FoxO1: A molecule for all seasons

Abstract

The FoxO family of forkhead transcription factors is at the crossroads of many signal transduction pathways that are evolutionarily conserved. Such pathways have been co-opted in differentiated tissues for a variety of vital and specialized functions, such as differentiation, proliferation, and survival in cells as diverse as adipocytes, hepatocytes, b-cells, myoblasts, thymocytes, and cancer cells. FoxO metabolic functions are relevant to glucose metabolism, tumor suppression, hematopoiesis, angiogenesis, and antioxidant defense. Among the FoxO isoforms, FoxO1 is a main target of insulin signaling and regulates metabolic homeostasis and organismal survival at many different levels. FoxO1 entered into the field of skeletal biology by a property that is unique among its functions in other organs. With the osteoblast as its target cell, FoxO1 not only acts on it to regulate bone homeostasis but also through it as a transcriptional modulator of the endocrine function of the skeleton in regulating glucose metabolism. Through its direct skeletal actions, FoxO1 promotes osteoblast proliferation by maintaining protein synthesis and redox balance. Through its endocrine actions on target tissues of insulin, FoxO1 acts by way of osteocalcin to suppress glucose production by pancreatic beta cells and hepatocytes and to decrease insulin production and sensitivity. These two parallel but opposing actions, one in favor of the skeleton and the other in disadvantage of glucose-regulating tissues, may signify an adaptive mechanism that integrates responses between different organs and is beneficial for whole-body physiology during stress and aging. ß

Endocrine role of bone: recent and emerging perspectives beyond osteocalcin

“…Similarly, the metabolic phenotype was corrected in heterozygous mice lacking one allele of Foxo1 in osteoblasts by the removal of one allele of OC. Utilising these models to investigate the mechanisms underlying the phenotype, it was established that Foxo1 regulates the bioactivity of OC via OST-PTP through direct binding to its promoter, reducing serum OC (Rached et al 2010, Kousteni 2011. In a separate study, the role of Atf4 was also investigated.…”

Forkhead Transcription Factor FOXO1 Is Regulated by Both a Stimulatory Thyrotropin Receptor Antibody and Insulin-Like Growth Factor-1 in Orbital Fibroblasts from Patients with Graves' Ophthalmopathy

“…One of the substrates of AKT is FOXO1, which is inactivated by phosphorylation by AKT (13). The current study demonstrates that the cellular localization of FOXO1 in response to either TSHR or IGF-1R activation is AKT-dependent.…”

“…The Forkhead box O-1 (FOXO1) transcription factor mediates diverse cell functions, including differentiation, adipogenesis, oxidative stress response, apoptosis, and cell proliferation in many different cell types (13,14). FOXO1 has recently been shown to be a critical downstream mediator of TSH and IGF-1 effects on thyrocyte proliferation by promoting its exclusion from the nucleus in a PI3K/pAKT-dependent fashion (15).…”

A decrease in hepatic microRNA-9 expression impairs gluconeogenesis by targeting FOXO1 in obese mice

“…Therefore, elucidation of the underlying molecular mechanism of gluconeogenesis as well as HGP is of potential benefit for the development of effective therapies for the treatment of IR and type 2 diabetes. The transcription factor forkhead box O1 (FOXO1) is implicated in multiple metabolic pathways [5]. In the liver, FOXO1 promotes HGP and activates the transcription of gluconeogenic enzymes, such as glucose-6-phosphatase (G6Pase) and PEPCK [6,7].…”