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1.
Regul Pept ; 146(1-3): 189-96, 2008 Feb 07.
Article in English | MEDLINE | ID: mdl-17997171

ABSTRACT

Inflammation is a key component in the development of atherosclerosis, and myocardial infarction (MI); therefore we investigated the association between an interleukin-6 signal transducer (IL6ST)/gp130 polymorphism, gp130 function and risk of MI. Structural modeling suggested that a non-conservative single nucleotide polymorphism in the gp130, Gly148Arg, can change the stability and functional properties of the molecule. In vitro studies were done with BAF/3 cells lacking endogenous gp130. Cells stably transfected with the gp130 148Arg variant proliferated less and showed slightly lower STAT-3 phosphorylation in response to gp130 stimulation as compared to cells transfected with gp130 148Gly. In a prospectively followed hypertensive cohort we identified 167 patients who suffered a MI during the study and compared them to matched controls (mean age 57 years, 73% males, n=482). Carriers of the 148Arg variant (f(Arg)=0.12) of the gp130 receptor had decreased odds ratio for MI in univariate analysis (0.56, 95% CI 0.34-0.91, p=0.02). In conclusion, a genetically determined structural variant of the IL-6 receptor subunit gp130 is, independently of other known risk factors, associated with decreased risk of MI. The variant is also associated with decreased IL-6 responsiveness and could lead to a configuration change in the gp130 receptor.


Subject(s)
Cytokine Receptor gp130/genetics , Hypertension/genetics , Interleukin-6/genetics , Myocardial Infarction/genetics , Polymorphism, Genetic , Adult , Aged , Cells, Cultured , Comorbidity , Female , Genetic Variation , Humans , Hypertension/epidemiology , Male , Middle Aged , Myocardial Infarction/epidemiology
2.
Diabetes ; 55(10): 2915-21, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17003362

ABSTRACT

Several lines of evidence indicate a causal role of the cytokine interleukin (IL)-6 in the development of type 2 diabetes in humans. Two common polymorphisms in the promoter of the IL-6 encoding gene IL6, -174G>C (rs1800795) and -573G>C (rs1800796), have been investigated for association with type 2 diabetes in numerous studies but with results that have been largely equivocal. To clarify the relationship between the two IL6 variants and type 2 diabetes, we analyzed individual data on >20,000 participants from 21 published and unpublished studies. Collected data represent eight different countries, making this the largest association analysis for type 2 diabetes reported to date. The GC and CC genotypes of IL6 -174G>C were associated with a decreased risk of type 2 diabetes (odds ratio 0.91, P = 0.037), corresponding to a risk modification of nearly 9%. No evidence for association was found between IL6 -573G>C and type 2 diabetes. The observed association of the IL6 -174 C-allele with a reduced risk of type 2 diabetes provides further evidence for the hypothesis that immune mediators are causally related to type 2 diabetes; however, because the association is borderline significant, additional data are still needed to confirm this finding.


Subject(s)
Diabetes Mellitus, Type 2/genetics , Interleukin-6/genetics , Polymorphism, Genetic , Promoter Regions, Genetic , Case-Control Studies , Genetics, Population , Humans , Odds Ratio , Risk
3.
Diabetes ; 55(5): 1205-13, 2006 May.
Article in English | MEDLINE | ID: mdl-16644674

ABSTRACT

Interleukin-1 (IL-1) is a major mediator of inflammation that exerts its biological activities through the IL-1 type I receptor (IL-1RI). The body weights of IL-1RI(-/-) mice of both sexes started to deviate from those of wild-type mice at 5-6 months of age and were 20% higher at 9 months of age. Visceral and subcutaneous fat mass, measured by dual-energy X-ray absorptiometry and magnetic resonance imaging, was markedly (1.5- to 2.5-fold) increased. Lean body mass and crown-rump length were also slightly (11 and 5%, respectively) increased, as was serum IGF-I. Obese IL-1RI(-/-) mice were insulin resistant, as evidenced by hyperinsulinemia, decreased glucose tolerance, and insulin sensitivity. To elucidate the mechanisms for the development of obesity, young pre-obese IL-1RI(-/-) mice were investigated. They showed decreased suppression of body weight and food intake in response to systemic leptin treatment. The decreased leptin responsiveness was even more pronounced in older obese animals. Moreover, spontaneous locomotor activity and fat utilization, as measured by respiratory quotient, were decreased in pre-obese IL-1RI(-/-) mice. In conclusion, lack of IL-1RI-mediated biological activity causes mature-onset obesity. This obese phenotype is preceded by decreased leptin sensitivity, fat utilization, and locomotor activity.


