Insulin-like Growth Factor-I (IGF-I) and Interleukin-6 (IL-6) regulate body fat

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.