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

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.