IL-6 and metabolism—new evidence and new questions

Abstract

Does the cytokine IL-6 play a role in the regulation of metabolism? From a rather unexciting existence as a lacklustre, but dependable player in the textbook version of the inflammatory response, IL-6 has recently taken centre stage in the search for culprits underlying the inflammatory component of the metabolic syndrome. Reduced insulin action following in vitro exposure of cultured adipose and hepatocyte cells to IL-6 has been submitted as evidence strongly implicating IL-6 in the direct induction of insulin resistance [1–4]. In contrast, data indicating that IL-6 deficiency in mice leads to obesity and insulin resistance provides evidence against a causative effect of IL-6 in insulin resistance [5]. Furthermore, contraction-stimulated release of IL-6 from skeletal muscle has been coupled to positive metabolic effects associated with exercise, such as the enhancement of insulin sensitivity [6]. Numerous explanations for these two divergent opinions have been put forward, including differences in model systems, chronic versus pulsatile exposure, and in vitro vs in vivo effects [7, 8]. In this issue of Diabetologia, Franckhauser and colleagues add another piece to the puzzle [9]. In an elegant set of experiments, circulating IL-6 levels were increased by introducing a cytomegalovirus-driven Il6 gene into several skeletal muscle groups in the mouse hindlimb by electrotransfer. This gene manipulation results in a rapid (within days) and sustained elevation of circulating IL-6 levels in an in vivo system. What is the effect of the enhanced whole body delivery of IL-6? Certainly, it appears that adipose cells do not thrive in the presence of IL-6. Mice lost 20% of their body weight in just 1 week, with the actual fat pad weight dropping by a remarkable 75%, and the remaining adipose cells appearing significantly smaller. Leptin levels fell in parallel with the reduction in fat mass. More surprising was the paradoxical reduction in circulating adiponectin levels (see Fig. 1). Despite the expeditious reduction in fat mass, the Il6expressing mice did not alter their food intake, suggesting that IL-6 is promoting increased energy expenditure and enhanced fat oxidation. The enhanced reliance on lipid as an energy source is confirmed by reduced circulating NEFA and triacylglycerol. Skeletal muscle glucose uptake in the basal state was reduced, again possibly pointing to a preferential utilisation of lipids. In response to a glucose challenge, Il6-expressing mice disposed of glucose more efficiently, suggesting that they are not insulin resistant per se. The latter issue is, however, complicated by the fact that the elevation in circulating IL-6 is accompanied by hypoglycaemia, which appears to stem from reduced hepatic glucose production, and an inappropriate fasting hyperinsulinaemia (postprandial insulin does not appear elevated above levels observed in control mice). The hyperinsulinaemia is accompanied by an unexpected increase in beta cell insulin content. Il6 overexpression also leads to increased Diabetologia (2008) 51:1097–1099 DOI 10.1007/s00125-008-1019-7