Deleting Liver FGF21 Boosts Glucose Control and Preserves Telomeres in Aging Female Mice

Fibroblast growth factor 21 (FGF21) is a liver-secreted hormone critical for metabolic homeostasis, yet most research has been conducted in male models. This study specifically addressed aged female physiology, filling a meaningful gap given that females show distinct metabolic responses to fasting, protein restriction, and caloric restriction, and that FGF21 levels fluctuate with female-specific physiological states such as pregnancy.

Using a hepatocyte-specific FGF21 knockout (FKO) mouse model, researchers studied 12-month-old female and male mice to assess the long-term consequences of lifelong hepatic FGF21 deletion. FKO females—but not males—had significantly lower body weight and markedly improved glucose tolerance on oral glucose tolerance tests, despite unchanged circulating FGF21 levels, suggesting extra-hepatic sources compensate systemically. Absolute liver weight was lower in FKO females, but this normalized to body weight, indicating proportional change rather than organ-specific atrophy.

At the gene expression level, RT-qPCR revealed strong downregulation of de novo lipogenesis genes—Srebp1c, Fasn, and Scd1—in FKO livers, alongside upregulation of fatty acid uptake (Cd36) and mitochondrial β-oxidation (Cpt1a) markers. Hepatic triglyceride content remained unchanged, and serum adiponectin was lower in FKO females. These changes suggest a shift in hepatic lipid flux rather than outright fat reduction, pointing to altered partitioning between lipid synthesis and oxidation.

A particularly compelling finding was the preservation of telomere length in both liver and adipose tissue of FKO females, an indicator of improved cellular aging and reduced replicative stress. Transcriptomic analysis corroborated this, showing broad downregulation of genes involved in cytoskeletal organization, immune activation, and hepatic fibrosis—canonical pro-aging and pro-inflammatory pathways. Among the most significantly downregulated genes was Chrna4, encoding a hepatocyte-expressed nicotinic acetylcholine receptor subunit previously implicated in protection against metabolic-associated steatohepatitis (MASH), positioning it as a potential novel mediator of FGF21's hepatic actions.

These results collectively suggest that hepatic FGF21, rather than being purely protective in aging females, may paradoxically drive pro-inflammatory and fibrotic signaling, and its deletion appears to redirect liver metabolism in a healthier direction. The sex specificity of these findings underscores the urgent need to include female subjects in FGF21 research and challenges the assumption that FGF21 supplementation strategies will translate equally across sexes.