Subject(s)
Obesity/genetics , Receptors, Interleukin-1/physiology , Absorptiometry, Photon , Adipose Tissue/anatomy & histology , Aging , Animals , Body Weight , Leptin/blood , Leptin/pharmacology , Mice , Mice, Knockout , Obesity/blood , Organ Size , Receptors, Interleukin-1/deficiency , Receptors, Interleukin-1/genetics
4.
Eur J Endocrinol ; 154(2): 349-54, 2006 Feb.
Article in English | MEDLINE | ID: mdl-16452551

ABSTRACT

OBJECTIVE: Ovariectomized (OVX) mice are known to gain body fat while exposure to estrogens decreases fat mass. We have previously shown that estrogen replacement therapy enhances the expression of receptors for the cytokine, leukemia inhibitory factor (LIF). LIF and other cytokines acting via the gp130 signal transducing receptor have been reported to decrease obesity. In the present study, we investigated whether LIF treatment can reduce obesity in OVX mice. DESIGN: Eight-week-old female C57Bl/6 mice were OVX or sham-operated. The mice were treated with LIF, 30 microg/kg or PBS via daily i.p. injections for 15 days (n = 9-10). METHODS: Dual X-ray absorptiometry and computerized tomography. RESULTS: We found that LIF treatment of OVX mice caused a significant reduction in the weight of white fat depots (P = 0.017) and serum leptin levels (P = 0.011). LIF also caused a significant decrease in brown fat mass (P = 0.036). Treatment with LIF decreased thymus weight but did not affect crown-rump length, femur length, trabecular bone mineral density or the weight of several non-fat organs including the uterus. CONCLUSION: The cytokine, LIF, decreases body fat mass in OVX mice, suggesting that estrogen signaling is not required for this effect.


Subject(s)
Adipose Tissue/drug effects , Interleukin-6/pharmacology , Obesity/drug therapy , Absorptiometry, Photon , Adipose Tissue, Brown/metabolism , Animals , Body Composition/drug effects , Body Weight/drug effects , Female , Leptin/blood , Leukemia Inhibitory Factor , Mice , Mice, Inbred C57BL , Obesity/blood , Obesity/metabolism , Organ Size/drug effects , Ovariectomy , Tomography, X-Ray Computed
5.
Am J Physiol Regul Integr Comp Physiol ; 291(3): R551-7, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16455769

ABSTRACT

Interleukin-6 (IL-6) deficient (-/-) mice develop mature onset obesity. Pharmacological studies have shown that IL-6 has direct lipolytic effects and when administered centrally increases sympathetic outflow. However, the metabolic functions of endogenous IL-6 are not fully elucidated. We aimed to investigate the effect of IL-6 deficiency with respect to cold exposure and cage-switch stress, that is, situations that normally increase sympathetic outflow. Energy metabolism, core temperature, heart rate, and activity were investigated in young preobese IL-6-/- mice by indirect calorimetry together with telemetry. Baseline measurements and the effect of cage-switch stress were investigated at thermoneutrality (30 degrees C) and at room temperature (20 degrees C). The effect of cold exposure was investigated at 4 degrees C. At 30 degrees C, the basal core temperature was 0.6 +/- 0.24 degrees C lower in IL-6-/- compared with wild-type mice, whereas the oxygen consumption did not differ significantly. The respiratory exchange ratio at 20 degrees C was significantly higher and the calculated fat utilization rate was lower in IL-6-/- mice. In response to cage-switch stress, the increase in oxygen consumption at both 30 and 20 degrees C was lower in IL-6-/- than in wild-type mice. The increase in heart rate was lower in IL-6-/- mice at 30 degrees C. At 4 degrees C, both the oxygen consumption and core temperature were lower in IL-6-/- compared with wild-type mice, suggesting a lower cold-induced thermogenesis in IL-6-/- mice. The present results indicate that endogenous IL-6 is of importance for stress- and cold-induced energy expenditure in mice.


Subject(s)
Cold Temperature , Energy Metabolism/physiology , Interleukin-6/deficiency , Interleukin-6/metabolism , Stress, Physiological/physiopathology , Animals , Energy Metabolism/genetics , Female , Interleukin-6/genetics , Male , Mice , Mice, Knockout , Norepinephrine/blood , Thermogenesis/physiology
6.
Endocrinology ; 145(6): 2680-6, 2004 Jun.
Article in English | MEDLINE | ID: mdl-14988384

