Fibroblast growth factor 21 (FGF21) is a key hormone for metabolic homeostasis under conditions such as obesity, aging and diabetes. While extensively studied in males, its role in female physiology remains poorly defined. This study evaluated the effects of hepatic FGF21 deletion in 12-month-old female mice using a liver-specific FGF21 knockout (FKO) model. FKO females exhibited reduced body weight and improved glucose tolerance, with no changes in circulating FGF21 levels. In the liver, RT-qPCR analysis showed that the expression of genes involved in de novo lipogenesis, including Srebp1c, Fasn, and Scd1, was downregulated, whereas markers of fatty acid uptake (Cd36) and β-oxidation (Cpt1a) were upregulated without alterations in hepatic triglyceride content and lower levels of serum adiponectin. Remarkably, telomere length in both liver and adipose tissue was preserved, indicating improved cellular aging. Hepatic transcriptomic analysis revealed a global downregulation of genes linked to cytoskeletal organization, immune processes and fibrosis. Among these, Chrna4, a hepatocyte-specific nicotinic acetylcholine receptor subunit implicated in protection against metabolic-associated steatohepatitis (MASH), was significantly reduced. These findings suggest that hepatic FGF21 deficiency in aged female mice promotes metabolic health by limiting pro-inflammatory and fibrotic pathways and preserving telomere integrity, with Chrna4 emerging as a potential mediator.

Bioactive triterpenoids present in plant-derived foods are emerging as modulators of metabolic health, although their molecular targets and mechanisms remain unclear. In this study, we characterize Pomolic acid and Hederagenin, two pentacyclic triterpenoids from Rosa canina, as antagonists and selective modulators of peroxisome proliferator-activated receptor gamma (PPARγ). Both compounds reduced lipid accumulation during 3T3-L1 adipocyte differentiation and antagonized rosiglitazone-induced PPARγ transactivation without intrinsic agonist activity. Pomolic acid behaved as a neutral antagonist, repressing adipogenic and lipogenic gene expression and preventing TRAP220 recruitment. In contrast, Hederagenin selectively modulated PPARγ target genes involved in lipid handling while limiting triglyceride accumulation. TR-FRET assays confirmed direct binding to the receptor, and molecular dynamics simulations revealed a betulinic acid─like binding mode that destabilizes helices H11-H12 and disrupts the AF-2 coactivator interface. These findings provide mechanistic insight into how structurally related dietary triterpenoids modulate PPARγ signaling and support them as candidates for metabolic disease strategies.