Search

Forkhead box O (FOXO) transcription factors have been implicated in regulating the metabolism, cellular proliferation, stress resistance, apoptosis, and longevity. Through the insulin receptor substrate → phosphoinositide 3-kinase → Akt signal cascade, FOXO integrates insulin action with the systemic nutrient and energy homeostasis. Activation of FOXO1 in liver induces gluconeogenesis via phosphoenolpyruvate carboxykinase (PEPCK)/glucose 6-phosphate pathway, and disrupts mitochondrial metabolism and lipid metabolism via heme oxygenase 1/sirtuin 1/Ppargc1α pathway. In skeletal muscle, FOXO1 activation underpins the carbohydrate/lipid switch during fasting state. Inhibition of FOXO1 under physiological conditions accounts for maintenance of skeletal muscle mass/function and adipose differentiation. In pancreatic β-cells, nuclear translocation of FOXO1 antagonizes pancreatic and duodenal homeobox 1 and attenuates β-cells proliferation and insulin secretion. Regardless, FOXO1 promotes the proliferation of β-cells through induction of Cyclin D1 in low nutrition, and elicits antioxidant mechanism to protect against β-cell failure during oxidative insults. In the brain, FOXO1 controls food intake through transcriptional regulation of the orexigenic neuropeptide Y, agouti-related protein, and carboxypeptidase E. In this article, we review the role of FOXO1 in the regulation of metabolism and energy expenditure based on recent findings from mouse models, and discuss the therapeutic value of targeting FOXO1 in metabolic diseases. Antioxid. Redox Signal. 14, 649–661.

Mitochondrial function is fundamental to metabolic homeostasis. In addition to converting the nutrient flux into the energy molecule ATP, the mitochondria generate intermediates for biosynthesis and reactive oxygen species (ROS) that serve as a secondary messenger to mediate signal transduction and metabolism. Alterations of mitochondrial function, dynamics, and biogenesis have been observed in various metabolic disorders, including aging, cancer, diabetes, and obesity. However, the mechanisms responsible for mitochondrial changes and the pathways leading to metabolic disorders remain to be defined. In the last few years, tremendous efforts have been devoted to addressing these complex questions and led to a significant progress. In a timely manner, the Forum on Mitochondria and Metabolic Homeostasis intends to document the latest findings in both the original research article and review articles, with the focus on addressing three major complex issues: (1) mitochondria and mitochondrial oxidants in aging-the oxidant theory (including mitochondrial ROS) being revisited by a hyperfunction hypothesis and a novel role of SMRT in mitochondrion-mediated aging process being discussed; (2) impaired mitochondrial capacity (e.g., fatty acid oxidation and oxidative phosphorylation [OXPHOS] for ATP synthesis) and plasticity (e.g., the response to endocrine and metabolic challenges, and to calorie restriction) in diabetes and obesity; (3) mitochondrial energy adaption in cancer progression-a new view being provided for H(+)-ATP synthase in regulating cell cycle and proliferation by mediating mitochondrial OXPHOS, oxidant production, and cell death signaling. It is anticipated that this timely Forum will advance our understanding of mitochondrial dysfunction in metabolic disorders.