ABSTRACT

IL-6 is produced and released in large amounts from skeletal muscle during prolonged exercise in both mice and humans, but there are few data indicating the biological significance of this. IL-6 exerts metabolic effects such as stimulating energy expenditure and reducing body fat mass. We have now investigated the effects of IL-6 deficiency on exercise endurance and energy expenditure in preobese and obese IL-6-deficient (IL-6(-/-)) mice. Four-month-old preobese and 7-month-old obese IL-6(-/-) male mice backcrossed to C57BL/6 and their littermate controls were exercised on a treadmill, and energy expenditure was measured as oxygen consumption with the use of indirect calorimetry. The preobese IL-6(-/-) mice were significantly leaner than the control mice, whereas the older IL-6(-/-) mice, as expected, had developed obesity. Resting young, but not older, IL-6(-/-) mice had an elevated respiratory exchange ratio (RER), indicating that they oxidize carbohydrates rather than fat for energy utilization. During exercise, the young and older IL-6(-/-) mice had a reduced endurance and a progressive decrease in oxygen consumption compared with control mice. There was no difference in RER in young IL-6(-/-) mice, whereas RER was enhanced in older IL-6(-/-), mice during exercise. In summary, IL-6(-/-) mice have reduced endurance and energy expenditure during exercise, suggesting that IL-6 is necessary for normal exercise capacity.


Subject(s)
Interleukin-6/metabolism , Obesity/physiopathology , Physical Endurance/physiology , Animals , Body Composition , Energy Metabolism , Glycogen/blood , Interleukin-6/deficiency , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Motor Activity , Obesity/blood , Obesity/metabolism , Pulmonary Gas Exchange
7.
J Clin Endocrinol Metab ; 88(9): 4379-83, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12970313

ABSTRACT

Recently, we demonstrated that intracerebroventricular injection of IL-6 increases energy expenditure and decreases body fat in rodents. Therefore, IL-6 may play a role in appetite and body weight control in the central nervous system. In the present study we evaluated cerebrospinal fluid (CSF) and serum IL-6 levels in humans in relation to body fat content and to CSF and serum levels of leptin. Thirty-two healthy overweight/obese male subjects with a body mass index range of 29.3-36.0 kg/m(2) were studied. Total and sc body fat were measured by dual energy x-ray absorptiometry and computed tomography, respectively. CSF IL-6 levels were in some individuals higher than serum IL-6 levels and correlated negatively with total body weight, sc and total body fat. In contrast, CSF leptin levels were 30-60 times lower than serum leptin levels and correlated positively with serum leptin, body weight, sc and total body fat. Furthermore, there was a negative correlation between CSF IL-6 and leptin. In conclusion, CSF IL-6 differs in many ways from CSF leptin. CSF IL-6 may be locally produced rather than serum derived, and body fat-regulating regions in the central nervous system may be exposed to insufficient IL-6 levels in more severe obesity.


Subject(s)
Adipose Tissue/anatomy & histology , Body Composition/physiology , Central Nervous System/metabolism , Interleukin-6/cerebrospinal fluid , Obesity/cerebrospinal fluid , Absorptiometry, Photon , Adult , Body Weight/physiology , Enzyme-Linked Immunosorbent Assay , Humans , Leptin/blood , Leptin/cerebrospinal fluid , Male , Middle Aged , Obesity/pathology , Serum Albumin/metabolism
8.
Growth Horm IGF Res ; 13 Suppl A: S28-32, 2003 Aug.
Article in English | MEDLINE | ID: mdl-12914723

ABSTRACT

We conducted an experimental study examining the site and mechanism of action of the anti-obesity effect of interleukin-6 (IL-6) in mice and rats. We used dual energy X-ray absorptiometry (DEXA) and computerized tomography to investigate the body composition of mice with knockout of the IL-6 gene and wild-type control mice. Rats were treated with IL-6 or vehicle through intracerebroventricular (ICV) cannulae. Energy expenditure was measured as oxygen consumption by indirect calorimetry in metabolic chambers. Results showed that the mice lacking IL-6 increased in body weight compared with wild-type mice from 6 months of age onward, although there was no marked difference in food intake between the pre-obese IL-6 knockout mice and the wild-type mice. IL-6 given as a single ICV injection to rats stimulated oxygen consumption; whereas, the same doses were ineffective when given peripherally. Chronic ICV IL-6 treatment decreased body weight and fat mass in rodents. Administration of IL-6 may decrease fat mass in mice and rats by stimulating energy expenditure at the CNS level, possibly in the hypothalamus.


Subject(s)
Anti-Obesity Agents/pharmacology , Interleukin-6/pharmacology , Adipose Tissue/drug effects , Animals , Blood Glucose/metabolism , Body Weight/drug effects , Brain/drug effects , Energy Metabolism/drug effects , Injections, Intraventricular , Interleukin-6/physiology , Mice , Mice, Knockout , Obesity/drug therapy , Obesity/metabolism , Oxygen Consumption/drug effects , Rats
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