title: FoxO6 in glucose metabolism (FoxO6).
abstract: The forkhead box O (FoxO) subfamily has four members, namely FoxO1, FoxO3, FoxO4, and FoxO6. Unlike the other three members of the FoxO family, FoxO6 has garnered considerably less attention because of earlier reports that FoxO6 expression was limited to the brain. Recent data indicate that FoxO6 is produced in the liver of both rodents and humans. Hepatic FoxO6 activity, which remains at low basal levels in fed states, is markedly induced in fasted mice. FoxO6 activity becomes abnormally higher in the liver of mice with dietary obesity or type 2 diabetes (T2D). Genetically engineered mice with elevated FoxO6 activity in the liver exhibit prediabetes, culminating in the development of glucose intolerance, fasting hyperglycemia, and hyperinsulinemia. Conversely, inhibition of FoxO6 activity in the insulin-resistant liver results in a reduction in fasting hyperglycemia, contributing to the amelioration of hyperinsulinemia in T2D mice. These new data suggest that FoxO6 is an important regulator of hepatic glucose metabolism in response to insulin or physiological cues. Insulin inhibits FoxO6 activity by promoting its phosphorylation and disabling its activity in the nucleus without altering its subcellular distribution via a mechanism that is distinct from other members of the FoxO subfamily. In this article, we comprehensively review the role of FoxO6 in glucose metabolism in health and disease. We also address whether FoxO6 dysregulation is a contributing factor for the pathogenesis of fasting hyperglycemia and discuss whether FoxO6 is a potential therapeutic target for improving fasting hyperglycemia in T2D.
authors: Division of Immunogenetics, Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA.
authors: Dae Hyun
authors: DH
authors: Kim
authors: Ting
authors: T
authors: Zhang
authors: Sojin
authors: S
authors: Lee
authors: H Henry
authors: HH
authors: Dong
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use; D008099:Liver / Q000378:metabolism*; D051379:Mice; D009765:Obesity / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*
chemical_list: C478770:FOXO6 protein, human; D051858:Forkhead Transcription Factors; D007004:Hypoglycemic Agents; D007328:Insulin; D005947:Glucose
keywords: FoxO6; FoxO6，葡萄糖异生，葡萄糖代谢，肝脏，2型糖尿病; gluconeognesis; glucose metabolism; liver; type 2 diabetes