Therapeutic potential of testosterone in hypogonadal males with MAFLD via AMPK pathways: Evidence from in vitro and in vivo high-fat diet models.

Abstract

Metabolic dysfunction-associated fatty liver disease (MAFLD) has been closely linked to testosterone (T) deficiency, yet no approved pharmacological treatments are currently available. This study explores the therapeutic potential of T therapy in hypogonadal males with MAFLD, focusing on its effects on AMP-activated protein kinase (AMPK) pathways. We utilized a high-fat (HF) diet-induced fatty liver and hypogonadism model in adult male C57BL/6N mice, alongside liver cell models (AML12 and THLE-3), to replicate MAFLD pathogenesis associated with overweight or obesity. Our results reveal that T inhibits lipid droplet accumulation in both human and mouse hepatocytes through AMPK activation. This activation reduces de novo lipogenesis, suppresses lipid droplet growth, and enhances fatty acid oxidation. In the HF diet mouse model, T treatment significantly alleviated hepatic steatosis, lowered body weight, improved glucose tolerance, and normalized lipid profiles, reflecting the results observed in vitro. Hematoxylin and Eosin staining confirmed the improvement in liver morphology, and further analyses demonstrated that T's effects were mediated via the modulation of AMPK and related lipid metabolism pathways. These preliminary findings suggest that T therapy could be a promising treatment for MAFLD in the context of hypogonadism, particularly through its multifaceted impact on AMPK activation and lipid metabolism. However, further research is needed to confirm these results across various metabolic dysfunction-induced MAFLD conditions and to validate them in human clinical trials.