Insulin's expanding control of forkheads

Like athletic ability, metabolic tone is recognized to vary greatly among individuals. The ability to oxidize or store fat, build up muscle glycogen, withstand fasting, or respond to insulin with decreased blood glucose levels can indeed change greatly even within the same individual, based on such factors as age, frequency of exercise, and diet. Such changes in metabolic tone re flect the collective abundances and activities of hundreds of enzymes and other metabolic proteins, integrated within complex networks of metabolic pathways in multiple tissues. Much of this is driven by the overall profile of transcriptional activities of the genes encoding these proteins. Among the major nuclear regulators of metabolic gene expression, transcription factors that belong to the forkhead gene family have garnered increasing attention. The Drosophila embryo forkhead mutant displays dual projections at the head, hence the name, and this fly gene shares a 110-aa DNA binding domain with 39 forkhead genes in humans (for review, see ref. 1). At least six of these gene products (see ref. 2 for nomenclature), Foxo1, Foxo3a, Foxo4 (previously termed FKHR, FKHRL1, and AFX1) and Foxa1, Foxa2, and Foxa3 (previously termed HNF3α, HNF3β, and HNF3γ) appear to share major roles controlling the development of key metabolic tissues such as pancreatic islet cells and liver. They also regulate dozens of metabolic genes. For example, both Foxo and Foxa transcription factors are known to up-regulate key enzymes in the hepatic gluconeogenesis pathway, which prevents hypoglycemia in fasting (3, 4). In this issue of PNAS, Wolfrum et al. show how Foxa2a may be regulated by insulin (5). Several lines of research have recently converged to highlight the Foxo subfamily as particularly exciting regulators of cell function. First, they are the closest orthologs to DAF-16, a Caenorhabditis elegans gene product found in genetic screens to …