Putting the brakes on FOXO1 in fat.

The Foxo1 forkhead transcription factor is a critical negative regulator of insulin action. In this issue of The EMBO Journal, Nakae and colleagues (Nakae et al, 2012) describe a novel Foxo1 Co-Repressor (FCoR) protein in adipocytes, showing that FCoR enhances the acetylation of Foxo1 to inhibit Foxo1 activity, promote adipocyte differentiation, and improve insulin sensitivity. The FoxO forkhead transcription factors have emerged as important targets of insulin and growth factor action, participating in a diverse array of biological processes. The Foxo1 isoform is a key regulator of insulin action, integrating cellular responses to changes in nutrient availability and oxidative stress (Accili and Arden, 2004). In the liver, Foxo1 induces gluconeogenesis, impairs mitochondrial metabolism, and promotes lipogenesis. In skeletal muscle, Foxo1 controls the shift from glucose to lipids as a source of fuel during fasting (Furuyama et al, 2003). In adipose tissue, Foxo1 inhibits the differentiation of adipocytes and augments insulin resistance via trans-repression of PPARg (Dowell et al, 2003; Nakae et al, 2003; Fan et al, 2009; Kim et al, 2009). Overall, Foxo1 deletion leads to improved insulin sensitivity (Kitamura et al, 2001). Foxo1 is controlled by post-translational modifications, such as phosphorylation and acetylation, which affect its subcellular location, DNA-binding properties, and transcriptional activity. Following its phosphorylation and activation by insulin and other growth factors, Akt can migrate to the nucleus where it directly phosphorylates Foxo1 (Biggs et al, 1999). Once phosphorylated, Foxo1 is excluded from the nucleus, effectively silencing its transcriptional activity. Foxo1 acetylation provides a second layer of regulation. Foxo1 can be acetylated by CBP and P/CAF and deacetylated by class I–III histone deacetylases such as Sirt1 and Sirt2. Acetylation inhibits Foxo1 activity by three distinct mechanisms: (1) acetylation of lysine residues within the forkhead domain impairs its ability to bind DNA; (2) acetylation of Foxo1 increases Akt-mediated phosphorylation of Ser-253 with subsequent nuclear exclusion; and (3) acetylation of Foxo1 causes nuclear exclusion independent of its phosphorylation state (Matsuzaki et al, 2005; Qiang et al, 2010). In contrast, Foxo1 deacetylation promotes nuclear retention. In an experimental tour-de-force, Nakae et al (2012), further illuminate how Foxo1 function is regulated in adipose tissue through the discovery of a novel Foxo1 co-repressor protein (Figure 1). Using yeast two-hybrid screening of a mouse adipocyte cDNA library, they identified a novel adipose-specific Foxo1 binding partner, named ‘FCoR’ (Foxo1 Co-Repressor). They show that FCoR is a 106-amino acid protein expressed in both white (WAT) and brown (BAT) adipose tissue, and binds to endogenous Foxo1. The authors also demonstrate that FCoR expression is required for adipocyte differentiation, presumably by repressing Foxo1.