Hepatic FoxO3 Supports Metabolic Resilience, Attenuates Age-Associated Obesity and Metabolic Dysfunction, and Mitigates Diet-Induced Steatohepatitis

Forkhead box O3 (FoxO3) is implicated in aging and metabolic regulation; however, its roles in the local and systemic control of aging remain incompletely understood. In this study, we characterized the effects of hepatocyte-specific Foxo3 deletion on hepatic metabolic and whole-body energy homeostasis during aging, and the susceptibility of mice to metabolic disease. Male hepatocyte-specific Foxo3 knockout (h-Foxo3-/-) mice developed moderate obesity and higher plasma insulin levels by middle age, despite no difference in food intake compared with wild-type mice. Indirect calorimetry revealed lower energy expenditure relative to body weight, a higher respiratory quotient, and less fatty acid oxidation, indicating a shift toward carbohydrate-dependent energy metabolism. Adipose tissue exhibited inflammatory cell infiltration and high expression of inflammatory and senescence markers, consistent with systemic insulin resistance. Although these findings suggested that hepatokine signaling regulates systemic metabolism, there was limited direct evidence for FoxO3-dependent hepatokine secretion. RNA-sequencing analysis suggested that fatty acid processing and xenobiotic and detoxification pathways were suppressed in h-Foxo3-/- liver and that gluconeogenic and proinflammatory programs were activated. h-Foxo3-/- mice exhibited hepatic steatosis and an increase in the oxidized glutathione concentration when consuming a regular diet, and those consuming a fat-, fructose-, and cholesterol-rich diet, which induces steatohepatitis, showed more severe fibrosis than controls. Collectively, these findings suggest that hepatic FoxO3 is a key regulator coordinating hepatic lipid processing, xenobiotic metabolism and detoxification, susceptibility to metabolic disorders, and systemic metabolic flexibility. Thus, hepatic FoxO3 contributes to the maintenance of metabolic resilience during aging.