| 1. |
- Jansson, John-Olov, 1954, et al.
(författare)
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On the site and mechanism of action of the anti-obesity effects of interleukin-6.
- 2003
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Ingår i: 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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Tidskriftsartikel (refereegranskat)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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| 2. |
- Stenlöf, Kaj, 1965, et al.
(författare)
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Interleukin-6 levels in the central nervous system are negatively correlated with fat mass in overweight/obese subjects.
- 2003
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Ingår i: The Journal of clinical endocrinology and metabolism. - 0021-972X. ; 88:9, s. 4379-83
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Tidskriftsartikel (refereegranskat)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.
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| 3. |
- Wallenius, Kristina, 1973, et al.
(författare)
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Liver-derived IGF-I regulates GH secretion at the pituitary level in mice.
- 2001
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Ingår i: Endocrinology. - 0013-7227. ; 142:11, s. 4762-70
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Tidskriftsartikel (refereegranskat)abstract
- We have reported that liver-specific deletion of IGF-I in mice (LI-IGF-I-/-) results in decreased circulating IGF-I and increased GH levels. In the present study, we determined how elimination of hepatic IGF-I modifies the hypothalamic-pituitary GH axis to enhance GH secretion. The pituitary mRNA levels of GH releasing factor (GHRF) receptor and GH secretagogue (GHS) receptor were increased in LI-IGF-I-/- mice, and in line with this, their GH response to ip injections of GHRF and GHS was increased. Expression of mRNA for pituitary somatostatin receptors, hypothalamic GHRF, somatostatin, and neuropeptide Y was not altered in LI-IGF-I-/- mice, whereas hypothalamic IGF-I expression was increased. Changes in hepatic expression of major urinary protein and the PRL receptor in male LI-IGF-I-/- mice indicated an altered GH release pattern most consistent with enhanced GH trough levels. Liver weight was enhanced in LI-IGF-I-/- mice of both genders. In conclusion, loss of liver-derived IGF-I enhances GH release by increasing expression of pituitary GHRF and GHS receptors. The enhanced GH release in turn affects several liver parameters, in line with the existence of a pituitary-liver axis.
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| 4. |
- Wallenius, Ville, 1970, et al.
(författare)
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Interleukin-6-deficient mice develop mature-onset obesity.
- 2002
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Ingår i: Nature medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 8:1, s. 75-9
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Tidskriftsartikel (refereegranskat)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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| 5. |
- Wernstedt, Ingrid, 1978, et al.
(författare)
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Increased levels of acylation-stimulating protein in interleukin-6-deficient (IL-6(-/-)) mice
- 2006
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 147:6, s. 2690-5
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Tidskriftsartikel (refereegranskat)abstract
- IL-6-deficient (IL-6(-/-)) mice develop obesity at 6-7 months of age. To elucidate the mechanisms of this mature-onset obesity, global gene expression profiles of 3-month-old preobese IL-6(-/-) were compared with those of IL-6(+/+) mice using DNA arrays. Genes that were up-regulated in IL-6(-/-) mice included the factors transthyretin and properdin in white adipose tissue and adipsin in muscle. These factors have been shown to influence the formation of acylation-stimulating protein (ASP), a cleavage product of complement C3. ASP stimulates the synthesis of triacylglycerol in adipocytes, and ASP-deficient mice are resistant to diet-induced obesity. In line with the increases in transthyretin, properdin, and adipsin, ASP levels in serum were increased by 31-54% in IL-6(-/-) compared with IL-6(+/+) mice. Furthermore, IL-6 replacement treatment in IL-6(-/-) mice decreased ASP levels significantly by 25-60%. In conclusion, ASP levels are increased in preobese IL-6(-/-) mice. This increase may result in increased triacylglycerol formation and uptake in IL-6(-/-) adipocytes and thereby contribute to the development of obesity in IL-6(-/-) mice.
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| 6. |
- Fäldt, Jenny, 1971, et al.
(författare)
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Reduced exercise endurance in interleukin-6-deficient mice
- 2004
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Ingår i: Endocrinology. - 0013-7227. ; 145:6, s. 2680-6
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Tidskriftsartikel (refereegranskat)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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| 7. |
- Isaksson, Olle, 1943, et al.
(författare)
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The somatomedin hypothesis revisited in a transgenic model.
- 2001
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Ingår i: 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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Tidskriftsartikel (refereegranskat)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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| 8. |
- Sjögren, Klara, 1970, et al.
(författare)
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Effects of liver-derived insulin-like growth factor I on bone metabolism in mice.
- 2002
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Ingår i: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. - 0884-0431. ; 17:11, s. 1977-87
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor (IGF) I is an important regulator of both skeletal growth and adult bone metabolism. To better understand the relative importance of systemic IGF-I versus locally expressed IGF-I we have developed a transgenic mouse model with inducible specific IGF-I gene inactivation in the liver (LI-IGF-I-/-). These mice are growing normally up to 12 weeks of age but have a disturbed carbohydrate and lipid metabolism. In this study, the long-term effects of liver-specific IGF-I inactivation on skeletal growth and adult bone metabolism were investigated. The adult (week 8-55) axial skeletal growth was decreased by 24% in the LI-IGF-I-/- mice whereas no major reduction of the adult appendicular skeletal growth was seen. The cortical cross-sectional bone area, as measured in the middiaphyseal region of the long bones, was decreased in old LI-IGF-I-/- mice. This reduction in the amount of cortical bone was caused mainly by decreased periosteal circumference and was associated with a weaker bone determined by a decrease in ultimate load. In contrast, the amount of trabecular bone was not decreased in the LI-IGF-I-/- mice. DNA microarray analysis of 30-week-old LI-IGF-I-/- and control mice indicated that only four genes were regulated in bone whereas approximately 40 genes were regulated in the liver, supporting the hypothesis that liver-derived IGF-I is of minor importance for adult bone metabolism. In summary, liver-derived IGF-I exerts a small but significant effect on cortical periosteal bone growth and on adult axial skeletal growth while it is not required for the maintenance of the trabecular bone in adult mice.
