FoxO proteins in insulin action and metabolism

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There is increasing evidence that Forkhead box ‘Other’ (FoxO) proteins, a subgroup of the Forkhead transcription factor family, have an important role in mediating the effects of insulin and growth factors on diverse physiological functions, including cell proliferation, apoptosis and metabolism. Genetic studies in Caenorhabditis (Caenorhabditis elegans) and Drosophila demonstrate that FoxO proteins are ancient targets of insulin-like signaling involved in the regulation of metabolism and longevity. Studies in mammalian cells reveal that FoxO proteins regulate cell cycle progression and promote resistance to oxidative stress; both in vivo and cell culture studies support the concept that FoxO proteins have an important role in mediating the effects of insulin on metabolism, including its effects on hepatic glucose production. Phosphorylation and acetylation modulate FoxO function and control nuclear–cytoplasmic shuttling, DNA binding and protein–protein interactions. FoxO transcription factors exert positive and negative effects on gene expression, through direct binding to DNA target sites and protein–protein interactions with other transcription factors and coactivators. This paper provides an overview of studies leading to the identification of FoxO proteins as targets of insulin action and the mechanisms mediating the effects of insulin-like signaling on FoxO function, emphasizing the role of FoxO proteins in mediating the effects of insulin on metabolism.

Section snippets

Introduction: identification of FoxO proteins as targets of insulin action

Forkhead box ‘Other’ (FoxO) proteins have emerged as important targets of insulin and growth factor action. Early studies focusing on the regulation of insulin-like growth factor binding protein-1 (IGFBP-1), the major short-term modulator of IGF bioavailability, provided important evidence that Forkhead transcription factors interact with insulin response sequences (IRSs) similar to the IRS first identified in the phosphoenolpyruvate carboxykinase (PEPCK) gene 1, 2. Reporter gene studies with

DNA binding

Several features distinguish FoxO proteins from other Forkhead transcription factors and account for their unique role in insulin and growth factor action. Forkhead proteins all have a highly conserved ‘winged-helix’ structural motif, which comprises the DNA binding domain, known as the Forkhead box, or Fox box, and they are classified based on homology within this region 14, 15. FoxO proteins (also known as Fox ‘Other’ proteins), the most divergent members of the Forkhead family, contain a

Other pathways to FoxO

Recent studies have shown that other pathways also regulate FoxO function. Glucose metabolism has been associated with altered FoxO1 protein stability, an effect that might be mediated through AMP-activated kinase, an important energy sensor [26]. The inhibitor of nuclear factor κB kinase (IKK), which is activated in certain malignancies, can phosphorylate and inhibit the function of FoxO3a [27], and signaling through the Rho/Rho-associated kinase pathway might also be important in regulating

FoxO-interacting proteins

Protein–protein interactions also have a crucial role in mediating the effects of FoxO proteins (Table 2). Transcriptional coactivators, such as CBP, p300, SRC-1 and the peroxisome proliferator-activated receptor-γ (PPAR-γ) coactivator 1α (PGC-1α), are bound by FoxO proteins and can be recruited to promoters with FoxO binding sites 33, 34, 35. Interaction with coactivators is also important for the ability of FoxO proteins to function cooperatively with other transcription factors, including

Physiological roles of FoxO proteins

As indicated in Figure 3, the physiological functions of FoxO proteins have been characterized at different levels. At the cellular level, FoxO proteins can inhibit cellular proliferation, promote apoptosis and enhance resistance to oxidative stress 32, 47, 48, 49. FoxO proteins also contribute to the regulation of metabolism through their effects in the liver, muscle, adipose tissue and pancreas. At the level of complex organisms, alterations in FoxO function affect the process of aging in

New directions

Although progress in understanding the functions of FoxO proteins has occurred at a remarkable rate, much remains to be learned. A new member of the FoxO family (FoxO6) with distinct nuclear–cytoplasmic shuttling functions has been identified in the central nervous system, where it might have a novel role in development [64]. Additional studies to characterize the functions of FoxO proteins in the central nervous system, including regions of the hypothalamus intimately involved in the

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