# Studies of Foxo1 over the Past 25 Years: Mechanisms of Insulin Resistance and Glucose Dysregulation

## TL;DR

This paper reviews 25 years of research on Foxo1, a key protein involved in insulin resistance and metabolic diseases, highlighting its role in regulating energy balance and potential for therapeutic targeting.

## Contribution

The paper provides a comprehensive review of Foxo1's evolving role from a simple insulin effector to a complex metabolic regulator with implications for disease treatment.

## Key findings

- Foxo1 integrates hormonal signals with energy balance and regulates glucose and lipid metabolism.
- Foxo1 contributes to immune modulation and aging-related pathologies.
- Targeting Foxo1 requires a nuanced approach due to its pleiotropic functions.

## Abstract

Forkhead box protein O1 (Foxo1) is an insulin-suppressed transcription factor that governs multiple biological processes, including cell proliferation, apoptosis, autophagy, mitochondrial function, and energy metabolism. Over the past 25 years, Foxo1 has evolved from a liner insulin effector to a pleiotropic integrator of systemic metabolic stress during obesity and aging. Foxo1 integrates hormonal signals with energy balance and plays a central role in glucose and lipid metabolism, organ homeostasis, and immune responses. Given its pleiotropic functions, therapeutic targeting of Foxo1 pathway will require a nuanced, context-specific approach. Here, we reviewed key advances in Foxo1 studies over the past 25 years, including multi-hormonal control of Foxo1 activity, Foxo1-mediated inter-organ crosstalk, immune modulation, and contributions to aging-associated pathologies. Understanding the regulation of Foxo1 and its pleiotropic function across multiple tissues will advance insight into the pathogenesis of metabolic diseases and promote the translation potential of Foxo1 signaling manipulation for the treatment of metabolic disorders, including insulin resistance and type 2 diabetes.