Over - expression of Foxf 2 in adipose tissue is associated with lower 1 levels of IRS 1 and decreased glucose uptake in vivo

31 Many members of the forkhead genes family of transcription factors have been implicated as 32 important regulators of metabolism, in particular glucose homeostasis e.g. Foxo1, Foxa3 and 33 Foxc2. The purpose of this study was to exploit the possibility that yet unknown members of 34 this gene family play a role in regulating glucose tolerance in adipocytes. We identified Foxf2 35 in a screen for adipose expressed forkhead genes. In vivo over-expression of Foxf2 in an 36 adipose tissue restricted fashion demonstrated that such mice display a significantly induced 37 insulin secretion in response to an intravenous glucose load as compared with wild type 38 littermates. In response to increased Foxf2 expression, Irs1 mRNA and protein levels are 39 significantly down regulated in adipocytes, however the ratio of serine versus tyrosine 40 phosphorylation IRS1 seems to remain unaffected. Furthermore, adipocytes over-expressing 41 FOXF2 have a significantly lower insulin mediated glucose uptake compared with wild type 42 adipocytes. These findings argue that Foxf2 is a previously unrecognized regulator of cellular 43 and systemic whole body glucose tolerance, at least in part, due to lower levels of IRS1. 44 Foxf2 and its downstream target genes can provide new insights with regard to identification 45 of novel therapeutic targets. 46