Metabolic effects of interleukin-6

• The levels of the cytokine interleukin-6 (IL-6) in the circulation are positively correlated with indices of obesity and metabolic disturbances. Paradoxically, plasma IL-6 levels increase markedly during prolonged and strenuous exercise, mainly due to increased production and release from working skeletal muscle. IL-6 increases lipolysis both in vivo and directly in fat tissue in vitro. Moreover, IL-6 affects energy balance, as centrally administered IL-6 increases energy expenditure in rats, and as IL-6 deficient (-/-) mice develop mature onset obesity. The general aim of this thesis was to further investigate the role of IL-6 in the regulation of metabolism. We had five specific questions; 1) Is IL-6 needed for a normal exercise capacity? 2) By what mechanism may IL-6 affect white adipose tissue? 3) Is IL-6 needed for normal sympathetic nervous system-mediated responses to psychological stress and/or to acute cold exposure? 4) Are cerebrospinal fluid (CSF) levels of IL-6 related to circulating levels of IL-6 and to body fat? and 5) Is the common -174 G/C single nucleotide polymorphism (SNP) of the human IL-6 gene promoter associated with body fat?To answer the first three questions we compared IL-6 -/- mice with littermate controls (WT) and the last two questions were elucidated in human subjects. In comparison with WT mice, IL-6 -/- mice had lower exercise endurance, lower oxygen consumption and heart rate in response to new-cage stress, and lower oxygen consumption and core temperature in response to cold temperature. Moreover, IL-6 -/- mice had lower lipid utilization and higher levels of acylation stimulating protein (ASP), a hormone that suppresses net lipolysis. In human males, the CSF levels of IL-6 did not correlate to circulating IL-6, but were negatively correlated to fat mass. Furthermore, the C genotype of the -174 G/C SNP in the human IL-6 gene promoter, that is the least effective initiator of IL-6 transcription, was associated with overweight in two Scandinavian study populations. The present results suggest that IL-6 is needed for increased energy expenditure in response to psychological stress and to cold exposure. These effects may be due to IL-6 stimulated sympathetic outflow at the level of the central nervous system and constitute a possible mechanism behind the mature-onset obesity in IL-6 -/- mice. In the periphery, IL-6 suppresses ASP, which may partly explain the increased fat mass and decreased lipid utilization in IL-6 -/- mice. In human subjects, the weak -174 C allele of the IL-6 gene promoter and low CSF IL-6 levels are associated with increased body fat. In conclusion, IL-6 seems to be a significant player in the metabolic regulation of fat mass in both mice and men.

Nyckelord

IL-6

cytokine

obesity

energy expenditure

lipolysis

ASP

sympathetic nervous system

exercise

-174 G/C IL-6 polymorphism

fat mass

stress response

cerebrospinal fluid

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