The FoxO transcription factor family, comprising FoxO1, FoxO3, FoxO4, and FoxO6, is a remarkable group of proteins that receive and integrate various upstream signals to control the transcription of a diverse set of downstream targets in both peripheral tissues and the central nervous system (CNS).
Their ability to integrate these signals and regulate gene expression highlights the complexity and adaptability of biological systems. The signaling pathway is essential in cellular metabolism, aging, and longevity. FoxO proteins are versatile regulators of crucial cellular processes, including metabolism, cell cycle arrest, DNA damage repair, apoptosis, autophagy, and oxidative stress resistance.
The FoxO protein plays a vital role in the insulin and insulin-like growth factor signaling pathway, responsible for crucial cellular metabolism, aging, and longevity functions. When this pathway doesn’t function properly, it can lead to Type 2 Diabetes Mellitus (T2DM), which is a metabolic disorder that is commonly associated with aging. Interestingly, research suggests that T2DM can increase the risk of developing Alzheimer’s disease (AD), which is a neurodegenerative disorder that is linked to metabolic disturbances in the brain. Misregulation of the FoxO signaling pathway may be responsible for age-related functional decline and age-related diseases because of its role in metabolic homeostasis and organismal longevity.
FoxO proteins are downstream effectors of the insulin signaling pathway that respond to nutrient changes and regulate metabolic homeostasis in different tissues and organs. In particular, the liver is susceptible to insulin, and its proper function depends on the regulation of FoxO. In hepatocytes, active FoxO1, FoxO3, and FoxO6 control the expression of two enzymes that play a crucial role in gluconeogenesis: glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Together, these proteins help maintain normal blood glucose levels. FoxO1 is also activated in skeletal muscle under stress conditions such as starvation or exercise. FoxO also plays a vital role in lipid homeostasis by regulating lipogenesis, fatty acid oxidation, lipid transport, and cholesterol metabolism. In the liver, FoxO1 suppresses the lipogenic master regulator sterol regulatory element-binding protein 1c (SREBP1c), activating the expression of genes involved in fatty acid biosynthesis, lipolysis, and fatty acid oxidation. FoxO1 also promotes the secretion of liver triglycerides into plasma. It downregulates the level of the proprotein convertase subtilisin/kexin type 9 (PCSK9) to preserve the LDL receptor (LDLR)-mediated clearance activity, leading to the breakdown of low-density lipoprotein (LDL)-cholesterol. In the hypothalamus, the food intake control center in the brain, FoxO1 regulates the expression of neuropeptides and affects appetite. It receives and integrates signals of nutritional status and responds by releasing neuropeptides.
As we age, the expression of FoxO decreases, which has been linked to a higher occurrence of age-related diseases in the elderly. Therefore, maintaining proper levels of FoxO activity may regulate lifespan and protect against age-related diseases. Increasing FoxO activity may hold the potential for treating or preventing age-related diseases.
Based on: https://doi.org/10.1186/s13578-021-00700-7