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| 9. |
- Sjögren, Klara, 1970, et al.
(författare)
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Liver-derived IGF-I is of importance for normal carbohydrate and lipid metabolism.
- 2001
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Ingår i: Diabetes. - 0012-1797. ; 50:7, s. 1539-45
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Tidskriftsartikel (refereegranskat)abstract
- IGF-I is important for postnatal body growth and exhibits insulin-like effects on carbohydrate metabolism. The function of liver-derived IGF-I is still not established, although we previously demonstrated that liver-derived IGF-I is not required for postnatal body growth. Mice whose IGF-I gene in the liver was inactivated at 24 days of age were used to investigate the long-term role of liver-derived IGF-I for carbohydrate and lipid metabolism. Serum levels of leptin in these mice were increased by >100% at 3 months of age, whereas the fat mass of the mice was decreased by 25% at 13 months of age. The mice became markedly hyperinsulinemic and yet normoglycemic, indicating an adequately compensated insulin resistance. Furthermore, they had increased serum levels of cholesterol. We conclude that liver-derived IGF-I is of importance for carbohydrate and lipid metabolism.
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| 10. |
- Skrtic, Stanko, 1970, et al.
(författare)
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Possible roles of insulin-like growth factor in regulation of physiological and pathophysiological liver growth.
- 2001
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Ingår i: Hormone research. - 0301-0163. ; 55 Suppl 1, s. 1-6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/AIMS: Almost all circulating insulin-like growth factor-1 (IGF-1) is produced and secreted from the liver. However, the possible role of IGF-1 in local regulation of liver functions including liver growth is unclear. In the present study, we investigated the role of IGF-1 on liver growth in vivo and in hepatic stellate cell function in vitro. RESULTS: Liver-specific knock-out of the IGF-1 gene by use of the cre-loxP system caused enhanced liver growth, possibly reflecting increased growth hormone (GH) secretion due to decreased negative feedback by IGF-1. Studies on cultured rat hepatic stellate cells (HSC) showed that IGF-1 and hepatocyte-conditioned medium (PCcM) time- and dose-dependently increased hepatocyte growth factor (HGF) mRNA and HGF immunoreactivity. IGF-1 and PCcM also enhanced DNA synthesis in the HSC cultures. The PCcM did not contain bioactive IGF-1 and was also able to stimulate proliferation when prepared under serum- and hormone-free conditions. CONCLUSION: In vivo results show that IGF-1 is not essential for normal growth of the intact liver. The in vitro results indicate that both IGF-1 and IGF- 1-independent factor(s) from hepatocytes can stimulate HGF production by HSC. It remains to be investigated whether these effects are of importance for liver regeneration or pathological conditions.
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| 11. |
- Wallenius, Kristina, 1973
(författare)
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Insulin-like Growth Factor-I (IGF-I) and Interleukin-6 (IL-6) regulate body fat
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this thesis was to investigate the role of insulin-like growth factor-I (IGF-I) and interleukin-6 (IL-6) in the regulation of metabolism and body fat mass. Circulating IGF-I is mainly liver derived, while a large part of circulating IL-6 is produced by adipose tissue.We have used a liver-specific and inducible IGF-I knockout (LI-IGF-I-/-) mouse model to study the role of liver derived IGF-I in the regulation of body fat. The LI-IGF-I-/- mice had decreased total body fat measured by dual-energy X-ray absorptiometry (DXA) and dissection of fat pads. Serum IGF-I levels were decreased by 85% in the LI-IGF-I-/- mice, while growth hormone (GH) levels were increased, due to lack of IGF-I feedback. Moreover, the LI-IGF-I-/- mice had increased numbers of pituitary GH-releasing factor (GHRF) receptors and GH-secretagogue (GHS) receptors and increased GH responsiveness to GHRF and GHS treatment. The LI-IGF-I-/- mice had elevated insulin levels both under basal conditions and after an intravenous glucose challenge, whereas serum glucose levels were not different from controls. The elevated insulin levels may be caused by the lack of insulin-like effects of IGF-I, or by the diabetogenic effect of GH. GH may also be responsible for the decreased fat mass due to its lipolytic effects.We found that IL-6 deficient (IL-6-/-) mice developed mature-onset obesity, as well as insulin and leptin resistance. Peripheral treatment with low doses of IL-6 partly reversed the obesity in IL-6-/- mice, but had no effect in control mice. To study the mechanism and site of action for the antiobesity effect of IL-6, we treated rats with a single IL-6 injection intracerebroventricularly (ICV) and found that ICV IL-6 acutely increased energy expenditure, while peripheral treatment had no such effect. Moreover, chronic treatment with IL-6 ICV for two weeks decreased body weight, total fat pad weight and serum levels of the fat-derived hormone leptin.The results from this thesis show that liver derived IGF-I and centrally acting IL-6 are important regulators of fat mass in mice.
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