FoxO integration of insulin signaling with glucose and lipid metabolism

Abstract

The forkhead box O family consists of FoxO1, FoxO3, FoxO4 and FoxO6 proteins in mammals. Expressed ubiquitously in the body, the four FoxO isoforms share in common the amino DNA-binding domain, known as 'forkhead box' domain. They mediate the inhibitory action of insulin or insulin-like growth factor on key functions involved in cell metabolism, growth, differentiation, oxidative stress, senescence, autophagy and aging. Genetic mutations in FoxO genes or abnormal expression of FoxO proteins are associated with metabolic disease, cancer or altered lifespan in humans and animals. Of the FoxO family, FoxO6 is the least characterized member and is shown to play pivotal roles in the liver, skeletal muscle and brain. Altered FoxO6 expression is associated with the pathogenesis of insulin resistance, dietary obesity and type 2 diabetes and risk of neurodegeneration disease. FoxO6 is evolutionally divergent from other FoxO isoforms. FoxO6 mediates insulin action on target genes in a mechanism that is fundamentally different from other FoxO members. Here, we focus our review on the role of FoxO6, in contrast with other FoxO isoforms, in health and disease. We review the distinctive mechanism by which FoxO6 integrates insulin signaling to hepatic glucose and lipid metabolism. We highlight the importance of FoxO6 dysregulation in the dual pathogenesis of fasting hyperglycemia and hyperlipidemia in diabetes. We review the role of FoxO6 in memory consolidation and its contribution to neurodegeneration disease and aging. We discuss the potential therapeutic option of pharmacological FoxO6 inhibition for improving glucose and lipid metabolism in diabetes.

Keywords: FoxO1; FoxO3; FoxO4; FoxO6; diabetes; glucose metabolism; insulin signaling; lipid metabolism; obesity.

Fig. 1. Schematic depiction of the mouse FoxO6 protein

FoxO6 is characterized by its amino DNA binding and carboxyl trans-activation domains. Within the DNA binding domain are the bipartite nuclear localization signal (NLS), consensus 14-3-3 protein-binding motif and two conserved Akt/PKB phosphorylation sites T26 and S184. Amino acid residues K173, K176, K190, K202 and K229 denote five distinct acetylation sites that are conserved across the species.

Fig. 2. FoxO6 is evolutionally conserved across the species

Amino acid sequences of FoxO6 proteins were aligned in different species. The conserved amino acids corresponding to the nuclear localization signal (NLS) and Akt/PKB phosphorylation sites Thr26 and Ser184 are marked in red box.

Fig. 3. FoxO6 mediates the inhibitory effect of insulin or insulin-like growth factor on target genes in central and peripheral tissues

In the liver, FoxO6 contributes to insulin-dependent regulation of gluconeogenesis via PEPCK and G6Pase. Similarly, insulin signaling through FoxO6 regulates hepatic MTP and APOB expression and modulates VLDL-TG production in the liver. FoxO6 also targets PGC1α for trans-activation, which in turns suppresses FoxO6 expression in myocytes. Such FoxO6-PGC1α feedback loop plays an important part in regulating myoblast differentiation and oxidative metabolism in skeletal muscle in response to exercise. In the brain, FoxO6 contributes to neuronal regulation of Myosin 6 (Myo6), Parkinson disease protein 7 (Park7), Glutamate receptor 1 (Gria1), cAMP-dependent protein kinase type I-alpha regulatory subunit (Prkar1a) and Amyloid-like protein 2 (Aplp2), key functions in memory consolidation.