Nuclear FoxO1 inflames insulin resistance.

Chronic activation of macrophage-mediated inflammatory signals in insulin-sensitive metabolic tissues is thought to be one of the causes of insulin resistance—one of the hallmarks of the metabolic syndrome. However, the mechanisms, components and dynamics by which this inflammatory response is spatially and temporally regulated are not completely understood. In this issue of The EMBO Journal, Olefsky and colleagues (Fan et al, 2010) report that FoxO1, which is suppressed by the action of AKT, triggers the Tlr4 inflammatory signalling pathway in macrophages. The authors further establish that inflammatory signalling pathways are also able to signal back to and suppress the activity of FoxO1 through AKT. The findings of this paper suggest an intriguing regulatory transcriptional/signalling loop in macrophages that may contribute to maintain and exacerbate inflammation and insulin resistance in other cell types such as adipocytes. Studies by many different laboratories have provided key evidence that, in both mouse models and humans, chronic inflammation is one of the pivotal mechanisms by which obesity is linked to insulin resistance (Hotamisligil et al, 1993; Weisberg et al, 2003; Xu et al, 2003; Cai et al, 2005; Solinas et al, 2007). Collectively, the picture that emerges from this research is that there is a hand-in-hand relationship between the signal transduction pathways that are involved in the control of the inflammatory cascade in insulin-sensitive metabolic tissues and the development of insulin resistance. The work from Olefsky’s laboratory published in this issue of The EMBO Journal adds another important piece to this picture from the vantage point of macrophage-mediated inflammation and the Forkhead transcrtiption factor, FoxO1 (Figure 1). FoxO proteins are direct substrates of Akt, which controls FoxO transcriptional activity by regulating its cytoplasmic/ nuclear translocation (Brunet et al, 1999). Due to the pivotal role of Akt in a diverse array of biological processes, the activity of FoxO proteins has been implicated in apoptosis, cell cycle, inflammation and metabolic pathways. Interestingly, FoxO1 is thought to account for a large part of the transcriptional metabolic effects of insulin signalling in mammals (Accili and Arden, 2004). For example, part of the suppressive effects of insulin on hepatic glucose output is