| 1. |
- Wallenius, Ville, 1970, et al.
(author)
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Interleukin-6-deficient mice develop mature-onset obesity.
- 2002
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In: Nature medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 8:1, s. 75-9
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Journal article (peer-reviewed)abstract
- The immune-modulating cytokine interleukin-6 (IL-6) is expressed both in adipose tissue and centrally in hypothalamic nuclei that regulate body composition. We investigated the impact of loss of IL-6 on body composition in mice lacking the gene encoding IL-6 (Il6-/- mice) and found that they developed mature-onset obesity that was partly reversed by IL-6 replacement. The obese Il6-/- mice had disturbed carbohydrate and lipid metabolism, increased leptin levels and decreased responsiveness to leptin treatment. To investigate the possible mechanism and site of action of the anti-obesity effect of IL-6, we injected rats centrally and peripherally with IL-6 at low doses. Intracerebroventricular, but not intraperitoneal IL-6 treatment increased energy expenditure. In conclusion, centrally acting IL-6 exerts anti-obesity effects in rodents.
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| 2. |
- Wernstedt, Ingrid, 1978, et al.
(author)
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A common polymorphism in the interleukin-6 gene promoter is associated with overweight
- 2004
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In: Int J Obes Relat Metab Disord. ; 28:10, s. 1272-9
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Human body fat mass is to a large extent genetically determined, but little is known about the susceptibility genes for common obesity. Interleukin-6 (IL-6) suppresses body fat mass in rodents, and IL-6 treatment increases energy expenditure in both rodents and humans. The -174 G/C single-nucleotide polymorphism (SNP) in the IL-6 gene promoter is common in many populations, and -174 C-containing promoters have been found to be weaker enhancers of transcription. Moreover, a SNP at position -572 in the IL-6 promoter has recently been reported to affect transcription. The objective was to investigate the association between the IL-6 gene promoter SNPs and obesity. DESIGN: Trans-sectional association study of IL-6 gene promoter SNPs and indices of obesity. SUBJECTS: Two study populations, the larger one consisting of hypertensive individuals (mean age 57 y, 73% males, n=485) and the other consisting of 20 y younger nonobese healthy females (n=74). MEASUREMENTS: Genotyping for the -174 IL-6 G/C and the -572 G/C SNPs, body mass index (BMI), serum leptin levels, serum IL-6 levels, C-reactive protein, fasting blood glucose and various blood lipids. RESULTS: The common -174 C allele (f(C)=0.46), but not any -572 allele, was associated with higher BMI and higher serum leptin levels in both study populations. In the larger population, there were significant odds ratios for the association of CC (2.13) and GC (1.76) genotypes with overweight (BMI>25 kg/m(2)). Moreover, as the C allele was common, it accounted for a significant population-attributable risk of overweight (12%; CI 2-21%), although its average effect was modest in this sample. CONCLUSION: Genetically determined individual differences in production of IL-6 may be relevant for the regulation of body fat mass.
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| 3. |
- Fäldt, Jenny, 1971, et al.
(author)
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Reduced exercise endurance in interleukin-6-deficient mice
- 2004
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In: Endocrinology. - 0013-7227. ; 145:6, s. 2680-6
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Journal article (peer-reviewed)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.
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| 4. |
- Isaksson, Olle, 1943, et al.
(author)
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Metabolic functions of liver-derived (endocrine) insulin-like growth factor I.
- 2001
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In: Hormone research. - 0301-0163. ; 55 Suppl 2, s. 18-21
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Journal article (peer-reviewed)abstract
- Until now it has been difficult to determine the relative importance of locally produced (autocrine/paracrine) versus systemically derived (endocrine) insulin-like growth factor I (IGF-I) in the intact organism. We recently eliminated IGF-I production in the livers of mice using the Cre/loxP recombination system. These mice displayed a reduction in serum IGF-I levels of more than 80%, but demonstrated normal body growth, suggesting that autocrine/paracrine-acting IGF-I, but not endocrine-acting IGF-I, regulates body growth. Long-term metabolic studies of mice in which IGF-I production had been inactivated in the liver, have shown that the mice have decreased fat mass, but increased serum levels of insulin and cholesterol. Despite the marked increase in plasma insulin following glucose administration, the glucose elimination was not altered in these animals. Thus, the mice showed an adequately compensated insulin resistance. In conclusion, liver-derived or endocrine IGF-I is not required for post-natal statural growth, but seems to be of vital importance for normal carbohydrate and lipid metabolism.
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| 5. |
- Isaksson, Olle, 1943, et al.
(author)
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The somatomedin hypothesis revisited in a transgenic model.
