-6 stimulates the hypothalamic-pituitary-adrenal (HPA) axis, activation of which is associated with central obesity, hypertension and insulin resistance. Thus we propose a role for IL-6 in the pathogenesis of CHD through a combination of autocrine, paracrine and endocrine mechanisms. This hypothesis lends itself to testing using interventions to influence IL-6 secretion and actions.
Atherosclerosis 03/2000; 148(2):209-14. · 3.79 Impact Factor
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ABSTRACT: We evaluated abdominal adipose tissue leptin production during short-term fasting in nine lean [body mass index (BMI) 21 +/- 1 kg/m(2)] and nine upper body obese (BMI 36 +/- 1 kg/m(2)) women. Leptin kinetics were determined by arteriovenous balance across abdominal subcutaneous adipose tissue at 14 and 22 h of fasting. At 14 h of fasting, net leptin release from abdominal adipose tissue in obese subjects (10.9 +/- 1.9 ng x 100 g tissue x (-1) x min(-1)) was not significantly greater than the values observed in the lean group (7.6 +/- 2.1 ng x 100 g(-1) x min(-1)). Estimated whole body leptin production was approximately fivefold greater in obese (6.97 +/- 1.18 microg/min) than lean subjects (1.25 +/- 0.28 microg/min) (P < 0.005). At 22 h of fasting, leptin production rates decreased in both lean and obese groups (to 3.10 +/- 1.31 and 10.5 +/- 2.3 ng x 100 g adipose tissue(-1) x min(-1), respectively). However, the relative declines in both arterial leptin concentration and local leptin production in obese women (arterial concentration 13.8 +/- 4.4%, local production 10.0 +/- 12.3%) were less (P < 0.05 for both) than the relative decline in lean women (arterial concentration 39.0 +/- 5.5%, local production 56.9 +/- 13.0%). This study demonstrates that decreased leptin production accounts for the decline in plasma leptin concentration observed after fasting. However, compared with lean women, the fasting-induced decline in leptin production is blunted in women with upper body obesity. Differences in leptin production during fasting may be responsible for differences in the neuroendocrine response to fasting previously observed in lean and obese women.
AJP Endocrinology and Metabolism 02/2000; 278(2):E280-4. · 4.75 Impact Factor
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ABSTRACT: To investigate in vivo adipose tissue production of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and their soluble receptors: TNF receptor type I (sTNFR-I), TNF receptor type II (sTNFR-II), and IL-6 receptor (sIL-6R), we determined arteriovenous differences in their levels across abdominal subcutaneous adipose tissue in obese subjects. Subjects had a median (interquartile range) age of 44.5 (27-51.3) yr, body mass index (BMI) of 32.9 (26. 0-46.6) kg/m(2), and %body fat of 42.5 (28.5-51.2) %. Although there was not a significant difference in the arteriovenous concentrations of TNF-alpha (P = 0.073) or sTNFR-II (P = 0.18), the levels of sTNFR-I (P = 0.002) were higher in the vein compared with artery, suggesting adipose tissue production of this soluble receptor. There was a significant arteriovenous difference in IL-6 (P < 0.001) but not in its soluble receptor (P = 0.18). There was no relationship between TNF-alpha levels and adiposity indexes (r(s) = 0.12-0.22, P = not significant); however, levels of both its soluble receptor isomers correlated significantly with BMI and %body fat (sTNFR-I r(s) = 0.42-0.72, P < 0.001; sTNFR-II r(s) = 0.36-0.65, P < 0.05- <0. 001). IL-6 levels correlated significantly with both BMI and %body fat (r(s) = 0.51, P = 0.004, and r(s) = 0.63, P < 0.001), but sIL-6R did not. In conclusion, 1) soluble TNFR-I is produced by adipose tissue, and concentrations of both soluble isoforms correlate with the degree of adiposity, and 2) IL-6, but not its soluble receptor, is produced by adipose tissue and relates to adiposity.
The American journal of physiology 12/1999; 277(6 Pt 1):E971-5.
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ABSTRACT: Circulating plasminogen activator inhibitor-1 (PAI-1) levels are elevated in patients with coronary heart disease and may play an important role in atherothrombosis. Levels are also raised in obese, hypertriglyceridaemic, or insulin-resistant subjects, which predispose people to coronary heart disease. It is unclear, though, which organ is responsible for PAI-1 secretion, either in health or disease. We measured arteriovenous differences across a subcutaneous adipose tissue bed in 25 subjects without coronary heart disease, which, combined with measures of adipose tissue blood flow, provides synthetic rates. There was no net increase in levels of PAI-1 activity (median change 0.23, interquartile range -0.59, 1.21 IU x L(-1), p=0.30) or of PAI-1 antigen (mean change -0.01, SD+/-2.93 ng x mL(-1), p=0.98) in these subjects. Assuming homogeneous production of PAI-1 by all adipose tissue beds, the contribution of adipose tissue to PAI-1 activity is 3.1% (interquartile range, -11.7, +7.0%) and to PAI-1 antigen 1.6% (interquartile range -14.5, +7.3%). Arteriovenous difference of PAI-1 activity and antigen did not relate to measures of obesity, triglyceride, insulin, fatty acids, or circulating concentrations or adipose tissue production of tumour necrosis factor-alpha or interleukin-6. We conclude that, at least in healthy subjects, subcutaneous adipose tissue does not contribute significantly to circulating levels of PAI-1.
Thrombosis Research 11/1999; 96(1):1-9. · 2.44 Impact Factor
