Chapter 13 - The forkhead box O family in insulin action and lipid metabolism

Abstract

The forkhead box O (FoxO) family consists of FoxO1, FoxO3, FoxO4, and FoxO6 transcription factors in mammalian cells. These four FoxO members are encoded by four distinct genes, which are situated on different chromosomes and are ubiquitously expressed in central and peripheral tissues. They share in common a “forkhead box” or “winged helix” domain, a highly conserved structural protein motif that is responsible for binding to chromatin DNA in the nucleus of cells. Their carboxyl domains, which are evolutionarily divergent in amino acid sequences, are responsible for interacting with variable cofactors to enhance or inhibit target gene expression via a trans-activation or trans-repression mechanism. The FoxO transcription factors are instrumental for integrating nutritional and hormonal signaling to key functions in diverse pathways including cell metabolism, proliferation, differentiation, oxidative stress, cell survival and senescence, autophagy, and aging. Genetic mutations in the FoxO genes, accompanied by alteration of FoxO expression and activity in cells, are associated with a variety of diseases including obesity, diabetes and cancer, or with altered lifespan in mammals. Among the four FoxO isoforms, FoxO1 is the best characterized one for its role in mediating the inhibitory effect of insulin or insulin-like growth factor on glucose and lipid metabolism. In this chapter, we provide an in-depth review of FoxO1 in insulin action and carbohydrate metabolism. We will review clinical and preclinical evidence that FoxO1 deregulation, resulting from insulin resistance, contributes to the dual pathogenesis of hyperglycemia and hyperlipidemia in obesity and type 2 diabetes. We will also review the role of FoxO1 in macrophages and its contribution to hepatic inflammation and nonalcoholic fatty liver disease. FoxO1 is viewed as a potential therapeutic target for improving glucose and lipid metabolism. We will discuss the potential therapeutic benefits and possible adverse effects of pharmacological inhibition of FoxO1 activity in insulin-resistant subjects with metabolic diseases.