- 2001
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In: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. - 1096-6374. ; 11 Suppl A
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Journal article (peer-reviewed)abstract
- Studies of insulin-like growth factor I (IGF-I) gene knockout mice models have clearly shown that IGF-I is necessary for prenatal as well as postnatal body growth in mice. Clinical studies of a patient with an IGF-I gene defect which caused complete absence of IGF-I, verified that it is important for intrauterine and postnatal growth. Recent studies of mice with liver-specific and inducible IGF-I gene knockout indicated that liver-derived IGF-I is not necessary for postnatal body growth, although serum IGF-I levels are decreased by more than 80% in these mice. Therefore, extrahepatic IGF-I is sufficient for maintenance of postnatal body growth in mice. Further investigations are needed to assess whether liver-derived circulating IGF-I is essential for other biological functions.
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| 6. |
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| 7. |
- Jansson, John-Olov, 1954, et al.
(author)
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On the site and mechanism of action of the anti-obesity effects of interleukin-6.
- 2003
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In: Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society. - 1096-6374. ; 13 Suppl A
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Journal article (peer-reviewed)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.
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| 8. |
- Lall, S, et al.
(author)
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Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues.
- 2001
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In: Biochemical and biophysical research communications. - : Elsevier BV. - 0006-291X. ; 280:1, s. 132-8
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Journal article (peer-reviewed)abstract
- Growth hormone secretagogues (GHSs) stimulate growth hormone (GH) secretion, which is lipolytic. Here we compared the effects of twice daily s.c. treatment of GH and the GHS, ipamorelin, on body fat in GH-deficient (lit/lit) and in GH-intact (+/lit and +/+) mice. In +/lit and lit/lit mice ipamorelin induced a small (15%) increase in body weight by 2 weeks, that was not further augmented by 9 weeks. GH treatment markedly enhanced body weight in both groups. Ipamorelin also increased fat pad weights relative to body weight in both lit/lit and +/lit mice. Two weeks GHS treatment (ipamorelin or GHRP-6) also increased relative body fat, quantified by in vivo dual energy X-ray absorpiometry (DEXA) in GH-intact mice. GH decreased relative fat mass in lit/lit mice and had no effect in GH-intact mice. Treatment with GHS, but not GH, increased serum leptin and food intake in GH-intact mice. Thus, GHSs increase body fat by GH-independent mechanisms that may include increased feeding.
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| 9. |
- Ohlsson, Claes, 1965, et al.
(author)
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Effects of growth hormone and insulinlike growth factor-I on body growth and adult bone metabolism.
- 2000
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In: Current opinion in rheumatology. - 1040-8711. ; 12:4, s. 346-8
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Journal article (peer-reviewed)abstract
- The anabolic action of growth hormone (GH) on bone is well demonstrated by the short stature and delayed bone maturation in children with GH deficiency and in acromegalic patients with increased cortical bone mass. The body growth is regulated by growth hormone and insulin-like growth factor-I (IGF-I). The classic somatomedin hypothesis of this regulation is that most IGF-I in the blood originates in the liver and that body growth is controlled by the concentration of IGF-I in the blood. We have recently abolished IGF-I production in the livers of mice by using the Cre/loxP recombination system. The mice, in which IGF-I production had been inactivated in the liver, displayed a more than 80% reduction in serum IGF-I. In contrast, they demonstrated a normal postnatal growth, indicating that extrahepatic, autocrine/paracrine-acting IGF-I is the main determinant of postnatal growth. GH is also important for normal adult bone remodeling. Adults with GH deficiency have reduced bone mass, and GH treatment increases bone mass in GH-deficient adults. Future clinical studies will determine whether some patients with decreased bone mass for other reasons will benefit from treatment with GH alone or in combination with other treatments.
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| 10. |
- Ohlsson, Claes, 1965, et al.
(author)
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The relative importance of endocrine versus autocrine/paracrine insulin-like growth factor-I in the regulation of body growth.
- 2000
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In: Pediatric nephrology (Berlin, Germany). - 0931-041X. ; 14:7, s. 541-3
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Journal article (peer-reviewed)abstract
- Body growth is regulated by growth hormone (GH) and insulin-like growth factor-I (IGF-I). The classical somatomedin hypothesis of this regulation is that most IGF-I in the blood originates in the liver and that body growth is controlled by the concentration of IGF-I in the blood. We have recently abolished IGF-I production in the livers of mice by using the Cre/loxP recombination system. These mice displayed a more than 75% reduction in serum IGF-I associated with increased serum levels of GH. In contrast, they demonstrated a normal postnatal growth, indicating that extrahepatic, autocrine/paracrine-acting IGF-I is the main determinant of postnatal growth. Thus, the "classical" somatomedin hypothesis needs revision. We propose the "dual somatomedin hypothesis" according to which: (1) autocrine/paracrine IGF-I is the main determinant of postnatal body growth and (2) liver-derived, endocrine-acting, IGF-I exerts negative feedback on GH secretion and possibly also exerts other effects on carbohydrate and lipid metabolism.
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