Novel repressor regulates insulin sensitivity through interaction with Foxo1

Forkhead box‐containing protein o (Foxo) 1 is a key transcription factor in insulin and glucose metabolism. We identified a F oxo1‐ CoR epressor (FCoR) protein in mouse adipose tissue that inhibits Foxo1's activity by enhancing acetylation via impairment of the interaction between Foxo1 and the deacetylase Sirt1 and via direct acetylation. FCoR is phosphorylated at Threonine 93 by catalytic subunit of protein kinase A and is translocated into nucleus, making it possible to bind to Foxo1 in both cytosol and nucleus. Knockdown of FCoR in 3T3‐F442A cells enhanced expression of Foxo target and inhibited adipocyte differentiation. Overexpression of FCoR in white adipose tissue decreased expression of Foxo‐target genes and adipocyte size and increased insulin sensitivity in Lepr db/db mice and in mice fed a high‐fat diet. In contrast, Fcor knockout mice were lean, glucose intolerant, and had decreased insulin sensitivity that was accompanied by increased expression levels of Foxo‐target genes and enlarged adipocytes. Taken together, these data suggest that FCoR is a novel repressor that regulates insulin sensitivity and energy metabolism in adipose tissue by acting to fine‐tune Foxo1 activity. This study characterizes a novel Foxo1 CoRepressor (FCoR) that regulates insulin sensitivity and energy metabolism as revealed by whole‐body knockout. As target of PKA phosphorylation, FCoR modulates Foxo's acetylation known to control Foxo's biological activity.